Clinical trial NCT03943550
Conditions: Ulcerative Colitis
Sponsor: Hoffmann-La Roche
Start date: 2019-05-13; Completion date: 2021-07-22
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The principal aim of this study is to evaluate the safety and tolerability of RO7049665 in participants with active ulcerative colitis (UC).

Detailed description:

Arms: arm 1: Participants will receive a subcutaneous (SC) dose of RO7049665 every 2 weeks for 4 doses. arm 2: Participants will receive a SC dose of matching placebo every 2 weeks for 4 doses.
Interventions: intervention 1: RO7049665 intervention 2: Placebo
Intervention descriptions: intervention 1: Multiple ascending doses of RO7049665 will be administered SC. intervention 2: Matching placebo will be administered SC.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title:
A Multicenter, Randomized, Double-Blind, Placebo Controlled Phase 
Ib Study to Investigate the Safety, Tolerability, Pharmacokinetics, 
Preliminary Efficacy, and Pharmacodynamics of Subcutaneously 
Administered RO7049665 in Participants With Active Ulcerative 
Colitis 
NCT Number:
NCT03943550 
Document Date:
Protocol Version Version 5: 20 Nov 2020 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO7049665 —F. Hoffmann-La Roche Ltd
Protocol WP40161, Version 5
PROTOCOL
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO CONTROLLED PHASE IB STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PRELIMINARY EFFICACY, 
AND PHARMACODYNAMICS OF 
SUBCUTANEOUSLY ADMINISTERED RO7049665 
IN PARTICIPANTS WITH ACTIVE ULCERATIVE 
COLITIS
PROTOCOL NUMBER:
WP40161
VERSION:
5
EUDRACT NUMBER:
2017-004599-74
IND NUMBER:
137,492
TEST PRODUCT:
RO7049665
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 15 December 2017
Version 2: 08 May 2018
Version 3: 15 October 2018
Version 4: 29 May 2019
DATE AMENDED:
Version 5: See electronic date stamp below
 
20-Nov-2020 17:19:45
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7049665—F. Hoffmann-La Roche Ltd
2/Protocol WP40161, Version 5
PROTOCOL ACCEPTANCE FORM
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO CONTROLLED PHASE IB STUDY TO 
INVESTIGATE THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PRELIMINARY EFFICACY, 
AND PHARMACODYNAMICS OF 
SUBCUTANEOUSLY ADMINISTERED RO7049665 
IN PARTICIPANTS WITH ACTIVE ULCERATIVE 
COLITIS
PROTOCOL NUMBER:
WP40161
VERSION NUMBER:
5
EUDRACT NUMBER:
2017-004599-74
IND NUMBER:
137,492
TEST PRODUCT:
RO7049665
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
Study Monitor.


RO7049665—F. Hoffmann-La Roche Ltd
3/Protocol WP40161, Version 5
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE
Protocol WP40161 Versions 4 has been amended and the rationale for each of the 
proposed changes is listed below.

New dose level: dose level 3, 15 mg, Q2W
In order to fully characterize the pharmacokinetic (PK), pharmacodynamics and 
safety profile of RO7049665, the Sponsor proposes to escalate to 15 mg 
RO7049665, maintaining the current biweekly (every 2 weeks [Q2W]) 
dose-administration regimen. The safety and tolerability of participants who have
received doses up to 7.5 mg Q2W RO7049665 to date is considered to be
acceptable with the majority of the adverse events (AEs) being mild to moderate. 
One participant has had AEs of injection-related reaction (IRR) and 
hypersensitivity (Grade 2). Eosinophil blood cell counts increase has occurred in 
the majority of treated participants, with one participant so far at 7.5 mg Q2W 
experiencing a severe AE of eosinophilia (Grade 3). The Grade 3 eosinophilia 
resolved with treatment and the participant was found to have preexisting 
untreated thyroiditis. Although there are dose-dependent effects on the 
eosinophil blood cell counts, to date no patient in study WP40161 has met the 
stopping criterion. The RO7049665 exposure from 15 mg Q2W dosing is 
expected to remain at least 2-fold below the corresponding exposure at the 
no-observed-adverse-effect level (NOAEL) of the 13-week Good Laboratory
Practice toxicity study in non-human primates. Expected increases of regulatory 
T cells (Tregs) and effector T cells (Teffs) counts in blood are predicted to remain 
within acceptable limits. There is no clear relationship between anti-drug 
antibodies (ADA) and dose based on the current data (Sections 2.2.2.1., 2.3, 4.1,
4.3, Table 5 of Section 6.1).

Removal of stopping criterion (absolute Treg cell count)
The stopping criterion relating to an absolute Treg increase of 450 cells/L 
within a dose level was previously implemented in response to a request from the 
Paul-Ehrlich-Institute (the German Health Authority) prior to availability of any 
multiple dose data with RO7049665 and in the absence of data on potential 
accumulation (Section 4.1.3.). Study WP40161 recently met this stopping 
criterion at the 7.5 mg dose level as described in Version 4 of the study protocol.
An increase in Treg cells reflects the primary mode of action of RO7049665 and is 
thus an expected and a desired effect. The current cutoff of 450 cells/µL is not
considered by the Sponsor to be a safety limit. To the Sponsor’s knowledge there 
is no published threshold beyond which Treg numbers in humans are considered 
a risk to human health or lead to a clinically meaningful impairment of the normal 
immune response. Recent data from the ongoing study WP40161 supports the 
absence of AEs related to increased Treg counts and there has been no Treg
accumulation observed with Q2W dosing. Therefore, the stopping criterion has 
been removed from the protocol.

Extended safety observation period for the new dose level
The safety observation period of the first 3 participants at a new dose level
remains the same while the observation period between the third and the fourth 
participants of the dose level has been extended to (a minimum of) 14 days. This 


RO7049665—F. Hoffmann-La Roche Ltd
4/Protocol WP40161, Version 5
longer interval between first doses will allow the review of the safety laboratory 
data prior to enrolling and dosing subsequent participants (Section 2.3 and 4.1).

Safety-management changes
The protocol has been updated following IRR and hypersensitivity AEs in one 
participant receiving 7.5 mg Q2W RO7049665/ placebo to include the 
management of participants who experience these type of reactions (Sections 
8.3.6. and 8.3.8). This is in line with a previously issued Dear Investigator Letter 
and includes a new individual participant stopping criterion (Section 4.1.4. and 
4.1.5) and suggested pre-medication (Sections 6.5.1. and 8.3.8). 

Change in sample size
Due to the new dose level the current sample size needs to be increased as the 
first cohorts have enrolled 10 or more participants per cohort. The sample size 
has therefore been adjusted to up to 65 participants (Section 9.2).

Alignment of assessments and additional safety monitoring (study day 50)
For additional safety monitoring measures at 15 mg Q2W, and to ensure that the 
eosinophil blood cell count can be followed in parallel to the blood flow cytometry, 
safety laboratory assessments (includes hematology, blood biochemistry and 
urinalysis) have been included at study Day 50 for participants receiving 15mg 
RO7049665 Q2W (Schedule of Activities [SoA], Section 1.3).

Updates in case of temporary interruptions to study treatment administration
The temporary interruption and study assessments and procedure sections 
(Sections 7.1.1. and 8) have been updated for greater clarity and to allow the 
participants in case of a dose interruption to continue the visit schedule, although
assessments and sampling specifically related to dosing can be omitted.

Other minor modifications
Additional minor changes have been made to improve clarity and consistency, 
including an update of background sections of the protocol in line with recent 
data of the study and changes to the Investigator Brochure, and an update of 
SoAs, study figure (Figure 1) and SoA footnotes. Time windows when collecting 
PK samples, vital signs and electrocardiograms post-dose have been added as 
per site feedback. Additionally it has been clarified that ova and parasite stool 
examination at screening may be done locally at sites having the possibility.
Following the outbreak of coronavirus disease 2019, a statement on impact to 
study WP40161 and the measures taken to date have been added to the benefit 
and risk section (Section 2.3). 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.
The Master ICF has been updated to accommodate the changes of the study protocol. 


RO7049665—F. Hoffmann-La Roche Ltd
5/Protocol WP40161, Version 5
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 13
1.1
Synopsis................................................................................ 13
1.2
Schematic of Study Design.................................................... 21
1.3
Schedule of Activities ............................................................ 21
2.
INTRODUCTION ........................................................................................ 28
2.1
Study Rationale ..................................................................... 28
2.2
Background ........................................................................... 28
2.2.1
Ulcerative Colitis.................................................................... 28
2.2.2
RO7049665 ........................................................................... 29
2.2.2.1
Previous Clinical Studies ....................................................... 30
2.3
Benefit/Risk Assessment....................................................... 33
3.
OBJECTIVES AND ENDPOINTS ............................................................... 39
4.
STUDY DESIGN......................................................................................... 39
4.1
Overall Design ....................................................................... 39
4.1.1
Length of the Study ............................................................... 40
4.1.2
Dose-Escalation Decision Criteria ......................................... 41
4.1.3
Stopping Rules Criteria.......................................................... 41
4.1.4
Individual Participant Stopping Criteria.................................. 42
4.1.5
Communication Strategy ....................................................... 42
4.2
Scientific Rationale for Study Design..................................... 43
4.2.1
Rationale for Study Population .............................................. 43
4.2.2
Rationale for Control Group................................................... 44
4.2.3
Rationale for Biomarker Assessments................................... 44
4.3
Dose Justification .................................................................. 45
4.4
End of Study Definition .......................................................... 46
5.
STUDY POPULATION................................................................................ 47
5.1
Inclusion Criteria.................................................................... 47
5.2
Exclusion Criteria................................................................... 49
5.3
Lifestyle Considerations......................................................... 52


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5.3.1
Meals and Dietary Restrictions.............................................. 52
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 52
5.3.3
Activity ................................................................................... 52
5.4
Screen Failures ..................................................................... 52
5.5
Recruitment Procedures........................................................ 53
6.
TREATMENTS............................................................................................ 53
6.1
Treatments Administered....................................................... 54
6.2
Preparation/Handling/Storage/Accountability ........................ 54
6.3
Measures to Minimize BIAS: Randomization and 
Blinding.................................................................................. 55
6.3.1
Method of Treatment Assignment.......................................... 55
6.3.2
Blinding.................................................................................. 56
6.4
Treatment Compliance .......................................................... 56
6.5
Concomitant Therapy ............................................................ 57
6.5.1
Permitted Therapy................................................................. 57
6.5.2
Prohibited Therapy ................................................................ 58
6.6
Dosage Modification .............................................................. 58
6.7
Treatment after the End of the Study..................................... 58
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 58
7.1
Discontinuation of Study Treatment....................................... 59
7.1.1
Temporary Interruption .......................................................... 59
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 59
7.3
Lost to Follow-Up................................................................... 60
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 60
8.1
Efficacy Assessments............................................................ 61
8.2
Safety Assessments .............................................................. 61
8.2.1
Physical Examinations........................................................... 61
8.2.2
Vital Signs.............................................................................. 62
8.2.3
Electrocardiograms................................................................ 63
8.2.4
Clinical Safety Laboratory Assessments................................ 63
8.2.5
Safety Biomarker Assessments............................................. 64


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8.2.6
Immunogenicity Assessments ............................................... 65
8.2.7
Local Pain and Skin Reactivity Assessments ........................ 65
8.2.8
Clinical Outcome Assessment............................................... 65
8.2.9
Medical History and Demographic Data ................................ 66
8.3
Adverse Events and Serious Adverse Events ....................... 66
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 66
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 67
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 67
8.3.3.1
Investigator Follow-Up........................................................... 67
8.3.3.2
Sponsor Follow-Up ................................................................ 68
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 68
8.3.4.1
Emergency Medical Contacts................................................ 68
8.3.5
Pregnancy ............................................................................. 68
8.3.6
Non-Serious Adverse Events of Special Interest................... 69
8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs ............................ 69
8.3.8
Management of Specific Adverse Events .............................. 69
8.4
Treatment of Overdose.......................................................... 70
8.5
Pharmacokinetics .................................................................. 70
8.6
Pharmacodynamics ............................................................... 71
8.7
Genetics ................................................................................ 72
8.7.1
Clinical Genotyping................................................................ 72
8.8
Biomarkers ............................................................................ 73
8.8.1
Exploratory Disease Biomarkers ........................................... 73
8.8.2
Samples for Research Biosample Repository ....................... 73
8.8.2.1
Overview of the Research Biosample Repository.................. 73
8.8.2.2
Sample Collection.................................................................. 74
8.9
Health Economics.................................................................. 75
8.10
Timing of Study Assessments ............................................... 75
8.10.1
Screening and Pre-treatment Assessments .......................... 75


RO7049665—F. Hoffmann-La Roche Ltd
8/Protocol WP40161, Version 5
8.10.2
Assessments during Treatment............................................. 75
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 76
8.10.4
Follow-Up Assessments ........................................................ 76
8.10.5
Assessments at Unscheduled Visits...................................... 76
9.
STATISTICAL CONSIDERATIONS ............................................................ 76
9.1
Statistical Hypotheses ........................................................... 76
9.2
Sample Size Determination ................................................... 76
9.2.1
Populations for Analyses ....................................................... 77
9.3
Statistical Analyses................................................................ 77
9.3.1
Demographics and Baseline Characteristics ......................... 77
9.3.2
Safety Analyses..................................................................... 78
9.3.3
Pharmacokinetic Analyses..................................................... 78
9.3.4
Efficacy Analyses .................................................................. 79
9.3.5
Immunogenicity Analyses................................................... 80
9.3.6
Pharmacodynamic Analyses ................................................. 81
9.3.7
Other Analyses...................................................................... 81
9.4
Interim Analyses .................................................................... 81
9.5
Summaries of Conduct of Study............................................ 82
10. REFERENCES ........................................................................................... 83
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.................................................................................... 84
LIST OF TABLES
Table 1
Schedule of Activities – Main Table ............................................ 22
Table 2
Schedule of Activities - Detailed Table........................................ 26
Table 3
Serum Pharmacokinetic Parameters of RO7049665 after 
Single Subcutaneous Administration .......................................... 32
Table 4
Objectives and Endpoints ........................................................... 39
Table 5
Summary of Treatments Administered........................................ 54
Table 6
Analysis Populations................................................................... 77
Table 7
Safety Statistical Analysis Methods ............................................ 78


RO7049665—F. Hoffmann-La Roche Ltd
9/Protocol WP40161, Version 5
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 21
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations.......... 85
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting............................................................. 93
Appendix 3
Procedures for Recording Adverse Events .............................. 101
Appendix 4
Clinical Laboratory Tests ......................................................... 106
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 109
Appendix 6
Pain and Skin Reactivity Assessments..................................... 113
Appendix 7
Mayo Clinical Score (MCS) .................................................. 114
Appendix 8
Rationales for Previous Protocol Amendments........................ 115


RO7049665—F. Hoffmann-La Roche Ltd
10/Protocol WP40161, Version 5
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
ASA
Aminosalicylate
AST
Aspartate aminotransferase
AUC
Area under the curve
AUCinf
Area under the serum concentration-time curve 
extrapolated to infinity
AUCtau
Area under the serum concentration-time curve over 
the dosing interval
BMI
Body mass index
BP
Blood pressure
Cmax
Maximum serum concentration observed
CL/F
Apparent clearance
CLS
Capillary leak syndrome
COA
Clinical outcome assessments
CRF
Case report form
CRO
Contract research organization
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
EIH
Entry-in-Human
ELISA
Enzyme-linked immunosorbent assay
ESF
Eligibility screening form
EU
European Commission
FDA
Food and Drug Administration


RO7049665—F. Hoffmann-La Roche Ltd
11/Protocol WP40161, Version 5
Abbreviation
Definition
FMT
Fecal microbiota transplant
GGT
Gamma-glutamyl transferase
GLP
Good laboratory practice
GS
Geboes Score
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
IL-2R
Interleukin-2 receptor
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio 
IRB
Institutional Review Board
IRR
Injection-related reaction
ISR
Injection-site reaction
IVRS/IWRS
Interactive (voice/web) response system
LPLO
Last participant, last observation
LRG
Leucine-rich alpha-2 glycoprotein
MAD
Multiple ascending doses
MCS-ES
Endoscopy Subscore of the Mayo Clinic Score
MP
6-Mercaptopurine
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute Common Terminology Criteria 
for Adverse Events
NGS
Next generation sequencing
NHI
Nancy Histology Index
NK
Natural killer cell
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter


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12/Protocol WP40161, Version 5
Abbreviation
Definition
pANCA
Perinuclear anti-neutrophil cytoplasmic antibody
PD
Pharmacodynamic
PK
Pharmacokinetic
PR
PR Interval
pSTAT5
Phosphorylated signal transducer and activator of 
transcription 5
RHI
Robarts Histology Index
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RBR
Research biosample repository
RNA
Ribonucleic acid
RR
RR interval
SAD
Single ascending dose
SAE
Serious adverse event
SC
Subcutaneous
SoA
Schedule of activities
SOC
Standard of care
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TOC
Test of cure
T1/2
Half-life
Teff
Effector T cell 
Tmax
Time to maximum concentration
Treg
Regulatory T cell
TNF
Tumor necrosis factor
UC
Ulcerative colitis
UCEIS
Ulcerative colitis endoscopic index of severity
ULN
Upper limit of normal
V/F
Apparent volume of distribution
WBC
White blood cell
WES
Whole exome sequencing
WGS
Whole genome sequencing


RO7049665—F. Hoffmann-La Roche Ltd
13/Protocol WP40161, Version 5
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO 
CONTROLLED PHASE IB STUDY TO INVESTIGATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, PRELIMINARY 
EFFICACY, AND PHARMACODYNAMICS OF SUBCUTANEOUSLY 
ADMINISTERED RO7049665 IN PARTICIPANTS WITH ACTIVE 
ULCERATIVE COLITIS
SHORT TITLE
Double-Blinded, Placebo-Controlled Phase 1b Study for Safety, 
PK, efficacy, PD of RO7049665 in Patients with UC
PROTOCOL NUMBER:
WP40161
VERSION:
5
TEST PRODUCT:
RO7049665
PHASE:
Ib
RATIONALE
RO7049665 is a novel dimeric interleukin 2 (IL-2) mutein that is being developed as a therapy 
for autoimmune conditions, including ulcerative colitis (UC). It is expected to treat the impaired 
regulatory T cell (Treg) numbers and/or function associated with autoimmune diseases without 
the broad based immuno-stimulatory effects of IL-2. Specifically, RO7049665 was engineered 
to address and overcome the pharmacologic, safety and functional liabilities of Proleukin
(aldesleukin), a recombinant human IL-2 therapy currently approved for the treatment of renal 
cell carcinoma and malignant melanoma.
This study (WP40161) will build upon experience gained in the healthy volunteer entry-in-
human (EIH) single ascending dose (SAD) study (WP39826). In study WP40161, RO7049665 
will be administered in multiple doses and to participants with an autoimmune condition for the 
first time. The principal aim of this study is to evaluate the safety and tolerability of RO7049665 
in participants with active ulcerative colitis. In addition, the pharmacokinetics (PK), preliminary
efficacy, pharmacodynamics (PD) and immunogenicity will also be explored. The study results 
will be used to support further clinical development of RO7049665.


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OBJECTIVES AND ENDPOINTS 
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
repeat dosing of subcutaneous (SC) 
injections of RO7049665 in participants 
with active ulcerative colitis (UC).

Incidence of dose-limiting or intolerable 
treatment-related adverse events (AEs).

Incidence, severity, and relationship of 
treatment-emergent AEs.

Incidence of abnormal laboratory 
findings.

Incidence of abnormal vital signs and 
electrocardiogram (ECG) parameters.
Secondary

To investigate the multiple-dose 
pharmacokinetics of RO7049665.

Pharmacokinetic parameters of 
RO7049665.

To investigate the effects of multiple 
doses of RO7049665 on changes in 
endoscopic appearance of the mucosa of 
the sigmoid colon.

Change from baseline in the Endoscopy 
Subscore of the Mayo Clinic Score 
(MCS-ES) at Day 29 and Day 57.

Change from baseline in the Ulcerative 
Colitis Endoscopic Index of Severity 
(UCEIS) at Day 29 and Day 57.

To investigate the effects of multiple 
doses of RO7049665 on changes in 
histologic appearance of mucosa in 
biopsies from the sigmoid colon.

Change from baseline to Day 29 and Day 
57 in histology score of sigmoid colon 
biopsies (Geboes Score [GS], Robarts 
Histology Index [RIH], or Nancy Histology 
Index [NHI]).

