Conditions: Alzheimers Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
Study BP41192 is a randomized, adaptive, placebo-controlled parallel group study to investigate the safety, tolerability, immunogenicity and pharmacokinetics of single-ascending intravenous (IV) doses of RO7126209 in healthy participants. RO7126209 is being developed for the treatment of Alzheimer's Disease.

Detailed description:
This study uses a parallel group design, with participants recruited in 5 planned sequential cohorts. Additional cohort(s) may be added if dose escalation stopping criteria are not met after cohort 5. Participants will receive a single IV dose of either RO7126209 or placebo. RO7126209 doses will be administered in ascending order. After the starting dose, subsequent doses will be selected in an adaptive manner during study conduct based on emerging safety, tolerability and PK data.

Arms:
arm 1: In Cohorts 1-5, there were ten participants in total who received placebo, two in each cohort. arm 2: Healthy volunteers will be administered a single intravenous dose of RO7126209 (0.1 mg/kg). arm 3: Healthy volunteers will be administered a single intravenous dose of RO7126209 (0.4 mg/kg). arm 4: Healthy volunteers will be administered a single intravenous dose of RO7126209 (1.2 mg/kg). arm 5: Healthy volunteers will be administered a single intravenous dose of RO7126209 (3.6 mg/kg). arm 6: Healthy volunteers will be administered a single intravenous dose of RO7126209 (7.2 mg/kg).

Interventions: intervention 1: RO7126209 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will be administered single-ascending intravenous doses of RO7126209 with at least 2 weeks between each dose level. After the starting dose, the subsequent doses will be selected in an adaptive design. Sentinel dosing will be employed. intervention 2: Participants will be administered a single intravenous dose of matching placebo.

Protocol document:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A Single-Center, Randomized, Adaptive, Investigator/Subject Blind, 
Single Ascending Dose, Placebo-Controlled Phase I Study to 
Investigate the Safety, Tolerability, Immunogenicity and 
Pharmacokinetics of Intravenously Administered RO7126209 in 
Healthy Participants 
NCT Number: NCT04023994 
Document Date: Protocol Version 4: 31-Jul-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.
RO7126209 —F. Hoffmann-La Roche Ltd
Protocol BP41192, Version 4
PROTOCOL
TITLE:
A SINGLE-CENTER, RANDOMIZED, ADAPTIVE, 
INVESTIGATOR/ SUBJECT BLIND, SINGLE 
ASCENDING DOSE, PLACEBO-CONTROLLED 
PHASE I STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, IMMUNOGENICITY AND 
PHARMACOKINETICS OF INTRAVENOUSLY 
ADMINISTERED RO7126209 IN HEALTHY 
PARTICIPANTS
PROTOCOL NUMBER:
BP41192
VERSION:
4
IND NUMBER:
140740
TEST PRODUCT:
RO7126209
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 15 May 2019
DATE AMENDED:
Version 2: 05 July 2019
Version 3: 19 December 2019
Version 4: See electronic date stamp below
 
31-Jul-2020 09:24:00
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7126209 —F. Hoffmann-La Roche Ltd
2/Protocol BP41192, Version 4
PROTOCOL ACCEPTANCE FORM
TITLE:
A SINGLE-CENTER, RANDOMIZED, ADAPTIVE, 
INVESTIGATOR/ SUBJECT BLIND, SINGLE 
ASCENDING DOSE, PLACEBO-CONTROLLED 
PHASE I STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, IMMUNOGENICITY AND 
PHARMACOKINETICS OF INTRAVENOUSLY 
ADMINISTERED RO7126209 IN HEALTHY 
PARTICIPANTS
PROTOCOL NUMBER:
BP41192
VERSION NUMBER:
4
IND NUMBER:
140740
TEST PRODUCT:
RO7126209
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 
Site Monitor.






RO7126209 —F. Hoffmann-La Roche Ltd
5/Protocol BP41192, Version 4
4.2.3
Rationale for Biomarker Assessments................................... 46
4.2.4
Rationale for CSF Sampling .................................................. 46
4.3
Dose Justification .................................................................. 46
4.3.1
Justification for Starting Dose................................................ 46
4.3.2
Justification for Dose Escalation............................................ 48
4.4
End of Study Definition .......................................................... 49
5.
STUDY POPULATION................................................................................ 49
5.1
Inclusion Criteria.................................................................... 50
5.2
Exclusion Criteria................................................................... 51
5.3
Lifestyle Considerations......................................................... 52
5.3.1
Meals and Dietary Restrictions.............................................. 52
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 52
5.3.3
Activity ................................................................................... 53
5.4
Screen Failures ..................................................................... 53
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 .......................................................... 57
6.5
Concomitant Therapy ............................................................ 57
6.5.1
Permitted Therapy................................................................. 57
6.5.2
Prohibited Therapy ................................................................ 57
6.6
Dose Modification.................................................................. 58
6.7
Treatment after the End of the Study..................................... 58
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 58
7.1
Discontinuation of Study Treatment....................................... 58
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 59


RO7126209 —F. Hoffmann-La Roche Ltd
6/Protocol BP41192, Version 4
7.3
Lost to Follow-Up................................................................... 59
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 60
8.1
Efficacy Assessments............................................................ 60
8.2
Safety Assessments .............................................................. 60
8.2.1
Physical Examinations........................................................... 60
61
8.2.3
Vital Signs.............................................................................. 61
8.2.4
Electrocardiograms................................................................ 61
8.2.5
Clinical Safety Laboratory Assessments................................ 62
63
8.2.6
MRI........................................................................................ 63
63
63
64
64
64
64
65
8.2.8
Medical History and Demographic Data ................................ 65
8.3
Adverse Events and Serious Adverse Events ....................... 65
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 65
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 66
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 66
8.3.3.1
Investigator Follow-Up........................................................... 66
8.3.3.2
Sponsor Follow-Up ................................................................ 67
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 67
8.3.4.1
Emergency Medical Contacts................................................ 67
8.3.5
Pregnancy ............................................................................. 68
8.3.6
Non-Serious Adverse Events of Special Interest................... 68


RO7126209 —F. Hoffmann-La Roche Ltd
7/Protocol BP41192, Version 4
8.3.7
Management of Specific Adverse Events .............................. 68
8.4
Treatment of Overdose.......................................................... 75
8.5
Lumbar punctures.................................................................. 75
8.6
Pharmacokinetics .................................................................. 75
8.6.1
Plasma................................................................................... 76
8.6.2
Cerebrospinal Fluid ............................................................... 76
8.7
Immunogenicity Assessments ............................................... 76
8.8
Pharmacodynamics and Biomarker Analyses ....................... 77
8.8.1
Biomarker Research Sample................................................. 77
8.8.2
Clinical Genotyping................................................................ 78
8.9
Health Economics.................................................................. 78
8.10
Timing of Study Assessments ............................................... 78
8.10.1
Order of Assessments ........................................................... 78
8.10.2
Screening and Pre-treatment Assessments .......................... 78
8.10.3
Assessments during Treatment............................................. 79
8.10.4
Assessments at Study Completion/Early 
Termination Visit.................................................................... 79
8.10.5
Follow-Up Assessments ........................................................ 79
9.
STATISTICAL CONSIDERATIONS ............................................................ 79
9.1
Sample Size Determination ................................................... 79
9.2
Populations for Analyses ....................................................... 80
9.3
Statistical Analyses................................................................ 80
9.3.1
Demographics and Baseline Characteristics ......................... 80
9.3.2
Safety Analyses..................................................................... 80
9.3.3
Pharmacokinetic Analyses..................................................... 81
9.3.3.1
Plasma Pharmacokinetic Parameters.................................... 81
9.3.3.2
CSF Pharmacokinetic Parameters ........................................ 82
9.3.3.3
Statistical Analyses................................................................ 82
9.3.4
Bayesian Analysis to Support Dose-Escalation 
Recommendations................................................................. 83
9.3.5
Immunogenicity Analyses...................................................... 83
9.3.6
Pharmacokinetic / Safety Relationships ................................ 84
9.4
Summaries of Conduct of Study............................................ 84




RO7126209 —F. Hoffmann-La Roche Ltd
9/Protocol BP41192, Version 4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AD
Alzheimer’s Disease
ADA
Anti-drug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ARIA
Amyloid-related imaging abnormalities
AST
Aspartate aminotransferase
AUC
Area under the curve
BBB
Blood-brain barrier
BE
Bioequivalence
BM
Bone marrow
BP
Blood pressure
BS
Brain shuttle
CL
Clearance
CL/F
Apparent clearance
CMC
Chemistry manufacturing and control
Cmax
Maximum concentration
CNS
Central nervous system
CR
Complete response
CRO
Contract research organization
CRP
C-reactive protein
CSF
Cerebrospinal fluid
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
CTD
Common technical document
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLE
Dose-limiting event
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture


RO7126209 —F. Hoffmann-La Roche Ltd
10/Protocol BP41192, Version 4
Abbreviation
Definition
EDTRS
Early Diabetic Treatment Retinopathy Study
EEA
European Economic Area
ESF
Eligibility screening form
EU
European Commission
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C
HDL
High-density lipoproteins
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
iDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IMC
Internal Monitoring Committee
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRF
Independent review facility
IRR
Infusion-related reaction
IUD
Intrauterine device
IV
Intravenous
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LH
Luteinizing hormone
LPLV
Last participant, last visit
LPLO
Last participant, last observation
MAD
Multiple-ascending doses


RO7126209 —F. Hoffmann-La Roche Ltd
11/Protocol BP41192, Version 4
Abbreviation
Definition
MD
Multiple doses
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NHP
Non-human primate
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter
PD
Pharmacodynamic
PET
Positron emission tomography
PK
Pharmacokinetic
PT
Prothrombin time
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
RNA
Ribonucleic acid
RR
RR interval
SAD
Single ascending dose
SAE
Serious adverse event
SC
Subcutaneous
SD
Single dose
SoA
Schedule of activities
SOC
Scientific Oversight Committee
SOP
Standard operating procedure
SPA
Statistical Programmer
SUSAR
Suspected unexpected serious adverse reactions
tmax
Time of maximum concentration observed
TQT
Thorough QT
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States


RO7126209 —F. Hoffmann-La Roche Ltd
12/Protocol BP41192, Version 4
Abbreviation
Definition
V
Volume
V/F
Apparent volume of distribution
WBC
White blood cell


RO7126209 —F. Hoffmann-La Roche Ltd
13/Protocol BP41192, Version 4
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A SINGLE-CENTER, RANDOMIZED, ADAPTIVE, INVESTIGATOR/ 
SUBJECT BLIND, SINGLE ASCENDING DOSE, PLACEBO-
CONTROLLED PHASE I STUDY TO INVESTIGATE THE SAFETY, 
TOLERABILITY, IMMUNOGENICITY AND PHARMACOKINETICS 
OF INTRAVENOUSLY ADMINISTERED RO7126209 IN HEALTHY 
PARTICIPANTS
PROTOCOL NUMBER:
BP41192
VERSION:
3
TEST PRODUCT:
RO7126209
PHASE:
I
RATIONALE
RO7126209 is a bispecific (2+1) monoclonal antibody (mAb) construct that combines, by 
recombinant fusion the anti-Aβ antibody gantenerumab with a Brain Shuttle module 
 
 RO7126209 is being developed for the 
treatment of Alzheimer's Disease. This is the first study in which RO7126209 will be 
administered to humans. A randomized, investigator and subject blind, adaptive, placebo-
controlled, parallel design was chosen to assess the safety, tolerability, immunogenicity and 
pharmacokinetics (PK) following single ascending doses of RO7126209 administered 
intravenously to healthy participants. 
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
single ascending intravenous (IV) doses 
of RO7126209 in healthy participants

Incidence, severity, and causal 
relationship of adverse events (AEs).

Incidence of abnormal laboratory 
findings.

Incidence of abnormal vital signs and 
electrocardiogram (ECG) parameters








RO7126209 —F. Hoffmann-La Roche Ltd
17/Protocol BP41192, Version 4
Due to the exploratory nature of this clinical study, its conduct can be discontinued at any time 
at the discretion of the Sponsor. This will not constitute a premature termination of the study.
The IMPs for this study are RO7126209 and matching placebo.
Length of Study
The total duration of the study for each participant will be approximately 16 weeks divided as 
follows:

Screening: Up to 8 weeks

In clinic period: Days -2 to 10

Final follow-up: Day 57 ± 4
End of Study
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur 57 ± 4 days after last dose administration.
PARTICIPANT POPULATION
The participants in this study will be healthy male volunteers, between 18 and 40 years of age, 
inclusive, who fulfill all of the given inclusion criteria.
INCLUSION/EXCLUSION CRITERIA
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1.
 
Age
2.
Type of Participants 
3.
Healthy status is defined by the absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination including 
vital signs, 12-lead ECG, ophthalmologic examination, hematology, blood chemistry, 
coagulation, serology, and urinalysis. 
4.
Weight
5.
Body mass index (BMI) of 18-30 kg/m2 inclusive
Sex
6.
Male participants
During the treatment period (from dosing on Day 1) and until the final follow-up visit (Day 57 4 
days), 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 a partner who is a woman of childbearing potential.


RO7126209 —F. Hoffmann-La Roche Ltd
18/Protocol BP41192, Version 4

With pregnant female partner, remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures such as a condom to avoid exposing the embryo.

Refrain from donating sperm from Day 1 of the study until 90 days after last dose.
 