To investigate the effects of multiple 
doses of RO7049665 on changes in 
disease activity.

Change from baseline in the Mayo Clinic 
Score (MCS) at Day 29 and Day 57.

To evaluate the immunogenicity of 
RO7049665.

Incidence of anti-drug antibodies (ADAs).

To investigate the effects of multiple 
doses of RO7049665 on immune cells in 
the periphery and in mucosal biopsies of 
the sigmoid colon.

Quantitative changes in WBCs (Tregs, 
Teffs, natural killer [NK] cells, B cells and 
eosinophils).
OVERALL DESIGN
Study Design

Study WP40161 is a multicenter, randomized, adaptive, and placebo-controlled study to 
investigate the safety, tolerability, pharmacokinetics (PK), preliminary efficacy, and 
pharmacodynamics (PD) of multiple ascending doses (MAD) of RO7049665 on top of 
standard of care (SOC) in participants with endoscopic evidence of moderate to severely 
active UC. Participants may be enrolled if they have a history of anti-TNFor anti-integrin 
therapy but may not be actively treated with these agents during the study.

Investigator and participant blind.

Participants within each cohort will be randomized in a 4:1 ratio to receive multiple SC 
injections of RO7049665 or placebo, respectively. Randomization occurs on Study Day -1, 
after a maximum 35-day screening period.
Treatment Groups and Duration
The investigational medicinal products are: RO7049665 and Placebo. 


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15/Protocol WP40161, Version 5
RO7049665 (5 mg/mL) and Placebo will be provided by the Sponsor in 2 mL colorless glass 
vials. Both must be prepared for SC injection in the abdomen under appropriate aseptic 
conditions and the solution for injection must be filtered prior to use. Both should be used 
immediately. 
The dosing interval will be every 2 weeks (Q2W) for 4 doses. Participants enrolled in dose 
level 1 cohorts will receive 3.5 mg of RO7049665 (or placebo), participants enrolled in dose 
level 2 cohorts will receive 7.5 mg of RO7049665 (or placebo), and participants enrolled in the 
cohorts of dose level 3 will receive 15 mg of RO7049665 (or placebo), based on data from 
study WP39826 (EIH study in healthy volunteers) and review of data from completed cohorts in 
this study. 
Safety and tolerability, ADA, PK, and selected PD data from at least 8 weeks of treatment in at 
least 5 participants (4 active, 1 placebo) at a dose level will be reviewed prior to enrolling 
participants into the next higher dose level for the first time (i.e., 7.5 mg and 15 mg).
Dose escalation and dose stopping rules are described in the protocol body.
Length of Study
The total duration of the study for each participant will be approximately 19 weeks, divided as 
follows:

Screening: Up to 5 weeks (35 days).

Dosing Period: Day 1 to Day 43. 

In-clinic period: From Day 1 to Day 2 for the first dose, from Day 15 to Day 16 for the 
second dose, from Day 29 to Day 30 for the third dose, and from Day 43 to Day 44 for the 
last dose.

Final follow-up: Day 99 3 days (8 weeks post last dose). 
End of Study
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities.
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur approximately 56 (3) days after last study drug 
administration.
Internal Monitoring Committee:
There will be a dedicated group of individuals from the Sponsor functioning as an internal 
monitoring committee (IMC), which will be independent to the project. The roles, responsibilities, 
membership, scope of activities, time of meetings and communication plan for the IMC will be
documented in an appropriate charter.
PARTICIPANT POPULATION
This study will enroll up to 65 participants with UC between 18 and 70 years of age, inclusive, 
with evidence of moderate to severely active disease (MCS 5: MCS-ES 2, stool frequency 
subscore 1, and rectal bleeding subscore 1), who have failed at least one prior standard of 
care therapy.
Inclusion Criteria
Participants are only eligible to be included in the study if all of the following criteria apply:


RO7049665—F. Hoffmann-La Roche Ltd
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Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Conference on Harmonisation (ICH) and local regulations. 
Informed consent may be obtained up to 3 months prior to randomization. A signed Informed 
Consent Form must be available from the participant before starting any study-specific 
assessments.
Age
2.
Between 18 to 70 years of age inclusive, at the time of signing the informed consent.
Type of Participants and Disease Characteristics
3.
Diagnosed with UC for at least 12 weeks prior to screening
4.
Screening colonoscopy for colorectal cancer conducted within the prior two years if:

History of pancolitis and disease duration 8 years, or

History of left-sided colitis and disease duration 12 years.
5.
Evidence of disease activity at time of screening as measured by MCS 5, with MCS-ES 2, 
extending at least 10 cm from the anal verge, stool frequency subscore 1and rectal 
bleeding subscore 1.
6.
Insufficient clinical response to standard of care (SOC) therapy or intolerance to SOC, where 
SOC may include (but not limited to): 

Glucocorticoids (Prednisolone at least 0.75 mg/kg/day or equivalent for at least 
4 weeks).

Treatment with JAK inhibitors of at least 8 weeks duration.

Immunomodulators (e.g., azathioprine, methotrexate, oral 5-aminosalicylate [5-ASA] 
or 6-mercaptopurine) at a standard therapeutic dose for at least 12 weeks. 

Therapy with an anti-TNFmonoclonal antibody of at least 3 months duration, or 
intolerance due to side effects of medication (not including anaphylaxis).

Treatment with anti-integrin therapy of at least 14 weeks duration.
Weight
7.
Body mass index (BMI) within the range of 18-35 kg/m2 (inclusive).
Sex
8.
Male and female participants
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for male and/or female 
enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and 
the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Female participants:
Compliance with contraception requirements:

Women of non-child bearing potential (WONCBP) may be enrolled. A woman is 
considered to be of childbearing potential if she is postmenarchal, has not reached a 
post-menopausal 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).


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For women of childbearing potential (WOCBP):

May enroll if not pregnant and not breastfeeding.

Agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
methods that result in a failure rate of < 1% per year during the treatment period and for 
at least 56 days after the last dose of study drug.
Examples of contraceptive methods with a failure rate of < 1% per year include bilateral 
tubal occlusion/ligation, male sterilization, proper use of hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.

Have a negative pregnancy test (blood) within the 35 days prior to the first study 
RO7049665/placebo administration.
For men: 
During the treatment period and for at least 56 days after the last dose of 
RO7049665/placebo, agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that together 
result in a failure rate of 1% per year, with partners who are women of childbearing 
potential (WOCBP).
With pregnant female partners, remain abstinent (refrain from heterosexual intercourse) 
or use contraceptive measures such as a condom to avoid exposing the embryo.

Refrain from donating sperm for 56 days after the last dose of RO7049665 or placebo.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Diagnosis of Crohn’s disease or indeterminate colitis
2.
History of infection with, hepatitis B, human immunodeficiency virus (HIV), active hepatitis C 
virus (HCV) infection, or other chronic infection.
3.
Active infections requiring systemic therapy with antibiotic, antiviral or antifungal or febrile 
illness within 7 days before Day -1.
4.
History of primary or acquired immunodeficiency
5.
History of chronic pulmonary disease with resultant abnormal pulmonary function
6.
History of clinically significant cardiac or cardiovascular disease or uncontrolled hypertension
7.
Evidence of infection with Clostridium difficile or other intestinal pathogen within 35 days
from the start of screening.
8.
Evidence of colonic dysplasia that cannot be completely removed
9.
Females: Pregnant or lactating.
10. History of and/or current suicidal ideations 
11. Any condition or disease detected during the medical interview/physical examination that 
would render the patient unsuitable for the study, place the patient at undue risk or interfere 
with the ability of the patient to complete the study in the opinion of the investigator, including 
malignant disease
12. Symptomatic herpes zoster within 3 months prior to screening.
13. History of tuberculosis or a positive QuantiferonGold test.


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14. History of clinically significant severe drug allergies, multiple drug allergies, allergy to any 
constituent of the product, or intolerance to topical corticosteroids.
15. Lymphoma, leukemia, or any malignancy within the past 10 years, except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected with no evidence of 
metastatic disease for 3 years and in situ carcinoma of the cervix that was completely 
removed surgically.
16. History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g., PQ/PR interval 220 ms, QT corrected for heart rate using Fridericia’s 
correction factor (QTcF) < 350 ms or 450 ms) or clinically significant cardiovascular 
disease (e.g., cardiac insufficiency, coronary artery disease, cardiomyopathy, congestive 
heart failure, family history of congenital long QT interval syndrome, family history of sudden 
death).
17. Fecal Microbiota Transplant (FMT), defined as receipt of any product derived from the feces 
of another human and administered per oral, per nasogastric or nasoduodenal, or per 
rectum within the last 6 months. 
Prior/Concomitant Therapy
18. Use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine), vedolizumab, anti-TNF-
therapeutic or any other immune systemtargeted biological therapy within 12 weeks or 
5 half-lives, whichever is longer, prior to screening
19. Rectal therapy with 5-ASA or corticosteroids within 2 weeks of screening
20. Use of any investigational drug within 12 weeks of screening
21. Leukocyte apheresis within 12 weeks of screening
22. Live vaccine(s) within one month prior to screening, or plans to receive live vaccines during 
the study or within 28 days of the last dose.
Prior/Concurrent Clinical Study Experience
23. Donation of blood or blood products in excess of 500 mL within 3 months of screening.
24. Exposure to more than 4 investigational treatments within 12 months prior to Day 1.
25. Current enrollment or past participation within the 90 days immediately preceding signing of 
informed consent in this or any other clinical study involving an investigational study 
treatment or any other type of interventional medical research.
Diagnostic Assessments
26. Abnormal hematologic values:

Anemia (Hgb 9 g/dL)

Leukocytosis (WBC 2ULN)

Thrombocytopenia (platelet count 100,000/L)

Thrombocytosis (platelet count 2 ULN)

Eosinophilia (eosinophil count 2 ULN)
27. Abnormal hepatic enzyme or hepatic function values:


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
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline 
phosphatase, or Gamma-glutamyl transferase (GGT) 2 ULN

Total bilirubin 2 ULN

International normalized ratio (INR) 1.2

Albumin 3g/dL
28. Positive HIV antibody test.
29. Presence of hepatitis B surface antigen (HBsAg) or positive for total hepatitis B 
core antibody (HBcAb), or positive hepatitis C by PCR test result at screening or within the 
3 months prior to starting study treatment.
Other Exclusions
30. History of regular alcohol consumption within 2 months of screening defined as:
An average weekly intake of 14 drinks for males or 7 drinks for females. One drink is 
equivalent to 12g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or
1.5 ounces (45 mL) of 80 proof distilled spirits.
31. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of drug of 
abuse
32. Patients under judicial supervision, guardianship or curatorship
NUMBER OF PARTICIPANTS
The study will enroll up to 65 participants to assess the safety and tolerability of repeated dosing
of RO7049665 (approximately 10 participants, randomized in the ratio of 4:1 RO7049665 to 
placebo, per cohort).
CONCOMITANT MEDICATIONS
Permitted Therapy
All concomitant medications throughout the duration of the study should be recorded in the case 
report form. Use of the following therapies will be permitted, as specified below:

Paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours prior to each 
RO7049665 or placebo dosing, not to exceed 4 g total during the week prior to each dosing. 

Participants who use the following therapies prior to screening and are on a stable regimen 
should continue their use: 
–
Oral contraceptives, hormone-replacement therapy, or other maintenance therapy.

Participants who are taking non-biologic SOC therapy for UC during the study will remain 
on their SOC therapy. Specific instructions for each SOC is provided below: 
–
Stable therapy for at least 2 weeks prior to screening with: 
o
oral 5-ASA, or
o
oral glucocorticoid (not to exceed 20 mg/day prednisone equivalent at start of 
trial, may be weaned after dosing with study drug has been initiated).
–
Stable therapy for at least 8 weeks with: 
o
azathioprine, or
o
6-mercaptopurine (MP), or 
o
methotrexate (and folic acid)

In the event of a systemic injection-related reaction (IRR) or systemic hypersensitivity 
AE: participants may receive pre-medication with paracetamol and antihistamines (as per 
local guidelines) prior to the next administration of study drug.


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Prohibited Therapy
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs and those specified as permitted therapies, unless the rationale for 
exception is discussed and clearly documented between the Investigator and the Sponsor.
Use of the following therapies will be prohibited during the study and for at least 14 days or at 
least 5 half-lives prior to initiation of study treatment, whichever is longer unless otherwise 
specified below:
-
Any rectal therapy 
-
Doses of glucocorticoids exceeding 20 mg/day of prednisone or equivalent
-
Non-steroidal anti-inflammatory medications (e.g.: ibuprofen, naproxen) due to a 
propensity for these treatments to worsen inflammation in ulcerative colitis.
Calcineurin inhibitors (e.g., tacrolimus, cyclosporine) and any immune system targeted biological 
therapy within 12 weeks or 5 half-lives, whichever is longer, before the start of screening.


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1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
The doses for dose level 1 (3.5 mg) and dose level 2 (7.5 mg) are based on results from the 
entry-in-human (EIH) Study WP39826, which supported safety, pharmacokinetics, and 
pharmacodynamics in healthy volunteers in single dosing. Dose level 3 (15 mg) is based on
initial analyses of results from repeat dosing with 3.5 and 7.5 mg in participants with 
ulcerative colitis in this study.
1.3
SCHEDULE OF ACTIVITIES
The schedule of activities is provided in Table 1 and Table 2. 


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Table 1
Schedule of Activities – Main Table
Activity
Screening / 
Baseline
a
Outpatient Phone 
Call
Outpatient visit
Outpatient 
Phone Call
Outpatient visit
Overall Study Day
D -36 to D -2
D -1
Day 1
Day 2
Day 4
Day 6
Day 8
Day 10
Day 15
Day 16
Day 19
Day 22
Day 29
Day 30
Day 33
Day 36
Dose/Day
Dose 1/Day -1
Dose 1/Day 1
Dose 1/Day 2
Dose 1/Day 4
Dose 1/Day 6
Dose 1/Day 8
Dose 1/Day 10
Dose 2/Day 1
Dose 2/Day 2
Dose 2/Day 5
Dose 2/Day 8
Dose 3/Day 1
Dose 3/Day 2
Dose 3/Day 5
Dose 3/Day 8
Time Relative (h)
***
***
0
24
72
120
168
216
336
360
432
504
672
696
768
840
Visit Window
(+/-1)
(+/-1)
(+/-1)
(+/-1)
(+/-1)
(+/-1)
(+/-1)
Assessments
Informed Consent
b
x
Demography
x
Medical History
x
Randomization
c
x
Physical Examination
d
x
x
x
x
x
x
Vital Signs
e
x
x
2
x
x
x
x
x
Eligibility
x
x
Tuberculosis Screening Test
f
x
Clinical Genotyping
g
x
ECG-12 lead
h
x
2
x
x
x
Hematology
i
x
x
x
x
x
x
x
x
Blood Chemistry
i
x
x
x
x
x
x
x
x
Urinalysis
i
x
x
x
x
x
x
x
x
Serology and viral PCR
j
x
Pregnancy Testing
k
x
x
x
x
Coagulation
x
Alcohol breath or blood test
x
x
Drugs of abuse
l
x
x
Colonoscopy or flexible sigmoidoscopy
m
x
x
Colon Biopsy
x
x
Stool Clostridium difficile
n
x
Stool Ova and Parasites
x
In-house period
x
x
x
x
x
x
x
Drug/Placebo Administration
x
x
x
Standard meal
o
x
x
x
x
x
x
x
PK samplingy
3
x
x
x
x
x
2
x
x
x
Blood flow cytometry
x
x
x
x
x
x
x
x
x
x
Blood epigenetic testing
x
x
x
x
x
Soluble PD biomarkers
p
x
x
x
x
x
x
x
Soluble disease biomarkers
q
x
x
x
x
sCD25w
x
x
x
x
x
x
Fecal Calprotectin
v
x
x
Abdominal skinfold thickness
x
Anti-drug antibodies
x
x
x
x
x
Local pain/Skin reactivity assessments
r
x
x
x
Clinical Outcome Assessment
s
x
x
x
x
x
x
x
Safety Phone Call
t
x
x
Safety biomarkers
u
Adverse Events
Previous and Concomitant Treatments
x
x
Dose 1
Dose 1 Outpatient Visits
Dose 3
Dose 2


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Table 1
Schedule of Activities – Main Table (cont.)
Activity
Follow Up visit
Outpatient visit
Hypersensitivity/ IRR 
(≥ Grade 2)
Early 
Termination Visit
Overall Study Day
Day 43
Day 44
Day 46
Day 48
Day 50
Day 52
Day 57
Day 71
Day 99
w
Unscheduled 
visit
Unscheduled visit
Unscheduled 
visit
Dose/Day
Dose 4/Day 1
Dose 4/Day 2
Dose 4/Day 4
Dose 4/Day 6
Dose 4/Day 8
Dose4/Day10
Dose 4/Day 15
Dose 4/Day 29
Unscheduled 
visit
Time Relative (h)
1008
1032
1080
1128
1176
1224
1344
1680
2376
Anytime
Anytime
Anytime
Visit Window
(+/- 1)
(+/-1)
(+/-1)
(+/-1)
(+/-3)
Assessments
Informed Consent
b
Demography
Medical History
Randomization
c
Physical Examination
d
x
x
x
x
Vital Signs
e
2
x
x
x
x
x
Eligibility
Tuberculosis Screening Test
f
Clinical Genotyping
g
ECG-12 lead
h
2
x
x
x
x
Hematology
i
x
x
X
x
x
x
x
x
x
Blood Chemistry
i
x
x
X
x
x
x
x
x
x
Urinalysis
i
x
x
X
x
x
x
x
x
x
Serology and viral PCR
j
Pregnancy Testing
k
x
x
x
x
Coagulation
x
x
x
x
Alcohol breath or blood test
x
Drugs of abuse
l
x
Colonoscopy or flexible sigmoidoscopy
m
x
Colon Biopsy
x
Stool Clostridium difficile
n
Stool Ova and Parasites
In-house period
x
x
Drug/Placebo Administration
x
Standard meal
o
x
x
PK sampling
y
3
x
x
x
x
x
x
x
x
x
x
x
Blood flow cytometry
x
x
x
x
x
x
x
Blood epigenetic testing
x
x
x
x
x
x
x
Soluble PD biomarkers
p
x
x
x
x
x
x
Soluble disease biomarkers
q
x
x
x
x
x
sCD25
w
x
x
x
x
x
x
x
Fecal Calprotectin
v
x
xv
Abdominal skinfold thickness
Anti-drug antibodies
x
x
x
x
x
x
x
Local pain/Skin reactivity assessments
r
x
x
x
x
x
Clinical Outcome Assessment
s
x
x
x
x
x
x
x
Safety Phone Call
t
Safety biomarkers
u
x
Adverse Events
Previous and Concomitant Treatments
x
x
Dose 4
 Dose 4 Outpatient Visits


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Table 1
Schedule of Activities – Main Table (cont.)
a) A 35-day maximum screening period will begin with the first assessment, not from consent.
b) Participants can be consented up to 3 months prior to randomization.
c) Randomization may be conducted on Day -1 or Day 1 prior to first dose.
d) A complete physical examination will be performed at screening (including height and weight), and abbreviated physical 
examinations at all other visits (no height measurement needed; weight only).
e) Single measurements of vital signs to be taken before blood collection for laboratory tests but after ECG collection when 
scheduled at the same time point. Includes single measurements of systolic and diastolic blood pressure, pulse rate, body 
temperature (tympanic) and respiratory rate. All measurements to be taken after the participant has rested in a supine 
position for at least 5 minutes. Vital sign assessments post-dose can be done with a deviation of 15 minutes.
f)
QuantiFERON-TB Gold testing should be performed.
g) Clinical genotyping is mandatory in countries where permitted.
h) ECGs should be performed prior to any scheduled vital sign measurements and blood draws. 12-lead ECGs will be obtained in 
triplicate (three consecutive interpretable 12-lead ECGs within a 2 - 5 minute interval) after the participant has been in a supine 
position for at least 10 minutes. Automated ECG intervals (PR [PQ], QRS, QT, QTcF) and HR will be captured or calculated, 
and the changes in T-wave and U-wave morphology will be documented. Measure baseline prior to endoscopy if endoscopy 
performed on the same day. ECG assessments post-dose can be done with a deviation of 15 minutes.
i)
Safety tests can be repeated during screening period at discretion of Investigator.
j)
Hepatitis B and HIV 1/2 antibody testing; HCV PCR.
k) Serum beta-human chorionic gonadotropin (β-HCG) at screening, urine on all other occasions (women of childbearing 
potential only).
l)
Drugs of abuse screen to include at minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines. Additional 
testing optional to local standards.
m) Endoscopy to be performed in the morning prior to dose on Day 29.
n) Clostridium difficile ELISA.


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Table 1
Schedule of Activities – Main Table (cont.)
o) Standard breakfast, lunch, dinner and snack to be provided at the times deemed convenient by the site.
p) For exploratory PD cytokines and other soluble markers.
q) LRG and ANCA screen. Based on outcome of ANCA screen, p-ANCA, c-ANCA, and atypical p-ANCA may be tested. LRG is 
optional.
r)
And at additional regular intervals at the Investigator’s discretion if an adverse event associated with local tolerability and pain 
is observed.
s) Partial Mayo Score.
t)
Site personnel will contact the participant. If deemed required by the Investigator, participants can be asked to come to the site 
for an unscheduled visit.
u) IgE, tryptase and exploratory safety biomarkers may be tested in case of participants experiencing signs and symptoms 
associated with injection-related reactions (IRRs). This includes hypersensitivity reactions.
v)
The Day 50 stool sample for measuring fecal calprotectin can be taken +/- 2 days. The other stool samples should be collected 
+/- 1 day.
w) Participants positive for anti-drug antibodies (ADA) will be requested to return and have additional ADA and sCD25 samples to 
monitor off-treatment ADA persistence.
x) Safety laboratory assessments on Day 50 are only for participants enrolled in dose level 3 (15 mg, Q2W).
y) PK samples collected within 24 hours post-dose, can be taken with a deviation of 15 minutes for samples taken up to 6 
hours after dosing with RO7049665/ placebo, and for samples thereafter with a deviation of 30 minutes.


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Table 2
Schedule of Activities - Detailed Table
Visit
Day
Scheduled 
Time (h)
Vital Signs
b
Physical 
Examination
c
ECG-12 
lead
d
PK Sample
e
ADA
Blood Flow 
Cytometry
Blood 
Epigenetic 
Testing
sCD25
Local Pain and 
Skin Reactivity
Day -1
x
x
x
x
Predose
x
x
x
x
x
x
0
2
x
6
x
x
12
x
x
x
Day 2
24
x
x
x
x
x
x
Day 4
x
Day 6
x
x
x
x
Day 8
x
x
x
x
x
Day 10
x
x
x
Predose
x
x
x
x
x
x
x
x
0
12
x
x
Day 16
x
Dose 2 outpatient visit
Day 22
x
x
x
Predose
x
x
x
x
x
x
x
0
12
x
Day 30
x
Dose 3 outpatient visit
Day 36
x
x
Predose
x
x
x
x
x
x
x
x
0
2
x
6
x
12
x
x
x
Day 44
24
x
x
x
x
Day 46
x
Day 48
x
x
x
x
Day 50
x
x
x
x
Day 52
x
x
x
Day 57
x
x
x
x
Day 71
x
x
x
x
x
Follow Up visit
Day 99
x
x
x
x
x
x
x
Unscheduled visit
Anytime
x
x
x
x
x
x
x
x
x
Hypersensitivity/ IRR 
(≥ Grade 2)
Anytime
x
x
x
x
x
Early Termination Visit
Anytime
x
x
x
x
x
Dose 4 outpatient visits
Day 1
Dose 4 in-house period
Day 43
Day 15
Dose 1 outpatient visits
Dose 1 in-house perioda
Dose 2 in-house period
Dose 3 in-house period
Day 29


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Table 2 - Schedule of Activities - Detailed Table – (cont.)
a) Randomization may be conducted on D-1 or D1 prior to first dose.
b) Single measurements of vital signs to be taken before blood collection for laboratory tests but after ECG collection when 
scheduled at the same time point. Includes single measurements of systolic and diastolic blood pressure, pulse rate, body 
temperature (tympanic) and respiratory rate. All measurements to be taken after the participant has rested in a supine position for 
at least 5 minutes. Post-dose vital sign assessments can be done with a deviation of 15 minutes.
c) A complete physical examination will be performed at screening (including height and weight), and abbreviated physical 
examinations at all other visits (no height measurement needed; weight only).
d) ECGs should be performed prior to any scheduled vital sign measurements and blood draws. 12-lead ECGs will be obtained in 
triplicate (three consecutive interpretable 12-lead ECGs within a 2-5 minute interval) after the participant has been in a supine 
position for at least 10 minutes. Automated ECG intervals (PR [PQ], QRS, QT, QTcF) and HR will be captured or calculated, and 
the changes in T-wave and U-wave morphology will be documented. Measure baseline prior to endoscopy if endoscopy performed 
on the same day. Post-dose ECG assessments can be done with a deviation of 15 minutes.
e)
PK samples collected within 24 hours post-dose can be taken with a deviation of 15 minutes for samples taken up to 6 hours 
after dosing with RO7049665/ placebo, and for samples thereafter with a deviation of 30 minutes.
.


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2.
INTRODUCTION
2.1
STUDY RATIONALE
RO7049665 is a novel dimeric interleukin 2 (IL-2) mutein that is being developed as a 
therapy for autoimmune conditions, including ulcerative colitis (UC). It is expected to 
treat the impaired regulatory T cell (Treg) numbers or function associated with 
autoimmune diseases without the broad-based immunostimulatory effects of IL-2. 
Specifically, RO7049665 was engineered to address and overcome the pharmacologic, 
safety and functional liabilities of Proleukin(aldesleukin), a recombinant human 
IL-2 therapy currently approved for the treatment of renal cell carcinoma and malignant 
melanoma.
Study (WP40161) has taken into consideration experiences gained in the healthy 
volunteer entry-in-human (EIH) single ascending dose (SAD) study WP39826. This is 
the first study where RO7049665 is administered in multiple doses and to participants 
with an autoimmune condition. The primary objective of this study is to evaluate the 
safety and tolerability of RO7049665 in participants with active UC. In addition, 
secondary objectives to be assessed are the pharmacokinetics (PK), preliminary efficacy, 
pharmacodynamics (PD) and immunogenicity. The study results will be used to support 
further clinical development of RO7049665.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Ulcerative Colitis
UC is a chronic, relapsing disease characterized by diffuse mucosal inflammation of the 
colon. Moderate to severe UC is a debilitating disease that can result in hospitalization 
for disease flares, potential bowel perforation or hemorrhage, and increased risk of 
colorectal cancer. Current goals of treatment include induction and maintenance of 
remission, improved quality of life, reduction in need for long-term corticosteroids, and 
minimization of cancer risk. Despite current medicinal and surgical treatments for UC 
(see Section 2.3), over 70% of patients with UC still lack a long-term efficacious therapy 
(Neurath 2017). Therefore, there is an urgent need for new treatments for UC in patients 
who do not respond to current treatments.
A loss of tolerance and a disruption in immune homeostasis are at the core of 
autoimmunity and have been strongly associated with reduced Treg numbers and 
impaired function. In many autoimmune diseases such as UC, a numerically and/or 
functional deficiency of Tregs is observed and considered a key factor for the failure to
maintain immune-homeostasis and suppress auto-reactivity to self tissues. As a 
molecule critical for immune homeostasis, IL-2 plays a key role in maintaining a state of 
tolerance to “self” through its effects on the induction and activation of Tregs. Low-dose 
aldesleukin has shown some clinical efficacy in patients with graft-versus-host disease 
(GVHD), hepatitis C-induced vasculitis, and moderate-to-severe systemic lupus 


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erythematosus (SLE) and is currently being explored in patients with type 1 diabetes and 
UC. 
2.2.2
RO7049665
RO7049665 is a novel IL-2 mutein immunocytokine. Compared to aldesleukin, 
RO7049665 has reduced binding affinity to IL-2 receptor (IL-2R)present on CD4and 
CD8effector T cells (Teff) and natural killer (NK) cells, with no loss of binding affinity to 
IL-2R, a required component of IL-2Rreceptors present at the highest levels on 
Tregs. By virtue of its reduced affinity to IL-2Rreceptors and its Treg selectivity, 
RO7049665 enhances the Treg-supporting function of human IL-2 without the 
broad-based IL-2R-mediated immunostimulatory effects of IL-2. RO7049665 therefore 
provides a novel selective immunotherapy to treat autoimmune diseases, including UC, 
with an expected improved safety profile compared to aldesleukin.
In a human whole blood assay, RO7049665 exhibited greatly reduced potency to induce 
pro-inflammatory cytokines compared to aldesleukin, with 600-fold lower potency for 
induction of Interferon (IFN), Interleukin 6 (IL-6), tumor necrosis factor (TNF), and 
Interleukin 1 (IL-1)and 5-fold lower potency for induction of Interleukin 8 (IL-8) 
compared to aldesleukin. A tissue cross-reactivity study of RO7049665 showed staining 
patterns consistent with known IL-2R expression profiles. 
Observed toxicities in both 4-week and 13-week good laboratory practice (GLP) 
toxicology studies in cynomolgus monkeys treated with RO7049665 were consistent with 
increased pharmacological activity of IL-2, and included skin findings (at the injection site 
and generally), increased heart rate, changes in blood leukocyte numbers including 
increased eosinophils as well as microscopic findings of tissue infiltrates, and changes in 
lymphoid tissues. Findings were dose-dependent and had resolved or were trending to 
resolution following a 4-week recovery period. At all dose levels tested in both studies, 
there was no evidence for capillary leak syndrome (CLS), a known toxicity of high dose 
IL-2 therapy.
Following subcutaneous (SC) administration of RO7049665 in the 13-week GLP 
toxicology study, exposure to RO7049665 on Day 1 increased less than dose 
proportionally over the dose range of 0.2 mg/kg to 3 mg/kg. Rapid development of ADAs 
was observed at a low dose (0.2 mg/kg), leading to almost complete loss of exposure 
and loss of PD response by study Day 50 in the majority of animals. The 
no-observed-adverse-effect level (NOAEL) dose in the female animals was 0.2 mg/kg 
weekly that retained exposure to the drug until the dosing cycle at Day 22, with 
maximum serum concentration observed (Cmax) and area under the curve 
(AUC)0-168h measured on Day 22 as 254 ng/mL and 8440 ng•h/mL respectively. At higher 
doses (1 mg/kg), a subset of the animals (approximately 50%) did not develop high 
ADAs and remained exposed until the end of the study but developed generalized skin 
rash. Assessment of PD markers and immune-lineage cell counts in the 13 week GLP 
study confirmed induction of phosphorylated signal transducer and activator of 


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transcription 5 (pSTAT5) and other markers of activation of Tregs, as well as expected 
changes of lymphocyte populations, including transient reduction followed by an 
increase of lymphocyte populations (total T cells, Tregs, CD4T cells, CD8T cells, NK 
cells, and B cells) and monocytes, with the increases of Tregs being of greater magnitude 
than that of other T cell populations.
2.2.2.1
Previous Clinical Studies
Study WP39826
Study WP39826, the first clinical trial where RO7049665 was administered to humans,
has completed dosing. The aim of this Entry-into-Human study was to investigate the 
safety, tolerability, PK and PD of single ascending doses of RO7049665 in a healthy 
male population. A total of 56 participants were administered single doses of 
RO7049665 or matching placebo injected subcutaneously in the abdomen.
A total of 9 doses were tested, ranging from 1.5 µg, which was the dose based on 
MABEL, up to 7500 µg. Thirty-eight participants (67.9%) received one SC injection of 
RO7049665, and 18 (32.1%) received placebo. Until Cohort 5, dose groups consisted of 
3 participants on RO7049665 and 2 on placebo, split in a sentinel group of 2 participants 
(1 on active and 1 on placebo), and at least 48 hours later, the remaining participants of 
the group. The number of participants under active treatment was increased to 6 in 
Cohorts 6 to 9, to allow for a better characterization of the safety, PK and PD parameters. 
In Cohort 9, only 5 subjects were enrolled into the active treatment arm due to 
recruitment limitations.
Overall RO7049665 was well tolerated. A total of 121 treatment-emergent adverse 
events (TEAEs) were reported across the dose range tested, 94 (77.7%) in the active 
treatment groups, and 27 (22.3%) in the placebo group. Across all groups, the most 
frequently reported TEAEs were nasopharyngitis, injection site erythema, injection site 
pruritus, headache, diarrhea and myalgia. The majority of TEAEs were mild in intensity, 
with the exception of 5 events (1 event of gastroenteritis, 3 events of food poisoning, and 
1 event of influenza-like illness) in 5 subjects on active treatment, rated as moderate in 
intensity but not related to the study drug by the Investigator of the study. There were no 
deaths or serious adverse events (SAE), and no withdrawals due to an adverse event 
(AE). There was no trend or pattern in the AEs observed with increasing doses or 
between active and placebo groups, with the exception of local injection site reactions 
(erythema, pruritus), observed in an increasing number of participants as the dose 
increased. All AEs related to the injection site were mild in intensity and resolved without 
treatment.
There were no trends observed in vital signs, electrocardiogram (ECG) intervals and lab 
safety results across the dose range tested.


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Immunogenicity was assessed, and positive results for anti-drug antibody (ADA) were 
observed in a total of 12 participants starting from Cohort 5 (dose of 190 µg). ADAs were 
of early onset (detected in first samples on Day 8 post-dose), generally transient, and 
exhibited dose dependency with regard to titers and incidence. The presence of ADA 
had no apparent impact on the safety, PK and PD profiles. Further analysis was 
performed and concluded that the ADAs were not capable of neutralizing recombinant 
human IL-2.
Serum RO7049665 concentration reached peak level (Cmax) approximately 12 hours 
post-dose and declined in an apparent biphasic manner, with a mean apparent terminal 
phase half-life of approximately 72 to 137 hours (see Table 3). Serum exposure levels of 
RO7049665 were below or close to the detection limit in the 1.5 and 5g dose groups 
and thereafter increased with increasing doses in a highly variable manner. Overall, no 
obvious deviation from dose-linearity was noted. Sufficient concentration data for reliable 
estimates of non-compartmental parameters in terms of both AUC and Cmax was 
available as of cohort 6 (650 g) and above (see Table 3). Although the data showed 
moderate between-subject variability, no relevant departure from linearity was noted. 
The mean serum apparent systemic clearance of RO7049665 appeared dose-
independent and ranged from 1.4 to 2.2 L/h. 
RO7049665 disposition occurred with a mean T1/2 of about 5 days, thus is expected to 
approach near-complete washout (Ctrough < 10% of Cmax) no later than 2 weeks post last 
dose. Accordingly, no substantial accumulation in reaching steady state is expected in a 
biweekly regimen.
At the highest dose of 7500 g RO7049665, exposure was 33% and 65% of the 
exposure at the no-observed-adverse-effect level (NOAEL) (established in female 
monkeys on Day 22) in terms of Cmax and AUC0-168h, respectively.


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Table 3
Serum Pharmacokinetic Parameters of RO7049665 after Single 
Subcutaneous Administration
Dose 
(g)
n
Cmax
(ng/mL)
Tmaxa
(h)
AUCinf
(ng h/m)
CL/F
(L/h)
VZ/F
(L)
T1/2
(h)
Expressed as Geometric means (%CV)
650
6
4.55 
(49.4)
12.00 
(6.00-24.00)
409 
(43.1)
1.59 
(43.1)
210 
(28.2)
91.8 
(52)
2200
6
11.0 
(58.8)
12.03 
(5.98-48.00)
1020 
(37.7)
2.16 
(37.7)
276 
(17)
121 
(23.2)
5000
5
46.5 
(27.4)
12.00 
(12.00-24.00)
2831 
(26.9)
1.77 
(26.9)
331 
(25.6)
130 
(18)
7500
6
68.7 
(85.6)
12.00 
(5.98-12.00
5266 
(55.4)
1.42 
(55.4)
281 
(62.4)
137 
(9.3)
AUCinf area under the serum concentration-time curve extrapolated to infinity; Cmax maximum 
serum concentration observed;  CL/F apparent clearance;  ND not determined;  
T1/2 terminal elimination half-life; Tmax time to maximum concentration;  Vz/F apparent 
volume of distribution. 
a Median (MinMax). 
Pharmacodynamic data showed that RO7049665 expanded the Treg cell pool, thereby 
delivering proof of pharmacology in a healthy population. The Treg expansion was dose-
dependent, and reached an absolute increase of 200 cells/µL at the maximum tested 
dose of 7500 µg, ranging from 123 to 297 cells/µL. This represented a mean-fold 
increase of 5.9 (2.9-7.6) from baseline. The peak was, on average, reached on Day 8, 
following a drop at 24 hours post-dose, and Treg levels were back to baseline values at 
Follow-up (Day 57). Overall, the estimated therapeutic range of Treg was achieved with 
the doses of 2200, 5000 and 7500 µg, eliciting a mean increase of 2, 4 and 6-fold, 
respectively, as compared to baseline. 
There was no expansion of natural killer (NK) cells in any dose group, and no significant 
trends observed in eosinophils. There was no obvious effect on Teff at doses up to 
2200 g. A possible weak trend for increase in Teff count occurred with doses of 5000 g 
and 7500 g, with mean change from baseline on Day 12 reaching up to 1.5-fold 
increase from baseline.
Study WP40161
In this ongoing study WP40161, to date, multiple doses (i.e., up to 4) of 3.5 mg and 7.5 
mg have been well tolerated, and they induced dose-dependent Treg cell expansions up to 
5-fold (mean at the highest dose of 7.5 mg) versus baseline. 
The most frequently reported AEs were injection site reactions (ISRs) and eosinophilia. 
The majority of AEs reported were mild or moderate (Grade 1 or 2) in intensity except 
for a low number of events of severe (Grade 3) intensity, including anemia, eosinophilia 
and hyperkalemia. No events of CLS were reported. Hypersensitivity reactions (Grade 2) 


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with some, or all, symptoms of erythema, edema of the forearm, scapula and right arm, 
have been reported, as well as injection-related reactions (IRR) with some, or all, 
symptoms of myalgia, fatigue, chills and redness of face and neck. All events either have 
resolved without sequelae or are ongoing. There have been no deaths reported to date.
Immunogenicity was assessed, and positive results for ADA were observed in 
approximately 50% of participants. There have been no results to date indicating ADAs 
with neutralizing potential against endogenous IL-2. The ADAs were not associated 
with changes in PK parameters, and did not impact exposure or PD.
No significant abnormalities on vital signs or ECG intervals have been reported to date 
and, besides the changes on eosinophils, no significant laboratory safety results have 
been noted in participants with UC receiving up to 4 doses of 3.5 mg and 7.5 mg Q2W 
of RO7049665.
Detailed descriptions of the chemistry, pharmacology, pharmacokinetics, efficacy and 
safety of RO7049665 are provided in the RO7049665 Investigator’s Brochure.
2.3
BENEFIT/RISK ASSESSMENT
UC is a chronic, relapsing disease characterized by diffuse mucosal inflammation of the 
colon. The precise etiology of UC is unknown; however, it is thought to be caused by an 
inappropriate inflammatory response to gut antigens in genetically predisposed 
individuals (Abraham and Cho 2009; Talley et al. 2011). The estimated incidence of UC 
in the United States is 9-12 cases per 100,000 persons per year, with an estimated 
prevalence of 205-240 cases per 100,000 persons (Danese and Fiocchi 2011). There is 
considerable variability in the incidence and prevalence of UC around the world.
Current management of UC includes initial use of aminosalicylates (e.g., sulfasalazine or 
mesalamine) and/or corticosteroids to induce remission or the use of biologic agents 
(e.g., tumor necrosis factor [TNF] inhibitors or integrin inhibitors) in patients with severe 
disease or in whom induction cannot be achieved with steroids. Once induction of 
remission has been achieved, maintenance therapy such as aminosalicylates, 
thiopurines (e.g., azathioprine or 6-mercaptopurine), or biologics (e.g., anti-TNF or 
anti-integrins) is given with the aim of maintaining disease control and avoiding 
long-term steroid use. Patients with severe acute disease or severe refractory disease 
may be considered for surgery (e.g., colectomy). Among multiple new molecular entities 
tested in patients with UC over the past two decades, only anti-TNF, anti-α4β7, and a 
pan-Jak inhibitor have demonstrated efficacy in patients with moderate to severe UC. 
Despite these recent additions to the treatment arsenal, over 70% of patients with 
moderate to severe UC still lack a long-term efficacious therapy (Neurath 2017). 
Study WP40161 is the first study involving dosing of RO7049665 in participants with UC
and the first study with repeat dosing. At the time of the commencement of Study 
WP40161, the safety data in healthy volunteers from the EIH Study WP39826 were
available. Potential risks have been defined based on clinical experience in healthy 


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volunteers, data from participants with UC in Cohorts 1 (3.5 mg) to  4 (7.5 mg; see 
Section 2.2.2.1), non-clinical pharmacology and toxicology data in the relevant animal 
species, and theoretical risks based on expected PD effects and the safety profile of 
Proleukin. 
The eligibility criteria, design and procedures adopted are considered to be appropriate 
for the safe conduct of the planned study. Participants will be closely monitored for 
safety consistent with standard practices, and will be under close medical observation 
during the study.
The doses planned for dose level 1 (3.5 mg) and dose level 2 (7.5 mg) were derived 
from data in the WP39826 healthy volunteer study. Single doses of 7500 g (7.5 mg) 
and below were safe and well tolerated in the subjects in WP39826, and induced dose-
dependent Treg expansions up to 6-fold (mean at the highest dose of 7500 g) from
baseline. The dose planned for dose level 3 (15 mg) was based on results from repeat 
dosing with 3.5 mg and 7.5 mg in participants with UC in this study (WP40161); both 
the 3.5 mg and 7.5 mg doses have been well tolerated to date. The Sponsor believes it is 
important to fully characterize the safety profile and PK/PD relationship of RO7049665 
in this study, which will also contribute to, and enable, an optimal design in future 
dose-setting studies.
Identified potential risks and plans for their mitigation are as follows:

Excessive Interleukin-2 Effects
Excessive IL-2 effects have been reported in the Proleukinlabel and include an 
increase in Teff, increased eosinophilia, cytokine storm, CLS (symptoms include 
hypotension, mental status changes, dyspnea, pulmonary edema, reduced urine 
output and tachycardia), flu-like symptoms (such as fever, headache, muscle and 
joint pain, fatigue, nausea/vomiting/diarrhea, loss of appetite), dry and/or itchy skin 
or rash, liver and kidney failure, infections including sepsis and new onset or 
exacerbation of autoimmune disorders. These are considered less likely to occur 
with RO7049665 due to its selective effect on Tregs. Limited expansion of Teff cells 
was observed at the two highest doses (5000 g and 7500 g) in the WP39826 
study. There will be close monitoring of Teff and eosinophils in blood, and of AEs 
suggestive of excessive IL-2 effects, with stopping criteria in place for CLS events,
eosinophil counts and in the event of systemic IRRs in a participant. Exploratory 
safety cytokines such as IL-6, IL-8, TNF-and IL-1may be measured in an ad hoc 
fashion (e.g., in participants experiencing symptoms associated with IRRs).