 
 
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Concomitant disease or condition that could interfere with, or treatment of which might 
interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose 
an unacceptable risk to the participant in this study.
2.
History of any clinically significant gastrointestinal, renal, hepatic, broncho-pulmonary, 
neurological, psychiatric, cardiovascular, endocrinological, ophthalmologic, hematological or 
allergic disease, metabolic disorder, cancer or cirrhosis.
3.
Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of drug of 
abuse within the last 5 years.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus 
(HIV) 1 and 2.
5.
 
 
 
6.
 
7.
History or presence of clinically significant ECG abnormalities 
 
 
 
.
8.
Clinically significant abnormalities 
 
 
 
9.
Any major illness within one month before the screening examination or any febrile illness 
within one week prior to screening and up to first dose administration.
10. Impaired hepatic function as indicated by screening aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) 1.5 the upper limit of normal (ULN) or abnormal total 
bilirubin unless due to Gilbert’s disease.




RO7126209 —F. Hoffmann-La Roche Ltd
20/Protocol BP41192, Version 4
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 14 days or 5 half-lives (whichever is longer) prior to 
study drug administration until follow-up. 
Use of the following therapies is prohibited during the study:

.

Vaccination is prohibited within two months prior to Day 1.

 
 

Use of all other concomitant medications, herbal preparations (whether as teas or 
formulations), including prescription, and over-the-counter drugs is prohibited from 14 days, 
prior to Day 1, or five times the elimination half-life of the medications, whichever is longer, 
until follow-up.


RO7126209 —F. Hoffmann-La Roche Ltd
21/Protocol BP41192, Version 4
1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
Screening
In-House Period
Ambulatory 
Visits
Follow-
up
Admission to 
Clinic/Eligibility 
Confirmation
Randomization and 
Study Drug
Administration
In-house 
Postdose 
Assessments
Day -56 to 
-3
Day -2 and 
Day -1
Day 1 (IV 
administration of 
RO7126209/placebo)
Until Day 10
From 
Day 15 to 
Day 43
Day 57 
± 4


RO7126209 —F. Hoffmann-La Roche Ltd
22/Protocol BP41192, Version 4
1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided in Table 1 and Table 2.


RO7126209 —F. Hoffmann-La Roche Ltd
23/Protocol BP41192, Version 4
Table 1
Overall Schedule of Activities
Assessment
Screeninga
Follow-
Up
Day -56/-3
Day
-2
Day 
-1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
10
Day
15±1
Day
22±1
Day
29±2
Day
43±3
Day 
57±4
Time relative to 
dose (h)
NA
NA
NA
0
24
48
72
96
120
144
168
NA
NA
NA
NA
NA
NA
Written Informed 
Consent

Inclusion/Exclusion 
Criteria


Brain MRI l 



Demographics

Medical History

Medication History


Physical 
Examination b



Vital Signs c















Respiratory rate j





12-lead ECG d












Neurological 
Examination











Full hematology








Full Blood 
q










RO7126209 —F. Hoffmann-La Roche Ltd
25/Protocol BP41192, Version 4
Assessment
Screeninga
Follow-
Up
Day -56/-3
Day
-2
Day 
-1
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
Day
8
Day
10
Day
15±1
Day
22±1
Day
29±2
Day
43±3
Day 
57±4
Time relative to 
dose (h)
NA
NA
NA
0
24
48
72
96
120
144
168
NA
NA
NA
NA
NA
NA
Sampling (Blood) i
Infusion-related 
reaction blood 
sample

-------------------------------------------------------
Previous and 
concomitant 
Medications
-------------------------------------------------------------------------------------------------------------------------------------------------------------------
Adverse Events h
-------------------------------------------------------------------------------------------------------------------------------------------------------------------
Anti-RO7126209
Antibodies



p
a)
Safety tests can be repeated once during screening period at discretion of the Investigator.
b)
A complete physical examination will be performed at screening (including height and weight), and abbreviated physical examinations at all 
other visits (including weight).
c)
Includes single measurements of systolic and diastolic blood pressure, pulse rate and body temperature. All measurements to be taken after 
the participant has rested in a supine position for at least 5 minutes.
d)
Triplicate 12-lead ECGs (within 5 minutes) will be measured after the participant has rested in a supine position for at least 10 minutes.
e)
Dipstick analysis of protein, blood, glucose, pH and leukocytes. 
f)
Hepatitis B, C, HIV 1 and 2.


RO7126209 —F. Hoffmann-La Roche Ltd
26/Protocol BP41192, Version 4
Table 1
Overall Schedule of Activities (cont.)
g)
Participants will have to be fasted (water consumption is permitted) for at least 10 hours prior to full panel biochemistry laboratory safety tests 
(with the exception of screening and follow-up where a fasting period of 4 hours is sufficient). On Day 1, no food is permitted from 2 hours prior 
to dosing until 4 hours after start of the infusion. On all other days of the in-house period, standard breakfast, lunch, dinner and snack will be 
provided up to discharge, at the times deemed convenient by the clinical site. 
h)
Intensity of adverse events will be graded on a five-point scale (Grade 1, Grade 2, Grade 3, Grade 4 and Grade 5) based on the NCI CTCAE 
(v5), which can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf 
i)
The Sponsor may decide to terminate PK sampling earlier and/or timing of PK sampling may be modified based on emerging PK data 
(e.g., consecutive postdose PK samples with below the limit of quantification [BLQ] concentration).
j)
Respiratory rate to be measured after the participant has rested in a supine position for at least 5 minutes.
 
 
 
 
 
o)
Participants will be randomized to two subgroups per dose group. One subgroup will have the CSF sampling on Day 3, the other subgroup on 
Day 5. The safety biomarker (blood) and coagulation sample will be taken accordingly.
p)
In case of ADA positive results at follow-up visit, the participant will be asked to come back to the unit monthly for additional ADA testing until 
this is no longer clinically indicated (see Section 8.7). At each visit a corresponding PK sample must be also taken. 


RO7126209 —F. Hoffmann-La Roche Ltd
27/Protocol BP41192, Version 4
Table 1
Overall Schedule of Activities (cont.)
 
 
 




RO7126209 —F. Hoffmann-La Roche Ltd
29/Protocol BP41192, Version 4
Procedure
Day -2
Day -1
Day 1
Nominal Time
Day 2
- 2 h
Predose
0 h
0.25 h
0.5 h
1 h
2 h
3 h
4 h
6 h
8 h
12 h
24 h
Drug Administration

a)
Participants will have to be fasted (water consumption is permitted) for at least 10 hours prior to full panel biochemistry laboratory safety tests 
(with the exception of screening and follow-up where a fasting period of 4 hours is sufficient. No food is permitted from 2 hours prior to dosing 
until 4 hours after start of the infusion on Day 1. On all other days of the in-house period, standard breakfast, lunch, dinner and snack will be 
provided at the times deemed convenient by the site.
b)
Triplicate 12-lead ECGs (within 5 minutes) will be measured after the participant has rested in a supine position for at least 10 minutes.
c)
Three triplicate ECGs (9 in total) will be recorded within 1 hour prior to breakfast (at least 2 hours prior to dosing) and used as the baseline 
time point.
d)
Includes single measurements of blood pressure (systolic and diastolic), pulse rate and body temperature. All measurements to be taken after 
the participant has rested in a supine position for at least 5 minutes.
e)
Order of Assessments: (1) ECGs; (2) Vital signs; (3) Respiratory Rate; (4) PK blood sampling; (5) Laboratory safety tests and other blood 
sampling (anti-RO7126209 antibodies).
f)
Dipstick analysis of protein, blood, glucose, pH and leukocytes.
g)
Respiratory rate to be measured after the participant has rested in a supine position for at least 5 minutes.
h)
Abbreviated physical examinations (including weight).
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2.
INTRODUCTION
2.1
STUDY RATIONALE
RO7126209 is a bispecific (2+1) monoclonal antibody (mAb) construct that combines, by 
recombinant fusion the anti-Aβ antibody gantenerumab with a Brain Shuttle module that 
 RO7126209 is being developed 
for the treatment of Alzheimer's Disease (AD). This is the first study in which
RO7126209 will be administered to humans. A randomized, investigator and subject 
blind, adaptive, placebo-controlled, parallel design was chosen to assess the safety, 
tolerability, immunogenicity and pharmacokinetics (PK) following single ascending doses 
of RO7126209 administered intravenously to healthy participants. 
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Background on Disease
The World Health Organization estimates that around 50 million people worldwide are 
living with dementia and that 10 million new cases are diagnosed every year. The total 
number of people with dementia is estimated to reach 82 million in 2030 and will almost 
triple by 2050 to 152 million. AD is the most common form of dementia, accounting for 
60%-70% of cases (World Health Organization 2017). The prevalence of AD increases 
with age, with a global prevalence of 5%-8% in people aged 60 years or over.
AD is clinically characterized by a progressive impairment in cognitive and executive 
abilities, which results in decreased function and gradual loss of independence 
(Mesterton et al. 2010). There is great inter-individual variability in AD progression with 
survival dependent on many factors, including age at onset. In general, the clinical 
picture evolves from “predementia” or “prodromal AD” to mild, moderate, and then 
severe AD. At the early stage of AD, a slight impairment of memory, language, and 
visuospatial function can be observed. As AD advances, patients become progressively 
impaired not only in terms of cognition but also in activities of daily living and the burden 
on caregivers significantly increases. The median survival time following a diagnosis of 
AD depends on the patient’s age at diagnosis and ranges from 8.3 years for persons 
diagnosed with AD at 65 years old to 3.4 years for those 90 years old (Brookmeyer et al. 
2002). On average, individuals live 6 years after diagnosis (Helzner et al. 2008). 
Pathologically, AD is characterized by the presence of cerebral Aplaques, 
neurofibrillary tangles, and a loss of neurons. Ais a peptide derived from proteolytic 
processing of the amyloid precursor protein, APP. This peptide exists in two major forms: 
A1-40 and A1-42 (Citron et al. 2004). Although the etiology of AD is not completely 
understood, current research suggests that Aprocessing and deposition play a critical 
role in the cascade of biological events involved in the pathogenesis of the disease. 
Consequently, therapies targeting this process have the potential to significantly alter the 
progression of the disease.