Hypersensitivity
As with all biologic agents, there is a theoretical risk for hypersensitivity reactions, 
which can range from a mild rash to a life-threatening anaphylaxis. Hypersensitivity 
reactions may occur acutely following drug administration or have a delayed onset, 


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e.g., serum sickness reactions due to accumulation of immune complexes. No 
events suggestive of a systemic hypersensitivity reaction were observed following 
the receipt of single doses of RO7049665 in the WP39826 study. ADAs were 
observed which could increase the risk of developing hypersensitivity reactions with 
repeat dosing.
Patients will be closely monitored for clinical signs and symptoms suggestive of
hypersensitivity reactions (both acute and non-acute). Patients developing 
hypersensitivity reactions will receive supportive care and treatment according to the 
institutional practice and local standard of care.
As mitigation, participants will receive all doses at an investigative site with 
resuscitation equipment available for immediate use and be housed at the site 
overnight. Dosing will also be staggered (see section on ADA below). Additionally, 
stopping rules will be in place in the event of systemic hypersensitivity AEs in a 
participant and for a participant experiencing a ≥Grade 3 hypersensitivity reaction 
considered related to the study drug and believed to pose an unacceptable risk if 
the dose is repeated.
Additional assessments may be performed (e.g., IgE, tryptase, ADA, safety 
cytokines and further exploratory safety biomarkers) in participants experiencing 
signs and symptoms suggestive of a hypersensitivity reaction.

ADA Formation
The development of ADAs is a potential risk for all therapeutic protein products with 
the possibility of cross-reactivity being a particular concern for products that have 
endogenous counterparts. Twelve out of the 38 subjects (i.e., 32%) who received 
RO7049665 in the WP39826 study were positive for ADAs, with a trend for 
increasing incidence and titres at higher doses. ADAs raised to RO7049665 could 
be asymptomatic or could potentially cause hypersensitivity reactions, a decrease in 
drug exposure, neutralization of the therapeutic effect, or scavenging and 
neutralization of endogenous IL-2, thus causing an IL-2 deficiency state. 
Hypersensitivity reactions could range from rash to anaphylaxis or serum sickness. 
Absence of IL-2 has been associated with autoimmune conditions such as 
autoimmune thyroiditis or type 1 diabetes. The ADAs observed in WP39826 
following single doses were not neutralizing to recombinant human IL-2 and had no 
apparent clinical consequences.
This is the first repeat dose and first patient study for RO7049665 and the safety 
monitoring and risk mitigation measures listed below will be implemented:
o
Participants will be monitored closely following the receipt of each dose and 
housed at a clinical research site for at least 24 hours post-dosing.


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o
Staggered dosing will be employed. There will be a 5-day interval between 
receipt of the first dose of the first, second, and third participants treated at a 
specific dose level. The fourth participant can receive the first dose 14 days 
after the first dose of the third participant, at the earliest. There will be an 
interval of 48 hours between administrations of the first dose for subsequent 
participants in each dose level.
o
Assessments of ADA development, their neutralising capability and the impact 
on continued dosing and dose escalation are planned at the following three
timepoints:
–
Once the ADA results up to and including Day 22 (i.e., one week 
after the second dose) are available for the first five participants 
(4 active and 1 placebo) at the 3.5 mg dose level and subsequently 
at the 7.5 mg dose level (i.e., two separate assessments).
–
Once the ADA results up to and including Day 57 (i.e., two weeks 
after the fourth dose) are available for the first five participants (4 
active and 1 placebo) at the 3.5 mg dose level. This is the dose 
escalation timepoint outlined in Section 4.1.2.
o
Inclusion of individual participants and study level stopping criteria relating to 
hypersensitivity reactions and development of neutralising antibodies to 
recombinant human IL-2 (See Section 4.1.3).
o
Signs and symptoms of autoimmune phenomena will be monitored and treated 
according to standard of care.
Concomitant therapy with immunomodulators such as azathioprine/6-
mercaptopurine (6-MP)/methotrexate may decrease the risk of ADA and neutralizing 
IL-2 antibody formation. Patients who are already on one of these therapies will 
continue; patients who are not already on these therapies will not be proactively 
started on them. The mechanism of action of RO7049665 is to induce tolerance via 
increases in Treg activity. This tolerance induction can potentially mitigate the risk of 
ADA and neutralizing IL-2 antibody formation. 

Increased Regulatory T Cells Causing Immunosuppression
There is a theoretical risk of immunosuppression from increased Treg cell count and 
an increased proportion of Tregs compared with total T cells. Infections, especially 
opportunistic infections, and malignancies are theoretical risks. Signs and symptoms 
of immunosuppression will be monitored and treated according to standard of care.
A stopping criterion specific for Tregs increases has also been included.


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
Injection Site Reactions
Localized injection site reactions (including erythema, pruritus and swelling) of mild 
intensity and resolving without treatment were observed following dosing with 
RO7049665 in the WP39826 study. There was a higher incidence at higher doses 
and injection site erythema was the most frequently observed event. The erythema 
was first observed at 2 to 6 days after dosing and had a duration varying from 3 to 
54 days until complete resolution. Assessments of local skin reactivity and pain 
following injection will be performed in this study to further characterize injection site 
reactions. Administration of serial doses in the same participant should be done in 
different quadrants of the abdomen.

Non-clinical Finding of Heart Rate Increase
Heart rate increases were observed in the 13-week good laboratory practice (GLP)
study in cynomolgus monkeys. The heart rate increases showed complete 
reversibility in recovery. The effects seen on heart rate were likely linked to the 
acute phase response and/or elevated cytokine levels, both of which were more 
pronounced after Week 1 and thus are considered secondary to the pharmacologic 
action of the study drug. These effects were completely reversible. No trend towards 
increased heart rate was observed in the WP39826 clinical study after single dosing. 
Vital signs and ECGs will be monitored in this study. Further details are provided in 
the RO7049665 Investigator’s Brochure.

Procedure-Related Risks
The procedures performed are flexible sigmoidoscopy (or possible colonoscopy at 
screening) with mucosal biopsies from the sigmoid colon, SC injections and blood 
draws. The risks associated with flexible sigmoidoscopy or colonoscopy with 
biopsies include bleeding, infection, and perforation of the intestine. SC injections 
may produce a local inflammatory reaction, which can range from a slight irritation to 
infection or possible necrosis. The risks associated with blood draws include 
hematoma, and rarely injury to neurovascular structures.

Risks Related to Concomitant Medications
Risks of Corticosteroid and RO7049665 Adjunctive Therapy
Long-term use of corticosteroids is associated with pleiotropic effects, which are 
well described (Ford et al. 2011). An increased susceptibility to infection is a known 
side effect. Addition of RO7049665 could theoretically further increase the risk of 
infection. Current standard of care includes the addition of other 
immune-modulating therapeutics on a background of corticosteroid therapy, with the 
goal of therapy being to discontinue corticosteroids. Patients in this study may 
continue on a maximum dose of prednisone that will not exceed 20 mg/day for a 
maximum of 12 weeks of therapy. Corticosteroid dose could be decreased in 
response to steroid-associated side effects to minimize the toxicity of chronic 


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therapy with corticosteroids. Addition of RO7049665 to background corticosteroid 
therapy will follow standard of care practices since rapid discontinuation of 
corticosteroids is not acceptable due to the risk of adrenal insufficiency. 

Exacerbation of UC
Patients with UC have a significant inflammatory burden from the ongoing disease. 
There is a potential risk of activating and expanding CD25+ Teff cells with 
RO7049665, or development of excessive IL-2 effects as described above.
To mitigate this risk, participants will be housed for at least 24 hours after each dose 
and monitored closely (e.g., vital signs, ECG, physical exam). There will also be 
ongoing PD monitoring of immune cell subsets and optional ad hoc cytokine testing. 
Reassuringly, in vitro experiments with peripheral blood mononuclear cells from 
participants with UC demonstrated that after in vitro treatment with RO7049665, 
there was activation of only a very minor fraction of CD25+ Teff (~3% of total CD4+
cells), and only at an RO7049665 concentration that was ≥ 1,000 fold higher than 
the concentration needed to activate Tregs (for details, see the RO7049665
Investigator’s Brochure). Limited expansion of Teff cells was observed at the two 
highest doses (5000 g and 7500 g) in the WP39826 study. Thus, the risk of 
disease worsening due to Teff activation in UC is considered minimal, while the 
potential benefit of increased Tregs is the reversal of the inflammatory process. 
Participants in the study will be monitored closely for signs of disease worsening, 
and dosing in a participant will be stopped if persistent disease worsening is evident.
To ensure appropriate safety monitoring, the participants will be housed at the clinical 
research unit during each dosing period. Participants will receive a given dose of 
RO7049665 every 2 weeks for a total of 4 doses. Participants will be monitored for 
24 hours in the clinical research unit after receipt of each dose. 
An assessment was conducted to determine whether there is any impact of the 
coronavirus disease 2019 (COVID-19) pandemic on the benefit/risk assessment of this 
study protocol including, but not limited to, the patient population under study and 
study treatment being evaluated. On the basis of that assessment, no impact is 
anticipated and the existing safety monitoring and management guidelines, and risk 
mitigation measures provided in the study protocol are considered adequate.
Overall, the expected benefits of RO7049665 in the treatment of autoimmune conditions 
are greater than the expected risks. The level of risk for UC participants is considered 
acceptable as it is mitigated by careful monitoring, careful dose escalation, and study 
stopping criteria (See Section 4.1.2 and 4.1.3).
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7049665 is provided in the 
RO7049665 Investigator’s Brochure. 


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3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 4.
Table 4
Objectives and Endpoints 
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
repeat dosing of subcutaneous (SC) 
injections of RO7049665 in participants 
with active ulcerative colitis (UC).
Incidence of dose-limiting or intolerable 
treatment-related adverse events (AEs).

Incidence, severity, and causal 
relationship of treatment-emergent AEs.

Incidence of abnormal laboratory 
findings.

Incidence of abnormal vital signs and 
electrocardiogram (ECG) parameters.
Secondary

To investigate the multiple-dose 
pharmacokinetics of RO7049665.

Pharmacokinetic parameters of 
RO7049665

To investigate the effects of multiple 
doses of RO7049665 on changes in 
endoscopic appearance of the mucosa of 
the sigmoid colon.

Change from baseline in the 
Endoscopy Subscore of the Mayo 
Clinic Score (MCS-ES) at Day 29 and 
Day 57.

Change from baseline in the Ulcerative 
Colitis Endoscopic Index of Severity 
(UCEIS) at Day 29 and Day 57.

To investigate the effects of multiple 
doses of RO7049665 on changes in 
histologic appearance of mucosa in 
biopsies from the sigmoid colon.

Change from baseline to Day 29 and 
Day 57 in histology score of sigmoid 
colon biopsies (Geboes Score [GS], 
Robarts Histology Index [RHI], or 
Nancy Histology Index [NHI]).

To investigate the effects of multiple 
doses of RO7049665 on changes in 
disease activity.

Change from baseline in the Mayo 
Clinic Score (MCS) at Day 29 and Day 
57.

To evaluate the immunogenicity of 
RO7049665.

Incidence of anti-drug antibodies 
(ADAs).

To investigate the effects of multiple 
doses of RO7049665 on immune cells in 
the periphery and in mucosal biopsies of 
the sigmoid colon.

Quantitative changes in WBCs (Tregs, 
Teffs, natural killer [NK] cells, B cells 
and eosinophils).
Tertiary/Exploratory

To explore the association of genotype 
with PD, efficacy and safety of 
RO7049665.

Correlation analysis of single nucleotide 
polymorphisms with PD, efficacy and 
AEs.
4.
STUDY DESIGN
4.1
OVERALL DESIGN
Study WP40161 is a multicenter, randomized, adaptive, Investigator and participant
blind, placebo-controlled study to investigate the safety, tolerability, PK, PD, and 


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preliminary efficacy of multiple ascending doses (MAD) of RO7049665 on top of 
standard of care (SOC) in participants with endoscopic evidence of moderate to severely 
active UC. The participants, investigators, and site personnel will be blinded to treatment 
assignments.
Since this is the first clinical study in which RO7049665 will be tested in participants 
diagnosed with UC and the first study in which multiple doses of RO7049665 will be
administered, a dose escalation design will be used.
All participants in the study will have evidence of active disease on endoscopy at 
screening (MCS 5, Endoscopy subscore of the Mayo Clinic Score [MCS-ES] 2, stool 
frequency subscore 1and rectal bleeding subscore 1). Participants will be eligible 
for the study if they are currently receiving non-biologic SOC therapy for UC and have 
not been treated with any biologic therapy within 3 months (or 5 half-lives, whichever is 
longer) before the start of screening. 
Participants will be randomized in a 4:1 ratio to receive multiple SC injections of 
RO7049665 or placebo, respectively (approximately 8 on active and 2 on placebo per 
cohort). Participants will receive their first doses in a staggered manner, with a five-day 
interval between the first dose of the first, second, and third participants. The fourth
participant can receive the first dose 14 days after the first dose of the third participant,
at the earliest. There will be a 48-hour interval between the first dose of subsequent 
participants in each dose level. Based on emerging data, dose levels may be expanded.
The dosing interval will be every 2 weeks (Q2W), for 4 doses. The first dose level will be 
3.5 mg, the second dose level will be 7.5 mg and participants enrolled in the cohorts of 
dose level 3 will receive 15 mg of RO7049665 (or placebo). The doses are based on 
safety, tolerability, PK and PD data derived from study WP39826 (see Section 4.3) and 
review of data from completed cohorts in this study. Each dose level will have cohorts of
approximately 10 participants, randomized in the ratio of 4:1 RO7049665 to placebo. 
Based on the emerging data there may be more than one cohort enrolled per dose level.
The second dose level may run in parallel with the first (see Section 1.2), after 
completion of recruitment into the lower dose level. However, prior to enrolling 
participants into the higher dose level, there will be an assessment of safety, tolerability, 
ADA, PK and selected PD data from at least 5 participants (4 on RO7049665, 1 on 
placebo) in dose level 1 who have received at least 8 weeks of treatment. 
An overview of the study design is provided in Section 1.2.
4.1.1
Length of the Study
The total duration of the study for each participant will be approximately 19 weeks 
divided as follows:


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
Screening: Up to 5 weeks (35 days).

Dosing Period: Day 1 to Day 43.

In-clinic period: From Day 1 to Day 2 for first dose, from Day 15 to Day 16 for the 
second dose, from Day 29 to Day 30 for the third dose, and from Day 43 to Day 44 
for the last dose.

Final follow-up: Day 99 3 days (8 weeks post last dose).
4.1.2
Dose-Escalation Decision Criteria 
The decision to escalate to the next dose level will be made following review of all 
relevant safety information collected, including available AEs, ECG, vital signs, clinical 
laboratory test results, ADA, selected PD data (quantitative changes in WBCs, Tregs, and 
eosinophils), and PK data collected up to at least 8 weeks in 5 participants (4 active and 
1 placebo) at the immediately preceding dose level. The dose-escalation procedure for 
this study is based on data and decisions from study WP39826, where dose-escalation
proceeded after a minimum of 3 participants on RO7049665 and 2 on placebo.
The decision to escalate will be made jointly by the Sponsor study team, the Sponsor’s 
IMC, the Investigators, and any other person considered necessary to assist with the 
decision.
4.1.3
Stopping Rules Criteria 
Dosing within a dose level will be stopped and no higher doses will be started if one of 
the circumstances or dose-limiting adverse events (DLAEs) listed below occurs in 
participants treated with RO7049665 within the same dose level, unless it is determined 
by the Investigator that the occurrence is not related to the study drug:

Eosinophil count increase to 5.0 x 109/L occurring in 3 or more participants in a 
single dose level. 

Grade 3 or higher (as defined by the Investigator) RO7049665-related AEs of the 
same type in 2 or more participants (See also Appendix 2).

Grade 3 or higher RO7049665-related laboratory abnormalities of same type in 2 or 
more participants in a single dose level.

Grade 2 or greater RO7049665-related changes in vital signs or ECGs 
(e.g., QTc 500 ms, or 60 ms longer than the pre-dose baseline) of same 
character in 2 or more participants in a single dose level.

Other findings (e.g., AEs or lab abnormalities) that, at the joint discretion of the 
Sponsor’s lead clinical scientist and safety science leader, the Sponsor’s IMC and 
the Investigators, indicate the dosing or dose escalation should be stopped.

Development of neutralizing antibodies to recombinant human IL-2 in one or more 
participants.
Dosing and dose escalation (alternatively, a lower dose level or less frequent dosing) 
may be resumed following further evaluation of the data and the benefit/risk profile, and


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upon the joint agreement of the Sponsor’s lead clinical scientist, safety science leader, 
the Sponsor’s IMC, and the study Investigator, and only once the necessary Ethics 
Committee (EC) and health authority approvals have been received.
4.1.4
Individual Participant Stopping Criteria 
Dosing will be stopped in a given individual participant if, compared with baseline, one of 
the following circumstances occurs: 

A second systemic IRR or hypersensitivity AE of any grade occurs (see 
Sections 4.1.5 and 8.3.8).

Grade 3 or greater severe AE or SAE considered related to study drug, including but 
not limited to:
o
IRR/ hypersensitivity reaction which is considered related to study drug 
and believed to pose an unacceptable risk if the dose is repeated.
o
CLS including severe, clinically significant respiratory distress syndrome, 
edema, effusions, or decrease in blood pressure 

Disease exacerbation requiring escalation of baseline treatment or other treatment 
strategies (pharmacological or surgical) signifying study treatment failure (See 
Section 7).

Development of neutralizing antibodies to recombinant human IL-2 (also see study 
stopping criteria Section 4.1.3).

Other findings that, at the discretion of the Investigator, indicate that dosing should 
be stopped.
Study closure information is provided in Appendix 1.
4.1.5
Communication Strategy
Information will be communicated during the study, as follows:

For all participants, the Investigator(s) must confirm to Roche that the participant 
has been dosed and provide a brief summary of the status of the participant in terms 
of safety and tolerability to RO7049665/ placebo, communicated by email or 
telephone between 24 to 48 hours of first dose. Please refer to the Cohort 
Management and Dose Escalation Document. 

In the event of a DLAE, or an event or findings meeting the stopping criteria defined 
in Section 4.1.4 , the Investigators will contact the Sponsor immediately to discuss 
participant status and action taken/to be taken.

In the event of a first systemic IRR or systemic hypersensitivity the Investigator 
must contact the Sponsor prior to the next dose for discussion.

The Sponsor will rapidly inform all investigational sites of any urgent safety
measures required to protect the clinical trial participants from any immediate 
hazard to their health and safety. 

Prior to dose-escalation, a dose-escalation meeting will be conducted by the 
Investigators, the Medical Monitor, and the Sponsor Clinical Team.


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
Upon reaching the minimum criteria for dose escalation consideration (minimum of 
5 participants having completed 8 weeks [DLAE period]) the Sponsor will organize a 
teleconference with the Investigators to discuss the safety and tolerability of 
RO7049665/ placebo. If the teleconference occurs prior to the end of the DLAE 
evaluation period, the Investigator will provide a final status prior to start of the next 
cohort. 
During each teleconference:
o
National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Version 5.0 Toxicities (see Appendix 2) will be 
discussed along with the results of PK data (if available), in addition to 
safety laboratory results and any other available data (as described in 
Section 4.1.2) that may assist the dose-escalation decision process. 
o
Dose-escalation will only proceed to the next dose level if the 
Investigators and the Sponsor (including IMC decision) are satisfied with 
the safety profile of the previous dose level and agree to move to the next 
dose level. 
o
If other RO7049665 dose levels are explored, it will be documented in 
writing and both the Sponsor and Investigators will approve the minutes 
of these meetings to confirm agreement.
In addition to these communications, the Sponsor and Investigators will be in regular 
contact throughout the study by email/telephone/fax, as per normal interactions during 
the conduct of a clinical study, and the Sponsor will arrange regular teleconferences and 
meetings to discuss study status.
The Sponsor will be available 24 hours a day to discuss any medical or study-related 
issues that may arise during the conduct of this study.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
4.2.1
Rationale for Study Population
This study will recruit male and female participants who have moderate to severe UC
according to standard criteria and based on guidelines from the health authorities. While 
it is anticipated that the PK and PD of RO7049665 in participants with UC will be similar 
to that in healthy volunteers, the strength of the PD effect may differ due to the baseline 
immune dysregulation present in participants with UC. Similarly, it is important to assess 
the safety of the immunomodulatory approach of RO7049665 in participants with 
baseline immune dysregulation that differs meaningfully from healthy volunteers. This 
population will enable collection of PD data at the site of the disease (i.e., colonic 
biopsies) and for preliminary efficacy evaluations to be made. Therefore, enrollment of 
participants with UC is necessary to enable the evaluation of RO7049665 as a potential 
treatment of moderate to severe UC.


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4.2.2
Rationale for Control Group 
RO7049665 will be compared against placebo-concurrent control, with participants 
randomized in a 4:1 ratio to receive multiple SC injections of RO7049665 or placebo, 
respectively. We will employ a blinded placebo arm in order to derive a preliminary 
assessment of the safety risk of RO7049665 in participants with UC and for equipoise in 
discriminating drug-relatedness of AEs. A placebo group will similarly inform the analysis 
of key biomarkers, including histopathologic changes in colonic biopsy samples and 
biomarkers used to establish PD effect. As we are studying participants with active 
disease it will be critical to distinguish disease-related complications from intervention 
associated safety signals, as well as study-drug related changes in leukocyte and 
cytokine biomarkers. RO7049665 is an investigational agent for the treatment of 
autoimmune diseases and not an established therapy, and both placebo and active 
participants will receive current standard of care background therapy, which mitigates 
the ethical concerns of a placebo group. 
4.2.3
Rationale for Biomarker Assessments 
Key objectives of the mandatory biomarker strategy are to confirm and further 
investigate the expected effect of drug on target cells (expansion of Tregs in number), to 
identify a safe dose at which target PD effect can be observed, as well as to confirm the 
magnitude and kinetics of this effect after multiple dosing and in the particular study 
population.
In addition to characterizing expected target PD effects, monitoring of biomarkers for 
unwanted events such as expansion of effector cells (T cells, NK cells, and Eosinophils) 
is an important objective. This could add valuable information towards an estimate of the 
therapeutic window of this novel drug MoA as changes in these markers may provide a 
means to predict the occurrence of safety events, also potentially informing stratification 
of patients. 
Additional objectives of the mandatory biomarker assessments are: (1) to investigate if 
systemic PD effects can be measured as surrogate markers for indicating tissue PD 
effects; (2) to identify which of the candidate systemic biomarkers shows highest 
correlation to tissue effects; (3) to determine if any tissue or systemic biomarkers can 
predict efficacy. 
Colon biopsies will be obtained to characterize immune cell infiltration and histologic 
appearance. Additional measurements which may be performed on colon biopsy derived 
material are whole transcriptome or targeted gene expression analyses. The objective of 
these measurements is to confirm expected changes in T cell subsets and to identify 
further mechanistic markers such as changes in inflammatory signatures or markers of 
tissue healing. Colon biopsies may furthermore be subjected to bacterial DNA or RNA 
analysis to determine the composition of the mucosa-associated microbiome in patients. 


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These data are of potential value for patient stratification purposes or for treatment 
monitoring.
Blood samples will be collected to quantify relative and absolute WBC counts (including 
B-cells, T-cells, NK-cells, and eosinophils). Furthermore, markers for quantification and 
characterization of Tregs and Teff subsets including, but not limited to, CD3, CD4, CD8, 
CD127, CD25, and FoxP3 will be determined. 
Serum and plasma samples will be collected to measure cytokines or other soluble 
biomarkers mechanistically linked to RO7049665’s mode of action. In addition, 
exploratory safety biomarkers may be measured in an ad-hoc fashion, (e.g., in 
participants experiencing symptoms associated with injection-related reactions).
Clinical blood genotyping data may be used to explore whether genotype may correlate 
with efficacy, influence the magnitude of PD effects or may impact the safety of 
RO7049665. 
Exploratory disease biomarkers in serum and stool samples will be tested for their ability 
to stratify participants and to evaluate their potential for non-invasive response to 
treatment monitoring.
Additional PD biomarkers and methods to obtain further confidence on the mechanism 
of action of RO7049665 in participants may be tested. Such assessments may include, 
but are not limited to, determining specific methylation signatures in blood or colon 
biopsies to quantify Treg or Teff subsets. The purpose of this assessment is to explore 
alternative T cell subset quantification methods and to understand their potential 
usefulness for replacing established methods with limited throughput and logistical 
challenges in later stages of clinical development.
4.3
DOSE JUSTIFICATION
The starting dose and dose justification are based on data from the EIH study (WP39826) 
in healthy volunteers. The therapeutic range of RO7049665 is unknown but is predicted 
to fall between a 2-fold and 10-fold expansion of baseline Treg cells (see RO7049665
Investigator’s Brochure). Average UC patient Treg counts are reported to lie within a 
range of 20 to 50 cells/L. Assuming literature derived values can be confirmed, the 
targeted expansion of Tregs up to an approximate maximum of 450 cells/L in this study 
is predicted to cover the efficacious Treg expansion range.
Data from WP39826 demonstrated 4-fold expansion of Treg cells in healthy volunteers 
after a single 5000 g dose of RO7049665 (mean peak Treg expansion to 155.2 cells/L) 
and a mean 5.8-fold expansion of Treg cells after a single 7500 g dose (with a mean 
peak of approximately 200 cells/L [range 123 – 297]). As the 2200 g single dose in 
the SAD study elicited a mean 2-fold increase in Treg cells, the starting dose of 3.5 mg 
(3500 g) in study WP40161 is expected to produce a measurable PK effect (specifically, 


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the expansion or Treg cells) however the overall expansion is projected to be at the low 
end of the hypothesized therapeutic target.
Single doses at these dose levels were safe and well tolerated in healthy volunteers with 
no SAEs and no DLAEs, with limited expansion of Teff and eosinophils and no observed 
effect on NK cells. The maximum Treg expansion was observed at Day 8 following the 
dose. In study WP40161, participants enrolled in dose level 1 cohorts will receive 3.5 mg 
of RO7049665 (or placebo) in multiple doses every 2 weeks, and the participants 
enrolled in cohorts of dose levels 2 and 3 will receive 7.5 mg and 15 mg respectively, of 
RO7049665 (or placebo) in multiple doses every 2 weeks. Two doses above 3500 g 
(3.5 mg) have been tested in single dosing in healthy volunteers in study WP39826 and 
were safe and well tolerated.
The averaged steady state exposure of RO7049665 following the top dose in this study 
is predicted not to exceed the NOAEL exposures in the monkey.
Assuming no effects of ADAs on PK or PD response, it is predicted that RO7049665 will 
result in an approximately 3-fold expansion in peak Treg count at the proposed starting 
dose of 3.5 mg Q2W. This starting dose regimen is predicted to have no effect on NK 
cells, and no to minimal effect on CD4+Teff (1.3 fold). Assuming the dose was not 
stopped due to dose stopping criteria, the dose could be escalated up to 15 mg Q2W for 
a more sustained Treg expansion, to exceed >2 fold expansion over the dosing interval 
(and achieve peak Treg at 3.7-fold). There will be monitoring of Teff cell counts and 
excessive IL-2 effects, as predictions indicate a trend for CD4Teff increase at the 15 mg 
dose (1.5 fold after the 4th dose).
Based on the safety results from the WP39826 study, and initial results from this 
current study, the proposed risk management and safety monitoring measures and the 
dose-escalation approach for this study, it is considered appropriate to study repeat 
dosing with RO7049665 up to a dose of 15 mg in participants with UC. Because safety 
and tolerability may be different between healthy volunteers and participants with UC, 
safety and tolerability will be reviewed on an individual basis and regular follow-ups are 
planned as detailed in the Schedule of Assessments.
Further details are provided in the RO7049665 Investigator’s Brochure.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the Schedule of 
Activities (Section 1.3).
The end of the study is defined as the date when the last participant last observation 
(LPLO) occurs. LPLO is expected to occur approximately 56 (3) days after last study 
drug administration.


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5.
STUDY POPULATION
This study will enroll up to 65 participants with UC between 18 and 70 years of age, 
inclusive, with evidence of moderate to severely active disease (MCS 5, MCS-ES 2, 
stool frequency subscore 1, and rectal bleeding subscore 1), who have failed at least 
one prior standard of care therapy. 
The study population rationale is provided in Section 4.2.1.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are only eligible to be included in the study if all of the following criteria 
apply:
Informed Consent
1. Able and willing to provide written informed consent and to comply with the study 
protocol according to International Conference on Harmonisation (ICH) and local 
regulations. Informed consent may be obtained up to 3 months prior to 
randomization. A signed Informed Consent Form must be available from the 
participant before starting and study-specific assessments.
Age
2. Between 18 to 70 years of age inclusive, at the time of signing the informed consent.
Type of Participants and Disease Characteristics
3. Diagnosed with UC for at least 12 weeks prior to screening
4. Screening colonoscopy for colorectal cancer conducted within the prior two years if:

History of pancolitis and disease duration 8 years, or

History of left-sided colitis and disease duration 12 years.
5. Evidence of disease activity at time of screening as measured by MCS 5, with 
MCS-ES 2, extending at least 10 cm from the anal verge, stool frequency subscore 
1and rectal bleeding subscore 1.
6. Insufficient clinical response to standard of care (SOC) therapy or intolerance to 
SOC, where SOC may include (but not limited to):

Glucocorticoids (Prednisolone at least 0.75 mg/kg/day or equivalent for at least 
4 weeks).


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
Treatment with JAK inhibitors of at least 8 weeks duration.

Immunomodulators (e.g., azathioprine, methotrexate, oral 5-aminosalicylate 
[5-ASA] or 6-mercaptopurine) at a standard therapeutic dose for at least 
12 weeks. 

Therapy with an anti-TNFmonoclonal antibody of at least 3 months duration, 
or intolerance due to side effects of medication (not including anaphylaxis).

Treatment with anti-integrin therapy of at least 14 weeks duration.
Weight
7. Body mass index (BMI) within the range of 18-35 kg/m2 (inclusive).
Sex
8. Male and/or female participants
The contraception and abstinence requirements are intended to prevent exposure of 
an embryo to the study treatment. The reliability of sexual abstinence for male 
and/or female enrollment eligibility needs to be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the participant. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
Female participants:
Compliance with contraception requirements:

Women of non-child bearing potential (WONCBP) may be enrolled. A woman is 
considered to be of childbearing potential if she is postmenarchal, has not 
reached a post-menopausal 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).
For women of childbearing potential (WOCBP), as defined in Appendix 5:

May enroll if not pregnant and not breastfeeding.

Agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of < 1% per year during the 
treatment period and for at least 56 days after the last dose of study drug.
Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal occlusion/ligation, male sterilization, proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices (see Appendix 5).

Have a negative pregnancy test (blood) within the 35 days prior to the first 
study RO7049665/placebo administration.


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For men: 
During the treatment period and for at least 56 days after the last dose of 
RO7049665 or placebo, agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures such as a condom plus an additional contraceptive method that 
together result in a failure rate of 1% per year, with partners who are women 
of childbearing potential (WOCBP, as defined in Section 1 of Appendix 5).
With pregnant female partners, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo.

Refrain from donating sperm for 56 days after the last dose of RO7049665 or 
placebo.
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Diagnosis of Crohn’s disease or indeterminate colitis.
2. History of infection with hepatitis B, human immunodeficiency virus (HIV), active 
hepatitis C virus (HCV) infection, or other chronic infection.
3.
Active infections requiring systemic therapy with antibiotic, antiviral or antifungal or 
febrile illness within 7 days before Day -1.
4.
History of primary or acquired immunodeficiency.
5.
History of chronic pulmonary disease with resultant abnormal pulmonary function.
6.
History of clinically significant cardiac or cardiovascular disease or uncontrolled 
hypertension.
7.
Evidence of infection with Clostridium difficile or other intestinal pathogen within 
35 days from the start of screening.
8.
Evidence of colonic dysplasia that cannot be completely removed.
9.
Females: Pregnant or lactating.
10. History of and/or current suicidal ideations 


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11. Any condition or disease detected during the medical interview/physical examination 
that would render the patient unsuitable for the study, place the patient at undue risk 
or interfere with the ability of the patient to complete the study in the opinion of the 
investigator, including malignant disease.
12. Symptomatic herpes zoster within 3 months prior to screening.
13. History of tuberculosis or a positive QuantiferonGold test.
14. History of clinically significant severe drug allergies, multiple drug allergies, allergy to 
any constituent of the product, or intolerance to topical corticosteroids.
15. Lymphoma, leukemia, or any malignancy within the past 10 years, except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years and in situ carcinoma of the cervix that 
was completely removed surgically.
16. History or presence of clinically significant ECG abnormalities before study drug 
administration (e.g., PQ/PR interval 220 ms, QT corrected for heart rate using 
Fridericia’s correction factor (QTcF), 350 or 450 ms) or clinically significant 
cardiovascular disease (e.g., cardiac insufficiency, coronary artery disease, 
cardiomyopathy, congestive heart failure, family history of congenital long QT 
interval syndrome, family history of sudden death).
17. Fecal Microbiota Transplant (FMT), defined as receipt of any product derived from 
the feces of another human and administered per oral, per nasogastric or 
nasoduodenal, or per rectum within the last 6 months. 
Prior/Concomitant Therapy
18. Use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine), vedolizumab, anti-TNF
therapeutic or any other immune systemtargeted biological therapy within 
12 weeks or 5 half-lives, whichever is longer, prior to screening.
19. Rectal therapy with 5-ASA or corticosteroids within 2 weeks of screening.
20. Use of any investigational drug within 12 weeks of screening.
21. Leukocyte apheresis within 12 weeks of screening.
22. Live vaccine(s) within one month prior to screening, or plans to receive live vaccines 
during the study or within 28 days of the last dose.


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Prior/Concurrent Clinical Study Experience
23. Donation of blood or blood products in excess of 500 mL within 3 months.
24. Exposure to more than 4 investigational treatments within 12 months prior to Day 1.
25. Current enrollment or past participation within the last 90 days immediately 
preceding signing of informed consent in this or any other clinical study involving an 
investigational study treatment or any other type of interventional medical research.
Diagnostic Assessments
26. Abnormal hematologic values:

Anemia (Hgb 9 g/dL)

Leukocytosis (WBC 2ULN)

Thrombocytopenia (platelet count 100,000/L)

Thrombocytosis (platelet count 2 ULN)

Eosinophilia (eosinophil count 2 ULN)
27. Abnormal hepatic enzyme or hepatic function values:

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase, or gamma-glutamyl transferase (GGT) 2 ULN

Total bilirubin2 ULN

International normalized ratio (INR)1.2

Albumin3 g/dL
28. Positive HIV antibody test.
29. Presence of hepatitis B surface antigen (HBsAg) or positive for total hepatitis B 
core antibody (HBcAb), or positive hepatitis C by PCR test result at screening or 
within the 3 months prior to starting study treatment. 
Other Exclusions
30. History of regular alcohol consumption within 2 months of screening defined as:
An average weekly intake of 14 drinks for males or 7 drinks for females. One 
drink is equivalent to 12g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) 
of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
31. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of 
drug of abuse.


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32. Patients under judicial supervision, guardianship or curatorship.
5.3
LIFESTYLE CONSIDERATIONS 
5.3.1
Meals and Dietary Restrictions
During the period from screening to the follow-up visit when participants are not resident 
in the unit, participants will be advised about the following requirements:

Coffee or tea consumption should be no more than 3 cups/day, and methylxanthine 
containing drinks must be 1 L/day.

Alcohol consumption should be no more than 2 drinks/day.
One drink is equivalent to 12g of alcohol: 12 ounces (360 mL) of beer, 5 ounces 
(150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
5.3.2
Caffeine, Alcohol, and Tobacco
Caffeine and tobacco should be avoided during the residential period.
Consumption of alcohol will not be allowed from 48 hours before dosing until the end of 
the residential period.
5.3.3
Activity
Light ambulatory activities will be permitted, with the level of activities kept as similar as 
possible on all days in the clinical research unit during the study. Participants are
required to refrain from intense physical activity from 96 hours before screening visit until 
the final follow-up visit.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized to study treatment/entered in the study.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be re-screened. Re-screened participants should be assigned the same participant 
number as for the initial screening. 
For re-screened participants, the following specific criteria must be met:

Screening colonoscopy or flexible sigmoidoscopy for inclusion must be completed 
within 3 weeks prior to first dose.

Serologies for hepatitis B, HIV, and PCR for HCV need not be repeated, and 
screening for latent tuberculosis infection need not be repeated if already done. 

Women of child bearing potential must repeat pregnancy testing.


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
Screening laboratory evaluation beyond those itemized above must be completed 
within 35 days of the starting dose. 

For participants who were initially excluded due to active Clostridium difficile-related 
infection, participants must have completed therapy and have been stable off 
therapy for at least 7 days prior to repeat Clostridium difficile testing for Test of Cure 
(TOC). Those who test negative may be eligible for re-enrollment.
5.5
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, clinical database and Independent Ethics Committees (IEC)/Institutional Review 
Board (IRB) approved newspaper/radio/social-media advertisements prior to consenting 
to take place on this study.
6.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.
The investigational medicinal product (IMP) required for completion of this study will be 
provided by the Sponsor. Study drug will be administered by the investigational staff (i.e., 
Investigator or study nurse) at the study center under supervision of the Investigator.


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6.1
TREATMENTS ADMINISTERED
Table 5 summarizes the treatments administered.
Table 5
Summary of Treatments Administered
Study Treatment 
Name:
RO7049665
Placebo
Dosage Formulation:
Solution for injection
Solution for injection
Unit Dose Strength:
5.0 mg/mL
N/A
Dose:
Starting dose 
3.5 mg (dose level 1), 7.5 mg
(dose level 2), and 15 mg (dose 
level 3)
N/A
Route of 
Administration:
SC injection
SC injection
Dosing Instructions:
RO7049665 must be prepared 
for dosing under appropriate 
aseptic conditions and should be 
used immediately. The solution 
for injection must be filtered prior 
to use
Placebo must be prepared for 
dosing under appropriate 
aseptic conditions and should 
be used immediately. The
solution for injection must be 
filtered prior to use
Packaging and 
Labeling:
RO7049665 and Placebo will be provided in 2 mL colorless glass 
vials. Each vial will be labeled as required per country requirement.
Storage Conditions
For RO7049665 and Placebo, if not used immediately, the total 
storage time of the dose solution prior to administration should not 
exceed 24 hours to limit the risk of microbial growth in case of 
accidental contamination. The recommended storage condition for 
the dose solution is 2C to 8C, but dose solutions may be stored at 
room temperature for up to a maximum of 4 hours
Manufacturer
F. Hoffmann-La Roche, Ltd.
F. Hoffmann-La Roche, Ltd.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the RO7049665 Investigator’s Brochure and Pharmacy Manuals for more 
details. 
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.