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Because of its increasing prevalence, long duration, and high cost of care, AD is 
expected to continue to represent a major public health problem for decades to come.
2.2.2
Background on RO7126209
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A detailed description of the chemistry, pharmacology, and safety of RO7126209 is 
provided in the RO7126209 Investigator Brochure (IB).
2.3
BENEFIT/RISK ASSESSMENT
No therapeutic benefit is anticipated for participants in this study as is common for 
Phase 1 studies involving healthy volunteers. There is no previous clinical experience 
with RO7126209 – this is a ‘first-in-human’ study.
The eligibility criteria, the study 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 for first-in-human studies, and 
under continuous medical observation during the study (until Day 10). The investigative 
site will be equipped with resuscitation equipment.
This study is adaptive in nature and planned doses may be adjusted (increased, 
decreased, or repeated) or intermediate doses explored based on emerging safety,
tolerability, and PK data. The starting dose of 0.1 mg/kg (see Section 4.3.1) is expected 
to be well tolerated and associated with no or only minimal effect(s).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Overall, the level of risk for healthy participants is considered acceptable as it is 
mitigated by careful monitoring, sentinel cohorts at every new ascending dose level, 
careful dose escalation, and study stopping criteria.


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More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7126209 is provided in the 
RO7126209 IB.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 3.
Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
single ascending intravenous doses of 
RO7126209 in healthy participants

Incidence, severity, and causal 
relationship of AEs.

Incidence of abnormal laboratory 
findings.

Incidence of abnormal vital signs and 
electrocardiogram (ECG) parameters
Secondary

To investigate the single intravenous dose 
pharmacokinetics (PK) of RO7126209 in 
plasma of healthy participants

Plasma PK parameters of RO7126209

To investigate the CSF penetration after a 
single dose of RO7126209 in healthy 
participants

CSF concentration of RO7126209

To evaluate the immunogenicity of a single 
dose of RO7126209 in healthy participants

Incidence of anti-RO7126209 antibodies 
(ADAs)
Exploratory

To explore PK/safety relationships of 
RO7126209 in healthy participants

Relationship between plasma exposure 
of RO7126209 and safety measurements


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4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.
Study BP41192 is a randomized, adaptive, placebo-controlled parallel group study to 
investigate the safety, tolerability, immunogenicity and pharmacokinetics of single
ascending intravenous doses of RO7126209 in healthy participants.
This study uses a parallel group design, with participants recruited in 5 planned 
sequential cohorts. Participants will receive a single IV dose of either RO7126209 or 
placebo. Thirty-six participants are expected to be enrolled in this study. 
, with 
the maximum number of participants not exceeding 60. A minimum of 4 active treatment 
and 2 placebo participants will be included in the first two dose levels. Starting at dose 
level 3, and in all subsequent cohorts, a minimum of 6 active treatment and 2 placebo 
participants will be included. Based upon the review of emerging data there will be the 
option to adjust the number of participants on active treatment or placebo per dose level. 
If a dose level is repeated or if a lower dose is investigated, the added group will consist 
of at least 2 participants on active and 1 on placebo.
In accordance with standard practice for first-in-human studies, RO7126209 doses will 
be administered in ascending order, starting with a dose of 0.1 mg/kg that is anticipated 
to be well tolerated (Section 4.3.1). Subsequent doses will be selected in an adaptive 
manner during study conduct based on emerging safety, tolerability and PK data. A 
Bayesian adaptive design using the continual reassessment method (CRM) for 
predicting (see Section 9.3.4 and Appendix 6) the anticipated maximum dose-limiting 
event (DLE) rate to guide dose effect relationship will also be applied for dose 
escalation.
Intermediate dose escalation steps other than those anticipated (Section 1.2) may be 
used, doses may be repeated, or adjusted based on safety, tolerability and PK data at 
each dose level, as well as on model-based prediction of the anticipated maximum DLE 
rate. 
In each dose group, sentinel dosing will be employed to allow for an evaluation of safety 
data by the Investigator up to 48 hours following intravenous administration of 
RO7126209 or placebo before subsequent participants are dosed.
 