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The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
Upon arrival of the IMPs at the site, site personnel will complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization/treatment assignment schedule and 
Pharmacy Manual.
The Investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments 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 site staff.
The Investigator, Institution, or the Head of the Medical Institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation and final disposition records).
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual or other specified location.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment 
All participants will be centrally assigned to randomized study treatment using an 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the 


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telephone number and call-in directions for the IVRS and/or the log in information and 
directions for the IWRS will be provided to each site. 
Participants will be randomly assigned in a 4:1 ratio to receive multiple SC injections of 
RO7049665 or placebo, respectively. The randomization numbers will be generated by 
the Sponsor or its designee. The randomization list will be made available to the 
individual responsible for PK/PD sample bioanalysis, and to statisticians or programmers 
at Roche. PK/PD data can be received and cleaned on an ongoing basis. The data will 
be handled and cleaned in a secure area which is not accessible by any blinded SMT 
member.
Please refer to the Cohort Management and Dose Escalation Document for details
regarding assignment of participants to treatment groups and cohorts. 
6.3.2
Blinding
This study is double-blinded. For this study it means that the participant, the 
Investigator(s), and all individuals in direct contact with the participant at the investigative 
site will be blinded. Members of the Sponsor’s project and study teams who do not have 
direct contact with the participant may be unblinded.
To allow informed recommendations or decisions regarding the dose-selection in this 
study, an integrated assessment of the safety, tolerability and available PK and/or PD 
will be made prior to each dose-decision.
If required, unblinded data (individual as well as at group level) may also be presented to 
the Drug Safety Committee or IMC or other experts of the Sponsor and at group level to 
the PI. 
The IVRS/IWRS will be programmed with blind-breaking instructions. The blind may be 
broken if, in the opinion of the Investigator, it is in the participant’s best interest to know 
the study treatment assignment. The Sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which 
the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition (e.g., antidote available). In this case, the 
Sponsor must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and case report 
form (CRF), as applicable. 
6.4
TREATMENT COMPLIANCE
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule. This individual will write the date 
dispensed and participant number on the study treatment vial label and on the Drug 
Accountability Record. This individual will also record the study treatment number 
received by each participant during the study.


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6.5
CONCOMITANT THERAPY
6.5.1
Permitted Therapy
Any medication (including over-the-counter [OTC] or prescription medicines, approved 
dietary and herbal supplements, nutritional supplements) used by a participant from 
30 days prior to screening until the follow-up visit must be recorded along with reason 
for use, dates of administration (including start and end dates) and dosage information 
(including dose and frequency).
The same information must be recorded for the following concomitant medications taken 
by a participant during the indicated period prior to screening until the follow-up visit:

Immunomodulators used 12 weeks prior to screening 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications electronic Case Report Form (eCRF).
All therapy and/or medication administered to manage AEs should be recorded on the 
Adverse Event eCRF.
Use of the following therapies will be permitted as specified below:

Paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours prior to 
each RO7049665 or placebo dosing, not to exceed 4 g total during the week prior to 
each dosing. All concomitant medications throughout the duration of the study 
should be recorded in the case report form.

In the event of a systemic IRR or systemic hypersensitivity AE, pre-medicate with 
paracetamol and antihistamines (as per local guidelines) prior to the next 
administration of study drug (Section 8.3.8). 

Participants who use the following therapies prior to screening and are on a stable 
regimen should continue their use: 
–
Oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy.

Participants who are taking non-biological SOC therapy for UC during the study will 
remain on their SOC therapy. Specific instructions for each SOC is provided below:
–
Stable therapy for at least 2 weeks prior to screening with: 
o
oral 5-ASA, or
o
oral glucocorticoid (not to exceed 20 mg/day of prednisone equivalent) at 
start of trial, may be weaned after dosing with study drug has been 
initiated).
–
Stable therapy for at least 8 weeks with 


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o
azathioprine, or
o
6-MP, or 
o
methotrexate (and folic acid).
6.5.2
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF.
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs and those specified (Section 6.5.1), unless the rationale for 
exception is discussed and clearly documented between the Investigator and the 
Sponsor.
Use of the following therapies will be prohibited during the study and for at least 14 days 
or at least 5 half-lives prior to initiation of study treatment, whichever is longer unless 
otherwise specified below:

Unless covered by the exceptions described in Section 6.5.1:
–
Any rectal therapy.
–
Doses of glucocorticoids exceeding 20 mg/day of prednisone or equivalent
– Non-steroidal anti-inflammatory medications (e.g., ibuprofen, naproxen) due to a 
propensity for these treatments to worsen inflammation in ulcerative colitis.

Calcineurin inhibitors (e.g., tacrolimus, cyclosporine) and any other immune system 
targeted biological therapy 12 weeks or 5 half-lives, whichever is longer, before the 
start of screening.
6.6
DOSAGE MODIFICATION
No dosage modification is permitted for any participant in the study.
Study drug may be temporarily halted and restarted, as described in Section 7.1 and 
Section 7.1.1.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7049665 to participants after conclusion of 
the study or any earlier participant withdrawal.
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT, AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study specific procedures as outlined in this 
protocol.


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Details on study and site closures are provided in Section 4, Appendix 1.
7.1
DISCONTINUATION OF STUDY TREATMENT
Dosing will be stopped in a given individual as described in Section 4.1.4. 
Participants who discontinue study treatment prematurely will be asked to return to the 
clinic for a study completion/early termination visit (see Section 8.10.3) and may undergo 
follow‑up assessments (see Section 8.10.4). See the SoA (Section 1.3) for data to be 
collected at the time of treatment discontinuation and follow-up and for any further 
evaluations that need to be completed.
The primary reason for premature study treatment discontinuation should be 
documented on the appropriate eCRF. 
Reasons for discontinuation of study treatment (or withdrawal from the study) include, 
but are not limited to, the following:

Participant withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study.

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant.

Pregnancy.
7.1.1
Temporary Interruption
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator or Sponsor), an interruption should be considered. 
Participants who have temporarily interrupted study treatment should be considered to 
restart as soon as medically justified in the opinion of the Investigator after discussion 
with Sponsor and would revert to the protocol-specified SoA (see Section 1.3) as soon as
dosing of study treatment is reinitiated.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants 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 participant from the study for 
medical conditions that the Investigator or Sponsor determines may jeopardize the 
participant’s safety if he/she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.


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When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will remain as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of specimens 
donated to the Research Biosample Repository (see Section 8.8.2).
Participants who withdraw from the study for safety reasons will not be replaced. 
Participants who withdraw from the study for other reasons may be replaced.
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and at 
safety and follow-up visits, and for any further evaluations that need to be completed.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Details regarding the discontinuation of sites or of the study as a whole are outlined in 
Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the Schedules of Activities 
(SoA; Section 1.3). Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Form (ICF) may 


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be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and were performed within the time-frame defined in the SoA.
Samples for laboratory tests will be sent to one or several central laboratories or to the 
Sponsor for analysis. Instruction manuals and supply kits will be provided for all central 
laboratory assessments.
Based on continuous analysis of the data in this study, any assessment, sample type or 
biomarker evaluation not considered to be critical for safety may be stopped at any time 
if the data from the assessments or samples collected does not produce useful 
information.
8.1
EFFICACY ASSESSMENTS
Flexible sigmoidoscopy (or colonoscopy at screening if required by inclusion criteria) will 
be performed at the time-points specified in the SoA (see Section 1.3). The endoscopy 
will be centrally read and scored using the MCS-ES and UCEIS scoring systems. The 
Endoscopy subscore of the Mayo Score will be modified so that a value of 1 does not 
include friability. Sedation and preparation for colonoscopy or flexible sigmoidoscopy 
may follow local standards. 
Mucosal biopsies will be obtained during flexible sigmoidoscopy at the most affected 
area 10 to 20 cm from the anal verge at screening/baseline and at Day 29 (Week 4) and 
Day 57 (Week 8) assessments. Biopsies will be assessed by standard histology for 
changes in inflammatory activity as measured by the Geboes Score (Geboes et al. 
2000), Robarts Histology Index (Mosli et al. 2017) and the Nancy Histology Index 
(Marchal-Bressenot et al. 2017).
Additional details will be provided in the Procedural Manual.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological, 
musculoskeletal in addition to head, eyes, ears, nose, throat, neck and lymph nodes 
systems. Height and weight will also be measured and recorded. Further examination of 
other body systems may be performed in case of evocative symptoms at the 
Investigator’s discretion.
The BMI will be calculated at Screening only. Height will be recorded at Screening only 
and body weight will be recorded at Screening, at all subsequent physical examinations 
and as clinically indicated.


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Skinfold thickness at the intended site of injection of the abdomen, and outside the five 
centimeter area directly around the navel, will be measured once on Day –1, using a 
skinfold caliper. The result will be reported in the eCRF.
A brief physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological and neurological systems, 
and measurement of body weight. 
A complete or abbreviated physical examination will be performed at the time-points 
specified in the SoA (Section 1.3) by trained medical personnel at the study center.
Attention should be paid to signs and symptoms suggestive of type 3 hypersensitivity 
reactions.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
As clinically indicated, limited, symptom-directed physical examinations should be 
performed. Changes from baseline abnormalities should be recorded in participant’s 
notes. New or worsened clinically significant abnormalities should be recorded as AEs 
on the Adverse Event eCRF.
8.2.2
Vital Signs
Blood pressure (BP), pulse rate, body temperature (tympanic or oral) and respiratory 
rate will be assessed at the time-points specified in the SoA (Section 1.3).
Blood pressure and pulse measurements will be assessed in a supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. When possible, the same arm should be used for all blood 
pressure measurements.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones).
Single measurements of vital signs (to be taken before blood collection for laboratory 
tests but after ECG collection when scheduled at the same time-point) will be performed 
in a supine position after 5 minutes rest and will include body temperature (tympanic), 
systolic and diastolic blood pressure, pulse rate and respiratory rate.
The timings of assessments may be amended or the number of assessments increased 
during study conduct on the basis of emerging data in order to allow for optimal 
characterization of the effect profile.


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8.2.3
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine. Measurements of PR, QRS complex (QRS), QT, and QTc intervals may 
be performed by the instrument or calculated using an external tool. Refer to 
Section 4.1.3 for QTc withdrawal criteria and additional QTc readings that may be 
necessary.
At each time-point at which triplicate ECGs are required, three individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 5 minutes 
apart. The full set of triplicates should be completed in less than 10 minutes.
To minimize variability, it is important that participants be in a resting position for 
10 minutes prior to each ECG evaluation. Body position should be consistently 
maintained for each ECG evaluation to prevent changes in heart rate. Environmental 
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG 
resting period and during ECG recording. ECGs should be performed prior to any 
scheduled vital sign measurements and blood draws. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. 
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory.
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcF (Fridericia’s correction) and RR will be calculated and 
recorded on the eCRF. Changes in T‑wave and U‑wave morphology and overall ECG 
interpretation will be documented on the eCRF. T-wave information will be captured as 
normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
8.2.4
Clinical Safety Laboratory Assessments
Planned time-points for all safety assessments are provided in the SoA (see Section 1.3).
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. A list of clinical laboratory tests to be performed is provided in 
Appendix 4 and these assessments must be conducted in accordance with the separate 
laboratory manual and the SoA (see Section 1.3). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 


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disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified.
If laboratory values from non-protocol specified laboratory assessments performed at the 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (e.g., SAE or AE or dose-modification) then, the results 
must be recorded in the CRF.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety.
Where the clinical significance of abnormal lab results is considered uncertain, screening 
lab tests may be repeated before randomization to confirm eligibility.
If there is an alternative explanation for a positive urine or blood test for drugs of abuse, 
e.g., previous occasional intake of a medication or food containing for example, codeine, 
benzodiazepines or opiates, the test could be repeated to confirm washout. 
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
8.2.5
Safety Biomarker Assessments
Quantitative changes in Treg, Teff, NK cells, and eosinophils will be evaluated as
exploratory safety biomarkers. Cytokines IL-6, IL-8, TNF-or IL‑1may be measured 
as exploratory safety biomarkers ad hoc in participants experiencing symptoms 
associated with injection‑related reactions. These assessments are described in 
Sections 8.6 and 8.8. 
IgE, tryptase, safety cytokines, and further exploratory safety biomarkers may be tested 
in case of participants experiencing signs and symptoms associated with IRRs. This 
includes hypersensitivity reactions.


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8.2.6
Immunogenicity Assessments 
Blood samples for ADA will be taken as described in the SoA (Section 1.3). The date 
and time of each sample will be recorded in the eCRF. Additional samples will be taken 
in participants with clinical signs of hypersensitivity reaction for ADA evaluation (see SoA 
Section 1.3). In each case, for each collected ADA sample, a corresponding PK sample 
will be collected at the same time-point for the determination of the RO7049665 
concentration (See Section 8.5). Additional ADA sampling may be required after the 
safety and follow-up visit (Day 99) for participants who are ADA positive at the Day 99 
visit. In this instance no corresponding PK sample is needed, however a sCD25 sample 
should be taken.
Validated ADA assays will be employed to detect ADAs against RO7049665. Samples 
which are positive for ADA will be further characterized and their neutralizing capability 
for recombinant IL-2 will be assessed using the neutralizing antibody (Nab) assay.
If required, remaining ADA samples may also be used for assay development/validation 
experiments. For exploratory purposes such as epitope characterization or 
IgG-IgM-isotyping, samples may be analyzed by assays which are not fully validated.
Such samples will be kept for up to 6 months after the finalization of the bioanalytical 
report.
Samples from placebo‑treated participants may not be analyzed in the first instance, but 
retained for subsequent analysis if appropriate.
Details on sampling procedures, sample storage and shipment are documented in the 
sample handling manual.
8.2.7
Local Pain and Skin Reactivity Assessments
Local pain and injection site reactions (ISRs; e.g., burning, bleeding, itching, bruising, 
redness, hive formation, or other) will be assessed at the time-points indicated in the 
SoA (Section 1.3, Appendix 6). Photographs of skin may be taken on an ad hoc basis 
but are not required per protocol. 
8.2.8
Clinical Outcome Assessment
Monitoring for signs and symptoms of worsening ulcerative colitis (e.g., rectal bleeding, 
stool frequency, abdominal pain, fever) will take place at every clinic visit. Elevation of 
the partial Mayo score (physician’s global assessment, rectal bleeding, and stool 
frequency) by more than 2 points from baseline over two consecutive visits (scheduled 
or unscheduled) will meet disease exacerbation criteria. If disease worsening criteria 
meet individual stopping criteria (see Section 4.1.4) then participants will be treated as 
judged appropriate by their treating physician. 


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8.2.9
Medical History and Demographic Data
Medical history includes clinically significant diseases and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the participant within 14 days prior to the screening visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious AEs of 
special interest and disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs are discussed in Sections 8.3.6 and 8.3.7.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity and causality; see Appendix 2) are 
recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3:

Diagnosis versus signs and symptoms:
–
Injection reactions 
–
Other AEs

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values

Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Lack of efficacy or worsening of the condition being studied

Hospitalization or prolonged hospitalization

Patient-reported outcome data  
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.


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Investigators will seek information on adverse events at each participant’s contact. All 
AEs, whether reported by the participant or noted by study personnel, will be recorded in 
the participant’s medical record and on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other adverse event should not be 
reported.
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the Day 99 safety and follow-up visit, or, 28 days 
after the last dose of study treatment in case of early termination.
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for AEs after the final follow-up visit.
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator 
considers the event to be reasonably related to the study treatment or study participation, 
the Investigator must promptly notify the Sponsor. For the procedure of reporting, see 
Appendix 2.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all participant evaluation time-points.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
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 event is 
otherwise explained, the participant is lost to follow-up (Section 7.3), or the participant 
withdraws consent. Every effort should be made to follow all SAEs considered to be 
related to study treatment or trial-related procedures until a final outcome can be 
reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 


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verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/ IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, investigators, IRB and EC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical monitors is available 
24 hours a day 7 days a week. Details will be available on a separately.
8.3.5
Pregnancy
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 56 days after the last 
dose of study treatment.


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Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 56 days after 
the last dose of study drug.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest 
Non-serious 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 Appendix 2 for reporting instructions).
Non-serious adverse events of special interest for this study include the following:

NCI CTCAE (v5.0) G2 hypersensitivity reaction/ IRR. 

Cases of an elevated alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) in combination with either an elevated bilirubin or clinical jaundice, as defined 
in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, 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 treatment is suspected.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Not applicable for the participants in this study. 
8.3.8
Management of Specific Adverse Events
Treatment of AEs will be considered on a case-by-case basis according to local 
standard of care.
For participants who report AEs of systemic IRRs or systemic hypersensitivities, 
following the first occurrence of an event, pre-medicate with paracetamol and 
antihistamine (as per local guidelines) prior to next administration of study treatment. 
At the reporting of an AE of systemic IRR or hypersensitivity, the Sponsor must be 
contacted.


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If a subsequent systemic IRR or hypersensitivity AE occurs, stop dosing in this 
participant (see Section 4.1.4). 
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental administration of a drug in a quantity that is 
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Sections 5 and 
5.2 of Appendix 2 for further details). 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
In the event of a dose administration error, the Investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Obtain a blood sample for PK analysis as soon as possible from the time of the last 
dose of study treatment, if requested by the Medical Monitor (determined on a 
case-by-case basis).
4.
If known, document the variance from planned dose administration, in the CRF.
8.5
PHARMACOKINETICS
Blood samples will be collected to determine serum concentration of RO7049665. 
Samples will be collected at the timepoints specified in the Schedules of Activities 
(Section 1.3) and at any time point when an ADA sample is taken (Section 8.2.6).
The date and time of each sample collection will be recorded in the eCRF. Serum 
RO7049665 concentrations will be measured using validated specific enzyme-linked 
immunosorbent assay (ELISA). If deemed appropriate, samples may also be assayed 
with non-validated exploratory methods.
During the course of the study, PK sampling time-points may be modified and/or up to 
3 additional PK samples may be collected per participant on the basis of emerging data 
in order to allow for optimal characterization of the PK profile of RO7049665, after 
agreement with the Sponsor’s clinical pharmacologist and the investigator. 
Additional PK samples will be taken at the time of treatment discontinuation, at time of 
ADA sample collection if additional ADA samples are collected, and if the participant 
experiences an infusion-related AE (such as an injection-related reaction [IRR]).


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Samples collected from placebo-treated participants will not be analyzed in the first 
instance, but retained for subsequent analysis if appropriate.
Any volume of blood samples remaining after the specified analyses may also be used 
for additional assay development or study or compound-specific validation experiments 
(e.g., for PK Parallelism Assessment and ADAs).
Samples will be destroyed within 2 years after the date of final clinical study report 
(CSR). 
Details on sampling procedures, sample storage and shipment are given in the Sample 
Handling Manual.
8.6
PHARMACODYNAMICS
Samples will be collected for PD assessments at the time points specified in the SOA
(Section 1.3). The date and time of each sample will be recorded in the eCRF.
Blood samples
Blood samples will be collected for the following assessments: 

To quantify relative and absolute WBC counts (T cells, B cells, NK cells, and 
eosinophils) by flow cytometry as well as complete white blood count differential. 
Tests include (but are not limited to) markers for quantification and characterization 
of Tregs and Teff cell subsets CD3, CD4, CD8, CD25, CD127 and FoxP3. 

Additional blood samples will be collected for potential evaluation of T cell subset 
specific methylation signature changes induced by drug. Decision to perform this 
exploratory assessment involving deoxyribonucleic acid (DNA) extraction will be 
made based on emerging PD data. 
Tissue samples
Tissue colon biopsy samples will be collected for the following assessments: 

To characterize infiltrating WBCs by histology (hematoxylin and eosin staining) and 
immunohistochemistry (IHC). IHC markers tested may include but are not limited to 
CD3, CD4 and FoxP3. 

RNA extraction on tissue colon biopsy samples may be performed in order to 
undertake optional whole or targeted transcriptome gene expression analysis. 

Bacterial DNA or RNA may be extracted for subsequent mucosa-associated 
metagenomic analysis.

Methylation signature changes induced by drug indicative of quantitative and 
specific changes of T cell subsets may be assessed. The decision to perform this 
exploratory assessment involving DNA extraction will be made based on emerging 
PD data. 


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Serum and plasma samples
Serum and plasma samples will be collected for the following assessments:

To measure cytokines or cytokine receptors mechanistically linked with the drug’s 
mode of action. Soluble biomarkers considered for testing include, but are not 
limited to, IL-5, IL-6, IL-8, IL-10 and sCD25.The final panel of soluble biomarkers will 
be informed by the outcome of the EIH study (WP39826) and the analysis of the 
resulting biomarker data, as well as by emerging data obtained in study WP40161.

Cytokines IL-6, IL-8, TNF-or IL‑1b may in addition be measured as exploratory 
safety biomarkers ad hoc in participants experiencing symptoms associated with 
injection‑related reactions.

Exploratory disease biomarkers with potential for patient stratification or 
non-invasive response to treatment may be tested including, but not limited to 
perinuclear anti-neutrophil cytoplasmic antibody (pANCA) and Leucine-rich 
Alpha-2 Glycoprotein (LRG)

Additional soluble biomarkers to obtain further confidence on mechanism of action 
of RO7049665 in humans, PD or disease markers may be tested. 
Stool samples 
Stool samples will be collected to evaluate exploratory disease biomarkers with potential 
for patient stratification or non-invasive response to treatment monitoring including but 
not limited to faecal Calprotectin.
Leftover biological samples. 
Any remaining stool, serum, plasma, blood or colon biopsy sample after the specified 
analyses may also be used for additional method, study or compound specific (assay) 
validation experiments or biomarker measurements. The stool, serum, plasma samples, 
and tissue colon biopsy samples will be destroyed within 5 years after the date of final 
CSR. For participants who consent to RBR, leftover samples will be transferred to RBR 
(see Section 8.8.2.1).
8.7
GENETICS
8.7.1
Clinical Genotyping
A mandatory whole blood sample will be taken for DNA extraction from every participant
in all countries where this assessment is permitted (See SoA Section 1.3). The DNA 
may be used for, but analysis is not limited to:

Genotyping of alleles in genes encoding proteins involved in IL 2-mediated signal 
transduction 

Genotyping of alleles in genes, for which genetic polymorphisms have been 
previously associated with autoimmune diseases.


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Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to the confidentiality standards described in Section 1.4 of Appendix 1.
Any remaining blood sample after the specified analyses may also be used for additional 
method, study or compound (assay) validation experiments. 
The DNA or blood samples will be destroyed within 5 years after the date of final CSR.  
For participants who consent to RBR, leftover blood and DNA samples will be 
transferred to RBR (see Section 8.8.2.1).
Details on processes for collection and shipment of these samples can be found in 
Sample Handling Manual.
8.8
BIOMARKERS
Samples will be collected for biomarker assessments at the time points specified in the 
Schedules of Activities (Section 1.3). Biomarkers will be evaluated as described in 
Sections 8.6, and 8.7.
8.8.1
Exploratory Disease Biomarkers
Exploratory disease biomarkers will be tested for their ability to stratify participants or to 
evaluate their potential for non-invasive response to treatment monitoring. Markers to be 
tested may include, but are not limited to perinuclear anti-neutrophil cytoplasmic 
antibody (pANCA), LRG, and faecal Calprotectin.
8.8.2
Samples for Research Biosample Repository
8.8.2.1
Overview of the Research Biosample Repository
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage and analysis of these specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for participants in the future.
For participants who consent to RBR, leftover samples will be transferred to RBR. 
Leftover specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, AEs, or progressive disease.

To increase knowledge and understanding of disease biology.

To study treatment 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.


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
To enable further exploratory biomarker research.
8.8.2.2
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 study treatment, target 
and/or disease:

Leftover plasma samples

Leftover serum samples

Leftover colon biopsy (and any derivatives) samples

Leftover blood samples for DNA extraction

Leftover extracted RNA and DNA samples

Leftover stool samples
The samples collected for DNA extraction include, but are not limited to, genomic 
analysis and 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 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.
Samples may be sent to one or more laboratories for analysis for WGS and other 
genomic analyses and associated clinical data may be shared with researchers who are 
not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participant will not be identified by 
name or any other personally identifying information. WGS data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies 
to increase researcher's understanding of disease pathobiology and guide the 
development of new therapeutic approaches. Given the complexity and exploratory 
nature of these analyses, WGS data and analyses will not be shared with investigators 
or study participants unless required by law.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate Laboratory Manual.
RBR specimens will be stored and used until no longer needed or until they are 
exhausted. The Research Biosample Repository storage period will be in accordance 


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with the IRB/EC‑approved Informed Consent Form and applicable laws (e.g., health 
authority requirements).
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1).
8.9
HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed consent may be 
obtained up to 3 months prior to randomization. Screening start will be defined as the 
first assessment done after signature of the informed consent form. Informed Consent 
Forms (ICFs) for enrolled participant and for participants who are not subsequently 
enrolled will be maintained at the study site.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed within 35 days prior to 
Day 1 unless otherwise specified.
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the schedule of activities. 
COA assessments (Section 8.2.7) should be performed prior to the completion of other 
study assessments.


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8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study (defined in Section 4.4) will be asked to return to 
the clinic 56 days after the last dose of study drug for a follow‑up visit.
Participants who discontinue from the study early will be asked to return to the clinic 
28 days after the last dose of study drug for a follow‑up visit.
8.10.4
Follow-Up Assessments
After the study completion/early termination visit, AEs should be followed as outlined in 
the SoA (Section 1.3) and in Sections 8.3.1 and 8.3.3.
Participants positive for ADAs at the study completion/early termination visit will be 
asked to return for further ADA assessments. 
8.10.5
Assessments at Unscheduled Visits 
Please see Section 1.3 for activities that are required to be performed in case of an 
unscheduled visit.
9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
Not applicable.
9.2
SAMPLE SIZE DETERMINATION
The study will enroll up to 65 participants to assess the safety and tolerability of 
repeated dosing of RO7049665 (approximately 10 participants, randomized in the ratio 
of 4:1 RO7049665 to placebo, per cohort).
The sample size for this study was selected on the basis of clinical judgment and 
practicality. It was not determined on the basis of power against a formal statistical 
hypothesis. However, with a full cohort of 8 participants treated at a given dose level, 
there is an 83% chance to observe at least one AE that has a true incidence rate of 20% 
at that dose level in the population. After 4 participants have been treated at a given 
dose level, there is a 59% chance of observing such an AE.


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9.2.1
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 6.
Table 6
Analysis Populations
Population
Description
Intent-to-treat (ITT)
All randomized participants will be included in the 
intent-to-treat population.
Per-protocol (PP)
All randomized participants that received the expected number 
of doses will be included in the per-protocol population.
Safety
All participants randomized to study treatment and who 
received at least one dose of the study treatment, whether 
prematurely withdrawn from the study or not, will be included 
in the safety analysis. 
Pharmacokinetic
Participants who have received active treatment will be 
included in the PK analysis population. Participants will be 
excluded from the PK analysis population if they significantly 
violate the inclusion or exclusion criteria, deviate significantly 
from the protocol, or if data are unavailable or incomplete 
which may influence the PK analysis. Excluded cases will be 
documented together with the reason for exclusion. All 
decisions on exclusions from the analysis will be made prior to 
database closure.
Efficacy
Participants who were included in the ITT population.
Pharmacodynamic
Participants who were included in the Safety analysis 
population.
Biomarker
Participants who were included in the Safety analysis 
population.
Immunogenicity
Participants who had at least one pre-dose and one post-dose 
ADA assessment will be included and analyzed according to 
the treatment they actually received. In first instance, only 
samples from RO7049665-treated participants will be 
analyzed. The relationship between ADA status and safety, 
efficacy, PK, and biomarker endpoints will be analyzed and 
reported descriptively.
9.3
STATISTICAL ANALYSES
9.3.1
Demographics and Baseline Characteristics
The following information collected at baseline will be summarized descriptively in the 
Safety analysis population to assess the comparability of treatment groups:

Demographics

Medical history

Concomitant medications

PD biomarkers


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
Measures of endoscopic and histological appearance of mucosa of sigmoid colon
9.3.2
Safety Analyses
All safety analyses will be based on the Safety analysis population, with participants 
grouped according to the treatment received (dose level / dose frequency).
Table 7
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results.
Summary tables of change from baseline over time will be displayed. See 
Appendix 4 for details on standard reference ranges and data 
transformation and the definition of laboratory abnormalities.
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
Other
Physical examination results, safety biomarkers and incidence of ADAs will 
be listed and summarized descriptively.
9.3.3
Pharmacokinetic Analyses 
PK parameters will be read directly from the serum concentration-time profiles or 
calculated by using standard non-compartmental methods. The following PK parameters 
will be computed for RO7049665. However, other PK parameters might be computed in 
addition as appropriate: 

Time to maximum concentration (Tmax) post the dose on Day 1, and on Day of last 
dose

Cmax post the dose on Day 1, and post the dose on Day of last dose

Area under the serum concentration-time curve after the first dose administration 
extrapolated to infinity (AUCinf) and over the dosing interval (AUCtau) after the last 
dose administration (where tau=2 weeks). If deemed useful, a partial AUC0-t may be 
used instead of AUCinf or AUCtau should extrapolation to infinity or up to tau not be 
considered reliable. 


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
Apparent clearance after the first dose administration (CL/F = Dose/AUCinf) as well 
as after the last dose administration (CLss/F = Dose/AUCtau) 

Apparent volume of distribution (V/F) after the first dose administration

Estimates of T1/2 after the first dose (Day 1) as well as washout after last dose 
administration
The dose proportionality will be evaluated in an exploratory manner. Cmax and AUCtau (or 
AUC0-t if deemed useful) post the dose on Day 1 and Cmax and AUCtau post the dose on 
Day of last dose will be tested for dose proportionality. This will be done using one way 
Analysis of Variance (ANOVA) to test the dose effect using dose normalization and a 
natural log transform.
In addition, to evaluate drug accumulation, individual as well as mean (SD) of apparent 
peak (12 hour post dose) and trough (predose) after each dose administration will be 
plotted graphically over the course of assessments as per Table 2. In addition, AUCtau
post the dose on Day 1 will be tested statistically against AUCtau post the dose on Day of 
last dose using an ANOVA with terms in the model for participants and day. A natural log 
transform of the data will be done prior to the analysis.
Individual and mean serum concentrations at each sampling time point for RO7049665 
will be presented by listings and descriptive summary statistics including arithmetic 
means, geometric means, ranges, standard deviations, and coefficients of variation. 
Individual and mean concentration versus time will be plotted on linear or 
semi-logarithmic scales as appropriate.
All PK parameters will be presented by individual listings and summary statistics 
including arithmetic means, geometric means, medians, ranges, standard deviations, 
and coefficients of variation.
9.3.4
Efficacy Analyses 
Preliminary efficacy will be evaluated as a secondary objective of the study by 
comparing between dose groups the following endoscopic and histologic measures of 
disease activity. Change from baseline to Day 57 will be analyzed and reported 
descriptively.

Change from baseline to Day 57 (and descriptively at Day 29) in endoscopic indices 
of disease activity (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] and 
MCS-ES

Change from baseline to Day 57 (and descriptively at Day 29) in histology score of 
sigmoid colon biopsies (GS, RHI, and Nancy Histology Index [NHI])


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In addition, preliminary efficacy will also be evaluated by comparing overall disease 
activity between dose groups using:

Change from baseline to Day 57 (and descriptively at Day 29) in MCS
The main foreseen intercurrent event for this study is early treatment discontinuation. In 
the scenario that no intercurrent events occur (i.e., all participants complete the 
expected number of doses), the estimand is uncontroversial as simply the mean 
difference between treatment groups in change from baseline to Day 57 in efficacy 
scores. If however, intercurrent events are observed, three different strategies will be 
employed to handle early treatment discontinuation, each leading to their own respective 
estimands.
A treatment policy strategy (ITT population) will be used to estimate the difference 
between dose groups in the change from baseline in endoscopy, histology and overall 
disease activity scores, regardless of whether early treatment discontinuation occurred. 
In the absence of missing data, this can be achieved using Analysis of Covariance 
(ANCOVA) with dose group as a factor, otherwise an imputation method will be applied 
as appropriate.
A composite strategy (ITT population) will be used for endoscopy and overall disease 
activity scores to estimate the difference in the proportion of responders between dose 
groups, where responders are defined as those participants who reach a threshold of 
change from baseline in efficacy scores, in the absence of early treatment 
discontinuation. Endoscopic response is defined as at least a 1 point decrease in the 
MCS-ES and at least a 3 point decrease in the UCEIS. Clinical response (overall 
disease activity) is defined as at least a 3 point and 30% decrease from baseline in the 
MCS. MCS remission is a stool frequency score of 1 or 0 (with at least a 1 point 
decrease), a rectal bleeding score of 0, and an endoscopy score of 1 or 0 but with no 
friability. Endoscopic remission will be defined as a UCEIS score of 1 or 0. Treatment 
failure is defined as non-response or early treatment discontinuation. In the absence of 
missing data this can be analyzed using logistic regression with dose group as a factor, 
otherwise an imputation method will be applied as appropriate.
An on-treatment strategy (PP population) will be used to estimate the difference between 
dose groups in the change from baseline in endoscopy, histological and overall disease 
activity scores, restricted to those participants who completed the expected number of 
doses of their randomly assigned treatment. In the absence of missing data this can be 
achieved using ANCOVA with dose group as a factor, otherwise an imputation method 
will be applied as appropriate.
9.3.5
Immunogenicity Analyses 
The immunogenicity analyses will include participants with at least one pre-dose and 
one post-dose ADA assessment.


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The numbers and proportions of ADA-positive patients and ADA-negative participants 
during both the treatment and follow-up periods will be summarized.

Participants are considered to be ADA positive if they are ADA negative at baseline 
but develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and the 
titer of one or more post-baseline samples is greater than the titer of the baseline 
sample by a scientifically reasonable margin such as at least 4-fold 
(treatment-enhanced ADA response).

Patients are considered to be ADA negative if they are ADA negative at baseline 
and all post-baseline samples are negative, or if they are ADA positive at baseline 
but do not have any post-baseline samples with a titer that is greater than the titer of 
the baseline sample by a scientifically reasonable margin such as at least 4-fold 
(treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported descriptively.
9.3.6
Pharmacodynamic Analyses 
All PD analyses will be based on the Safety analysis population. Individual and mean PD 
data and parameters will be presented by listings and descriptive summary statistics 
including means, geometric means, medians, ranges, standard deviations, and 
coefficients of variation. Listings for the change from baseline (absolute and relative) and 
difference to placebo, as appropriate, and the corresponding summary statistics may 
also be presented. Graphical displays may be used, as appropriate.
9.3.7
Other Analyses
Exploratory biomarker analyses may be performed to investigate:
The association of biomarkers with improvements in endoscopic appearance of the 
mucosa, inflammatory infiltrate, or AEs.
Genotyping data may be analyzed for association with PD, efficacy, or safety of
RO7049665.
The dose-exposure-response for pharmacological, clinical endpoints, and safety 
markers may be evaluated using graphical and pharmacometric analyses. Modeling and 
simulation may also be used for dose-escalation/decision purposes. If required, the 
population PK/PD analysis will be reported separately from the main CSR.
9.4
INTERIM ANALYSES
No formal interim analyses are planned.


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9.5
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed. Data for study drug administration and concomitant 
medication will be listed. The number of participants who were randomized, discontinued 
and completed the study will be summarized and listed.


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10.
REFERENCES
Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361:206678.
Cerosaletti K, Schneider A, Schwedhelm K, et al. Multiple Autoimmune-Associated 
Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 
1 Diabetic and Multiple Sclerosis Patients. PloS One. 2013;8(12):e83811.
Chen X, Oppenheim JJ. Contrasting effects of TNF and anti-TNF on the activation of 
effector T cells and regulatory T cells in autoimmunity. FEBS Lett. 
2011 585:36118.
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011;365:171325.
Ford AC, Bernstein CN, Khan KJ, Abreu MT, Marshall JK, Talley NJ, Moayyedi P. Am J 
Gastroenterol 2011;106(4):590-9
Geboes K, Riddell R, Ost A, et al. A reproducible grading scale for histological 
assessment of inflammation in ulcerative colitis. Gut. 2000; 47(3):404-409.
Investigator’s Brochure RO7049665.
Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in 
graft-versus-host disease. N Engl J Med. 2011;365(22):2055-2066.
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, Bastien C, Cahn V, Cadiot G, 
Diebold MD, Danese S, Reinisch W, Schreiber S, Travis S, Peyrin-Biroulet L. Gut 
2017;66:43-49.
Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory 
T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl 
Med. 2013; 15:179ra43
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, Shackelton LM, 
Walker CW, Nelson S, Vandervoort MK, Frisbie V, Samaan MA, Jairath V, Driman 
DK, Geboes K, Valasek MA, Pai RK, Lauwers GY, Riddell R, Stitt LW, Levesque 
BG. Gut 2017;66:50-58.
Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol 
Hepatol. 2017; 14(5):269-278.
Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-Cell Responses to Low-Dose 
Interleukin-2 in HCV-Induced Vasculitis. N Engl J Med. 2011;365:2067-2077.
Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical 
therapies for inflammatory bowel disease. Am J Gastroenterol 2011;106 
Suppl 1:S2-25.
von Spee-Mayer C, Siegert E, Abdirama D, et al. Low-dose interleukin-2 selectivity 
corrects regulatory T cell defects in patients with systemic lupus erythematosus. 
Ann Rheum Dis. 2016;75 :1407-1415.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
and Appendix 3 (procedures of recording), Appendix 4 (clinical laboratory tests),
Appendix 5 (contraceptive guidance and collection of pregnancy information. Appendix 6
(pain and skin reactivity assessments), Appendix 7 (mayo clinical score [MCS]) and 
Appendix 8 (rationales for previous protocol amendments). Additional study-related
appendices are in order of appearance in the protocol.


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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and
applicable local, state, and federal laws. Studies conducted in the European Union (EU)/ 
European Economic Area (EEA) will comply with the EU Clinical Trial Directive 
(2001/20/EC).
1.2.
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the participant (e.g., 
advertisements, diaries etc), 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 participant 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 (Section 2.3.1 of this 
Appendix).
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. 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.
1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 


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(HIPAA) requirements, where applicable, and the IRB/IEC or study center. The Sponsor 
or its designee must review and approve any proposed deviations from the Sponsor's 
sample ICFs 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. Participants must be re-consented to the most current 
version of the ICF(s) during their participation in the study. A copy of the ICF(s) signed 
by all parties must be provided to the participant.
The Consent Forms must be signed and dated by the participant before his or her 
participation in the study. The case history or clinical records for each participant shall 
document the informed consent process and that written informed consent was obtained 
prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes if required as per local 
regulations.
Participants 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 participant 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 participant. All signed and 
dated Consent Forms must remain in each participant’s study file or in the site file and 
must be available for verification by study monitors at any time.
A participant who is re-screened is not required to sign another ICF if the re-screening
occurs within 30 days from the previous ICF signature date.
Consent to Participate in Exploratory Testing of Residual Material 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research described in Section 8. A separate signature 
will be required to document a participant's agreement to allow any remaining specimens 
to be used for exploratory research.
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 participant the 
objectives, methods, and potential hazards of participation in the RBR. Participants will 


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be told that they are free to refuse to participate and may withdraw their specimens at 
any time and for any reason during the storage period. A separate, specific signature will 
be required to document a participant’s agreement to provide optional RBR specimens. 
Participants who decline to participate will not provide a separate signature.
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a participant who is participating in the 
Research, the participant's specimens and data will continue to be used as part of the 
RBR.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
Approval by the Institutional Review Board or Ethics Committee
Sampling for 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 Institutional 
Review Board or Ethics Committee (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 will not be applicable at that site
Withdrawal from the Research Biosample Repository
Participants who give consent to provide specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a participant wishes to withdraw 
consent to the testing of his or her specimens, the Investigator must inform the Medical 
Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if the 
trial is ongoing, must enter the date of withdrawal on the RBR Withdrawal of Informed 
Consent eCRF. The participant will be provided with instructions on how to withdraw 
consent after the trial is closed. A participant's withdrawal from Study WP40161 does not, 
by itself, constitute withdrawal of specimens from the RBR. Likewise, a participant’s 
withdrawal from the RBR does not constitute withdrawal from Study WP40161. Data 
already generated before time of withdrawal of consent to RBR will still be used.
1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 


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The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality for Research Biosample Repository
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Participant medical information associated with RBR specimens is confidential and may 
only be disclosed to third parties as permitted by the Informed Consent Form (or 
separate authorization for use and disclosure of personal health information) signed by 
the participant, unless permitted or required by law.
Data derived from RBR specimen analysis on individual participants will generally not be 
provided to study investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
investigators or participants unless required by law.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.
Monitoring and Oversight Research Biosample Repository
Specimens collected for the RBR will be tracked in a manner consistent with Good 
Clinical Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Roche monitors and auditors will have direct access to 
appropriate parts of records relating to participant participation in RBR for the purposes 


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of verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the samples.
1.5.
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 one year after completion of the study (i.e., LPLO).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
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.