 
There will be at least 2 weeks between each dose level in order to permit adequate time 
for collation and review of emerging data before the next dose is administered.


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The participants, investigators, and site personnel (except site personnel responsible for 
study drug accountability, reconciliation, record maintenance and drug preparation) will 
be blinded to treatment assignments.
Participants in the sentinel group will receive a single IV infusion of study medication 
(RO7126209 or matching placebo
 
4.1.1
Length of the Study
The total duration of the study for each participant will be approximately 16 weeks 
divided as follows:

Screening: Up to 8 weeks

In clinic period: Days -2 to 10

Final follow-up: Day 57 ± 4
4.1.2
Treatment Groups
The following tentative dose levels are planned:

Dose level 1: 0.1 mg/kg RO7126209 or matching placebo

Dose level 2: 0.3 mg/kg RO7126209 or matching placebo

Dose level 3: 0.9 mg/kg RO7126209 or matching placebo

Dose level 4: 2.7 mg/kg RO7126209 or matching placebo

Dose level 5: 5.4 mg/kg RO7126209 or matching placebo
The dose levels are tentative, and may be revised based on emerging data. Higher 
doses than planned may be administered provided that all the dose escalation 
increments and stopping rules are followed. 
 
 with a maximum of 60 participants 
enrolled in the study.
If the safety data (AEs, ECGs, vital signs, laboratory safety tests, 
 
assessments) of the first 48 hours following intravenous administration of RO7126209 or 
placebo is acceptable based on the judgment of the Investigator, the remaining 
participants will be dosed
 after the first dosing occasion. 
4.1.3
Dose Escalation Decision Criteria
The decision to escalate to the next dose level will be made jointly by the Sponsor study 
team, the Investigator and any other person the Investigator or Clinical Pharmacologist 
considers necessary to assist with the decision (Section 4.1.4 and Section 4.1.5).






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Due to the exploratory nature of this clinical study, its conduct can be discontinued at 
any time at the discretion of the Sponsor. This will not constitute a premature termination 
of the study.
4.1.5
Communication Strategy 
A safety review team will provide dose recommendations for all cohorts of the study. The 
representatives of the safety review team will be from Clinical Pharmacology, Biometrics, 
Safety Science, Clinical Science, and Operations together with the Investigator(s) and 
the Project lead of the CRO (and any other the Investigator or Clinical Pharmacologist 
considers necessary to assist with the decision).
There will be an ongoing review of available data (see Section 4.1.3) prior to dosing 
remaining participants of a dose group after evaluation of the sentinel cohort and 
initiation of the next dose. A Dose Escalation Meeting will be conducted between the 
Sponsor study team and Investigator prior to dosing of the next dose level. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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.
Additional details for communication strategy and dose-escalation procedure can be 
found in the separate Medical Data Review Plan.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
4.2.1
Rationale for Study Population
The study will be conducted in healthy male participants aged 18 to 40 years (inclusive). 
The healthy volunteer population has been selected to minimize the risk of ARIA. ARIA-
E (edema) and ARIA-H (microhemorrhages) are common side effects of monoclonal 
antibodies targeting fibrillar forms of amyloid beta. As the main objective of this study is 
the characterization of the general safety and tolerability profile, immunogenicity and
pharmacokinetics of RO7126209, the absence of confounding diseases in healthy 
volunteers allows for a clearer and more consistent assessment of the main objectives. 
In addition, healthy volunteers are unlikely to require concomitant medications which 
could impact PK and safety parameters.
In line with the above paragraph the age range has been limited to 40 years to reduce 
the risk of amyloid plaque in the brain. According to a recent publication (Pletnikova 
2018) the risk of occurrence of diffuse amyloid plaque in the study population is low. 
 
 
 
4.2.2
Rationale for Control Group
This study is designed to be adequate and well-controlled. Participants will be 
randomized to RO7126209 or placebo treatment. The randomization scheme to active 
and placebo groups is considered necessary to generate an adequate within study 
comparator dataset to allow proper evaluation of the magnitude of any treatment effects. 
The study is Investigator/participant-blind to eliminate potential bias.