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Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study 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 destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities. 
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.


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2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
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 participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
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.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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.
2.3.3.
Dissemination of Clinical Study Data
A clinical study report containing the results of this trial will be made available to anyone 
who requests a copy.
2.3.4.
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ 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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3.
ADMINISTRATIVE STRUCTURE
The Sponsor of this trial is F. Hoffmann-La Roche Lt. The Sponsor is responsible for the 
study management (monitoring will be outsourced to a CRO), data management, 
statistical analysis, and medical writing for the clinical study report (CSR). The CSR will 
be written and submitted to Health Authorities in the timeframe as required by applicable 
regulatory requirements. The protocol will be submitted to country's IRB/IEC.
3.1
INTERNAL MONITORING COMMITTEE (IMC)
A dedicated group of selected Sponsor representatives, which will be independent to 
the project, will be reviewing the safety data of the study. The roles, responsibilities, 
membership, scope of activities, time of meetings and communication plan for the IMC 
will be documented in an appropriate charter.
4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to, the 
following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants

Participant enrollment is unsatisfactory.
If general study stopping criteria are met, the study will be paused and the Sponsor will 
conduct a full review of all available safety data. The study will resume if the Sponsor 
and investigator agree and after informing and receiving agreement from relevant Health 
Authorities and Ethics Committees.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.


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Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a patient or clinical investigation participant
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An adverse event can therefore be:

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.
Events Meeting the AE Definition:

Any deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 
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 
treatment.

Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

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).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE unless the progression is unexpectedly accelerated and 
not in line with the natural history of the disease. If the “Lack of efficacy” would not 
require safety reporting such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.


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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.


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
Other significant events:
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
For protocol-specific significant events, see Sections 4.1.4 and 7.1 for 
consideration.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
The Investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor. 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
ASSESSMENT OF SEVERITY
The terms “severe” and “serious” are not synonymous, i.e.:
–
Severe refers to a category utilized for rating the intensity of an event; and both AEs 
and SAEs can be assessed as severe.
–
Serious refers to an event that meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.


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The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 1
Adverse Event Severity Grading Scale
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 livinga
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily livingb,c
4
Life-threatening consequences or urgent intervention indicatedd
5
Death related to adverse eventd
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 and 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 6 of this Appendix for reporting instructions), per the definition of 
serious adverse event in Section 2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for 
reporting instructions), per the definition of serious adverse event in Section 2 with the 
exception of Grade 4 laboratory abnormality events which should only be reported as a SAE 
if it meets one or more of the serious conditions outlined in Section 2 (Definition of Serious 
Adverse Events) of Appendix 2.
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 Appendix 3 for 
reporting instructions).
3.2.
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration:

Temporal relationship of event onset to the initiation of study treatment.


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
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
5.
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 treatment:

Serious adverse events.

Non-serious adverse events of special interest (NSAESI).

Pregnancies (see Section 8.3.5).

DLAEs (see Section 4.1.3; see the eCRF completion guideline for further guidance).


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The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS, NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST AND DOSE-LIMITING ADVERSE EVENTS
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.


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Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period, if the event is believed to be related to prior study 
treatment the event should be reported directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or 
email address provided to investigators.
5.2
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. 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, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). For RO7049665 and placebo, 
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.
In addition, all special situations associated with RO7049665 and placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and 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.


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
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.
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.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI 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 using the following reference document{s}:

RO7049665 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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Appendix 3
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.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
1.1.
INJECTION REACTIONS
Adverse events that occur during or after study drug administration and are judged to be 
related to study treatment injection should be captured as a diagnosis (e.g., 
injection-related reaction, injection-site 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 Injection Reaction eCRF. If a 
participant 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 Injection Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS 
For adverse events other than injection reactions, a diagnosis (if known) should be 
recorded on the Adverse Event eCRF rather than individual signs and symptoms (e.g., 
record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the Adverse Event eCRF. If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time-points. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between participant evaluation 
time-points and subsequently recurs. Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


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6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3 ULN or >2 x baseline value if abnormal at 
baseline) 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. Therefore, investigators must report 
as an adverse event the occurrence of either of the following:

Treatment-emergent ALT or AST3 ULN (or >2 x baseline if value was abnormal 
at baseline) in combination with total bilirubin2 ULN.

Treatment-emergent ALT or AST3 ULN (or >2 x baseline if value was abnormal 
at baseline) 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 Appendix 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 a non-serious adverse event of special 
interest (see Section 8.3.6).
7.
DEATHS
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see 
Appendix 3).
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").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).


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9.
LACK OF EFFICACY OR WORSENING OF ULCERATIVE 
COLITIS
Medical occurrences or symptoms of deterioration that are anticipated as part of 
ulcerative colitis should be recorded as an adverse event if judged by the Investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time 
during the study. When recording an unanticipated worsening of ulcerative colitis on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., “accelerated ulcerative colitis”).
10.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 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:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration).

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
–
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease.
–
The participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by a local laboratory with the exception of 
Clostridium difficile, which will be tested at a central laboratory. Ova and parasite stool 
examination at screening may be done locally at sites with such capabilities. The results 
of the local laboratory assessments must be captured in source documentation and 
entered into the eCRF. 
Any additional laboratory test (e.g., safety biomarkers listed in the Schedule of Activities 
but not listed in Table 1) will be performed by a central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.


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Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, non-fasting 
glucose, urea, creatinine, creatine kinase (CK), 
protein, albumin, phosphate, calcium, total and direct 
bilirubin, alkaline phosphatase, ALT, AST, urate, 
hSCRP, GGT
Coagulation

Prothrombin time (i.e., INR) and activated 
thromboplastin time (aPTT).
Viral Serology

HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, 
HIV-2 antibody), hepatitis B surface antigen (HBsAg), 
total hepatitis B core antibody (HBcAb), hepatitis C 
virus (HCV) by PCR.
Pregnancy Test

All women of childbearing potential (including those 
who have had a tubal occlusion/ligation) will have a 
blood pregnancy test at screening. Urine pregnancy 
tests will be performed at specified subsequent visits. 
If a urine pregnancy test is positive, it must be 
confirmed by a blood pregnancy test.
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood. 

If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine will 
be sent to the laboratory for microscopy and culture. If 
there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no 
need to perform microscopy and culture.

Microscopic examination (red blood cells [RBCs], white 
blood cells [WBCs], casts, crystals, epithelial cells, 
bacteria), if blood or protein is abnormal.
Other Screening Tests

Urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, and 
benzodiazepines).

Alcohol breath or blood test (as per local procedure).

Clostridium difficile (ELISA)

Ova and parasite stool examination
Other Tests

IgE

Tryptase


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The results of each test must be entered into the CRF.
Investigators must document their review of each laboratory safety report.
Laboratory results that could unblind the study that are performed centrally will not be 
reported to investigative sites or other blinded personnel until the study has been 
unblinded.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.

Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in participant listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.


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Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
a.
Pre-menarchal
b.
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview.
c.
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.


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2.
CONTRACEPTION GUIDANCE

Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 1 below.
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly.
Table 1
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependenta
(Failure rate of 1% per year when used consistently and correctly)
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User-Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion/ligation
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.


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3.
PREGNANCY TESTING
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice.
4. 
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5 Pregnancy). This applies only to male participants who receive 
RO7049665.
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The 
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
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 update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant 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. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.

Female participants who become pregnant
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 


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termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in Appendix 2.
While the Investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
5
ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as 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 of Appendix 2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male patient exposed to study treatment 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 of 
Appendix 2).


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Appendix 6 Pain and Skin Reactivity Assessments
Pain Assessment:
Pain will be assessed by the participant according to a 100-mm horizontal VAS: 

0 = no pain,

100 = worst pain imaginable.
Skin Reactivity Assessment:
ISRs (i.e., burning, bleeding, itching, bruising, redness, hive formation, or other) will be 
assessed at the time-points indicated in the SoA. Assessment will be made according to 
a 0−3 scale:

0 = no skin reactivity

1 = mild skin reactivity (participant aware of the sign, but finds it easily tolerable)

2 = moderate skin reactivity (the participant has discomfort enough to cause 
interference with usual activities)

3 = severe skin reactivity (the participant is incapacitated and unable to work or 
participate in many or all usual activities).
The size of the injection site skin reactions will be captured according to a 0−4 scale:

0: unable to assess

1:20 mm in diameter

2: ≤ 40 mm in diameter

3: ≤ 60 mm in diameter

4: > 60 mm in diameter


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Appendix 7
Mayo Clinical Score (MCS)
Note: In accordance with the WP40161 protocol, the endoscopy subscore of the Mayo Clinic 
Score (MCS-ES) will be modified so that a value of 1 does not include friability.
Reference:
Schroeder et al. 1987


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Appendix 8
Rationales for Previous Protocol Amendments
Protocol WP40161 Version 4
Protocol WP40161 Versions 2 and 3, and the local German Version 3 DEU-1, were 
updated in response to health authority feedback from the Paul-Ehrlich-Institute (PEI; the 
German Health Authority. Appendix 8 lists the rationales of protocol amendments 
Versions 2 and 3).
Protocol WP40161 Version 3 has been amended to incorporate the following changes
into the global protocol:

The stopping criterion relating to an increase in absolute regulatory T (Treg) cell 
count of 450 cells/L has been updated in response to the Paul-Ehrlich-Institute 
(PEI), the German Health Authority, to include a halt to the dosing if reached at any 
measurement following any dose administration, rather than at dose administration 
number 4, in 3 or more participants in a single dose level. The current cut-off 
of >450 cells/µL is not considered by the Sponsor to be a safety limit and is 
supported by recent data from the entry-into-human study WP39826 and data from 
a cynomolgus monkey 13-week GLP toxicity study, and to the Sponsor’s knowledge
there is no published threshold beyond which Treg cell numbers in humans are 
considered a risk to human health. Therefore, the current cut-off will be maintained 
throughout the study treatment period.

In order to resume dosing (or other dose adjustment) if a stopping criterion for the 
study is met, the requirement of health authority approval prior to resumption of 
dosing has been added for improved clarity as requested by the PEI.

Further changes in response to the German ethics committee have been
implemented, i.e., inclusion criterion 1 have been adjusted (minor change for clarity, 
that a written informed consent is available at the time of inclusion of the patient). 
The order of the statistical sections has been aligned with the order of objectives
and endpoints and the efficacy assessments at Day 57 will be summarized 
descriptively.

For the WP40161 study protocol, the dose unit has been adjusted from microgram 
(µg) to milligram (mg) in line with the RO7049665 dose vial (in mg/mL). Furthermore, 
a consistent use of dose level and cohort has been introduced throughout the 
protocol.

The screening window has been increased by one week (i.e., to Day 35 prior to 
first dose instead of Day 28) in order to maximize the window of the patient’s 
screening assessments. The study allows re-screening if specific criteria are fulfilled, 
among other for re-testing patients found to be positive to Clostridium difficile (where 
the time for treatment and re-testing may go beyond 28 days) and for the planning 
of the endoscopic screening assessment in relation to the ova and parasite stool 
examination that has a long turnaround time.


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
The number of patients per cohort has been adjusted to approximately 10 
participants.

The collection timing of the fecal calprotectin stool sample has been changed to 
increase the flexibility of obtaining the sample from the patient and modified relative 
to the preparation requirements prior to endoscopic assessments on Days 29 and 
57.

Colon biopsies may be subjected to metagenomic DNA or RNA analysis to 
determine the composition of the mucosa-associated microbiome in patients. These 
data are of potential value for patient stratification purposes or for treatment 
monitoring.

The skinfold thickness measurement is not required until the time of study treatment 
administration. In case a patient would be excluded after screening the 
measurement would not be required. Therefore, the time of measurement has been 
set to Day 1. 

Participants positive for anti-drug antibodies (ADA) will be requested to return and 
have additional ADA and soluble CD25 (sCD25) samples to monitor off-treatment 
ADA persistence. It has been clarified too that a corresponding pharmacokinetic (PK) 
sample does not have to be collected after the official study period and last planned 
safety follow-up visit (Day 99) in participants positive for ADA. As the ADA assay is 
sensitive for sCD25, time points have been moved and one new added to measure 
sCD25 concentrations toward the end of the study.

The diagnostic term of "Injection-Related Reaction" (IRR) has been updated to the 
more general term of "Injection Reaction" (IR) with the options of either “Injection–
Site Reaction” (ISR) to signify a local reaction or IRR to signify a systemic reaction
as required for study WP40161. The reporting requirements for the eCRF have 
been updated accordingly.
Other:
Additional minor changes have been made to improve clarity and consistency
between synopsis and protocol body, i.e.:
-
The study figure and footnote have been aligned for consistency with the 
protocol. 
-
For the hematology laboratory assessments “other cells” have been 
removed from the differential count as this definition does not apply, 
“sediment” has been removed from the microscopic urine examination as the 
main components are listed, i.e., casts, crystals, epithelial cells, bacteria.
-
Study discontinuation criteria have been introduced for clarity and to align 
with company requirements.
-
The adverse event (AE) reporting time during the study treatment phase has 
been adjusted and aligned with given safety and follow-up visit (Day 99) and 
clarified in case of early termination.


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-
Insufficient response to standard of care with previous treatment with Janus 
kinase (JAK) inhibitors has been introduced to complete the list of inclusion 
criterion #6. 5- aminosalicylate (5-ASA) has been introduced to inclusion 
criterion #6 for clarity and consistency.
-
Positivity for total hepatitis B core antibody (HBcAb) has been introduced to 
exclusion criterion 29 for clarity and to align with the clinical laboratory 
assessment (Appendix 4).
-
The schedule of activities (SoA) tables and footnotes have been updated to 
ensure consistency with changes in the protocol body.
-
Reporting of any medication used by the patient prior to screening has been 
aligned between the permitted and prohibited therapy sections 
(Sections 6.5.1. and Section 6.5.2.).
-
For clarity the Mayo Clinical Score (MCS) table is shown (Appendix 7).
-
The reporting requirements for special situations (i.e., accidental overdose 
and medication error) and dose-limiting adverse events (DLAEs) have been 
updated in line with global company requirements.
-
Minor changes have been introduced to align with new updates to the 
Sponsor’s protocol template.
Protocol WP40161 Version 3
Protocol WP40161 was previously amended (Version 2) in response to health authority 
feedback (United States Food and Drug Administration [US FDA]) pre-investigational 
new drug application [IND] and Paul-Ehrlich-Institut [PEI]; the German Health Authority). 
Protocol WP40161 V3 will be submitted globally for the purpose of study conduct.
Protocol WP40161 Version 2 has been amended to incorporate the following changes 
based on experience in the single ascending dose (SAD) entry-into-human (EIH) study 
of RO7049665, study WP39826:

The starting dose and dose escalation structure have been included. The overall 
cohort structure has been simplified to include two doses (i.e., the same dose level 
may be administered in more than one cohort) with well understood safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers. The 
WP39826 study has been summarized (including safety, PK, and PD). The number 
of expected participants has been modified and updated to reflect changes to the 
study design.

In response to FDA feedback, the cohort that included RO7049665 as an adjunct to 
anti-tumor necrosis factor (TNF)-treatment has been removed. 

Based on the identification of anti-drug antibodies (ADA) in study WP39826, the 
risk-benefit section has been updated, additional safety monitoring has been 
introduced (including management of potential hypersensitivity reactions), a 


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staggered enrollment plan has been implemented, and all doses will be 
administered with a 24 hour in-house stay for safety monitoring. 

The dose regimen of every 4-week (Q4W) has been removed based on safety, PK, 
and PD data from WP39826. The overall length of the study has been modified to 
reflect the timing of the every 2-week (Q2W) regimen, which will be maintained 
throughout the study. 

Based on the PK and PD findings from WP39826, the Schedule of Activities’ (SoA) 
tables have been revised to optimize timing of PK and PD measurements. The 
SoAs have been updated to include injection-related reaction (IRR) sampling as 
needed, an early termination visit if required, Clostridium difficile enzyme-linked 
immunosorbent assay (ELISA) at screening, ova and parasite exam included at
screening. Hepatitis C screening has been changed to from antibody screen to a 
polymerase chain reaction (PCR)-based assay. Follicle-stimulating hormone (FSH) 
sampling has been removed. Footnotes have been updated as applicable.

The timing of key efficacy assessments (Ulcerative Colitis Endoscopic Index of 
Severity [UCEIS] and Mayo Clinic Score [MCS]) has been shifted from week 10 to 
week 8, and have been clarified as an assessment day rather than week. 

The blinding definition has been clarified.

Most tertiary/exploratory objectives have been removed. These objectives included 
exploratory cytokines that are not fully identified. Objectives will now focus on safety, 
tolerability, PK, PD, and early efficacy in the primary and secondary endpoints.  

In response to FDA feedback, the definition of the patient population with 
moderately to severely active ulcerative colitis (UC) has been updated and clarified 
to include overall MCS, stool frequency subscore, and rectal bleeding subscore.

A communication strategy has been introduced to detail management of staggered 
dosing, dose escalation, and safety risks. 

The requirement for genotype testing has been changed to clarify this is mandatory 
only in countries where this testing is permitted.

The sections on overdose and medication error (i.e., accidental deviation in the 
administration of a drug) have been updated in line with new Sponsor template 
language relating to overdose, medication error, drug abuse, and drug misuse. 

General changes and updates to the protocol have been made to improve 
consistency and clarity and aligned with updated Sponsor and protocol template 
requirements.

In Appendix 5 the contraceptive requirements and recommendations have been 
clarified.
Protocol WP40161 Version 2
Protocol WP40161 version 1 has been amended to incorporate the following changes in 
response to questions raised by Paul-Ehrlich-Institut (PEI; German Health Authority):


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
The stopping criteria have been updated in order to allow administration of 
RO7049665 while maintaining participant’s regulatory T (Treg) cell levels within an 
upper limit of 450 cells/l. In order to allow complete evaluation of all participants in 
a cohort and at a given dose (with possible variations in the participant’s Treg
numbers after RO7049665 administration), the new stopping criterion will apply after 
four administrations given every second week (or after three administrations if given 
every 4 weeks) of RO7049665. The dose escalation criteria have also been updated 
to limit dosing beyond a level resulting in increases in off-target effects on 
eosinophils, above 5.0x109 cells/L in 3 or more patients in a dose cohort.  

The Sponsor will implement an internal monitoring committee (IMC) for reviewing, 
specifically safety-related data on an ongoing basis for dose-escalation decision 
making.

The individual participant stopping criterion with regards to other findings as a 
reason to stop dosing with RO7049665, has been modified to allow Investigator 
discretionary reasons only (instead of at the discretion of Investigator and Sponsor).

The dose escalation criteria have been modified allowing dose-escalation between 
all non-biologic standard of care (SOC) cohorts based on the same criteria as for 
cohorts 1 and 2, i.e., safety and tolerability in at least 5 participants during the first 8 
weeks.

Inclusion criterion number 6 has been modified to clearly define insufficient 
treatment response and treatment intolerance to pharmacological treatment and 
failure based on defined previous doses and duration of treatment in accordance 
with CHMP/EWP/18463//2006 Rev.1 Guidelines on the development of new 
medicinal products 4 for the treatment of Ulcerative Colitis and the ECCO guidelines 
on ulcerative colitis. 

Inclusion criterion 9 will remain as is, i.e., with use of contraceptive methods 
resulting in a failure rate of 1% per year during the treatment period and for at least 
28 days, as the Sponsor considers that this sufficiently covers the time prediction of 
5 elimination half-lives. 
Other:

Additional minor changes have been made to improve clarity and consistency
between synopsis and protocol body (i.e., the numbering of inclusion and exclusion 
criteria in the synopsis versus protocol body have been adjusted).