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Monoclonal antibodies targeting fibrillar forms of amyloid beta like gantenerumab may be 
associated with the occurrence of ARIAs. The gantenerumab target dose of 510 mg SC
Q2W is administered only after an up-titration period of 9 months to mitigate incidence 
and severity of ARIAs. As this side effect is also expected to occur before reaching the 
target dose of RO7126209, the starting dose has been lowered to reach brain exposures 
similar to gantenerumab doses that have not been associated with ARIAs in patients
with AD. 
 
 
0.1 mg/kg 
 
 
 
 
 
The population selected for BP41192, healthy young male volunteers, is not expected to 
experience ARIAs due to lack of fibrillar forms of amyloid beta in the brain. However, 
clinical experience with gantenerumab and the potential for ARIA findings have been 
taken into account in order to characterize the general safety and tolerability profile and 
PK of the dose range which is likely to be tested in future studies in Alzheimer’s Disease 
patients. 
Safety Margins
The safety margins associated with the starting dose based on the preclinical 
toxicokinetic data, and estimated NOAEL in the 2-week GLP toxicology study and 
projected human PK are provided in Table 4 below. Note that, taking a conservative 
approach, the high exposure scenario was used for the calculation of the safety margins. 
If safety allows, the highest dose to be tested in the SAD will be selected so that the 
 
 
 






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5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
 
Age
2.
Type of Participants 
3.
Healthy status is defined by the absence of evidence of any active or chronic 
disease following a detailed medical and surgical history, a complete physical 
examination including vital signs, 12-lead ECG, ophthalmologic examination,
hematology, blood chemistry, coagulation, serology, and urinalysis. 
4.
Weight
5.
BMI of 18-30 kg/m2 inclusive
Sex
6.
Male participants
During the treatment period (from dosing on Day 1) and until the final follow-up visit (Day 
57 4 days), 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 a partner who is a woman of 
childbearing potential (WOCBP, as defined in Section 1 of Appendix 5).

With pregnant female partner, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid exposing 
the embryo.

Refrain from donating sperm from Day 1 of the study until 90 days after last dose.
 
 
 
 


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5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Concomitant disease or condition that could interfere with, or treatment of which 
might interfere with, the conduct of the study, or that would, in the opinion of the 
Investigator, pose an unacceptable risk to the participant in this study.
2.
History of any clinically significant gastrointestinal, renal, hepatic, broncho-
pulmonary, neurological, psychiatric, cardiovascular, endocrinological, 
ophthalmologic, hematological or allergic disease, metabolic disorder, cancer or 
cirrhosis.
3.
Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of 
drug of abuse within the last 5 years.
4.
Positive result on hepatitis B (HBV), hepatitis C (HCV), or human immunodeficient 
virus (HIV) 1 and 2.
5.
 
 
6.
 
7.
History or presence of clinically significant ECG abnormalities
 
 
8.
Clinically significant abnormalities (as judged by the Investigator)
 
 
9.
Any major illness within one month before the screening examination or any febrile 
illness within one week prior to screening and up to first dose administration.
10. Impaired hepatic function as indicated by screening aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) 1.5the upper limit of normal (ULN) or 
abnormal total bilirubin unless due to Gilbert’s disease.
11. Any clinically relevant history of hypersensitivity or allergic reactions, either 
spontaneous or following drug administration, or exposure to foods or environmental 
agents.
12. History of hypersensitivity to biologic agents or any of the excipients in the 
formulation.
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Prior/Concomitant Therapy
14. Use of prohibited medication or herbal remedies as described in the section of 
concomitant medications
15. Prior administration of gantenerumab (RO4909832)
16. Any vaccination within two months prior to Day 1
Prior/Concurrent Clinical Study Experience
17. Participation in an investigational drug medicinal product or medical device study 
within 30 days before screening or within seven times the elimination half-life if 
known, whichever is longer.
23. Other Exclusions
18. Participants who regularly smoke more than 5 cigarettes daily or equivalent and are 
unable or unwilling not to smoke during the in-house period.
19. Donation or loss of blood over 500 mL within three months prior to Day 1 and 
donation of blood for the duration of the study until follow-up. 
20.
 
 
21. Claustrophobia, presence of pacemakers, aneurysm clips, artificial heart valves, ear 
implants, or foreign metal objects in the eyes, skin, or body that would 
contraindicate an MRI scan.
22. Inability or unwillingness to meet study requirements (see inclusion criteria).
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
Participants will have to be fasted (water consumption is permitted) for at least 10 hours 
prior to laboratory safety tests for full panel biochemistry (with the exception of screening 
and follow-up where a fasting period of 4 hours is sufficient). 
On dosing day (Day 1), no food is permitted from 2 hours prior to dosing until 4 hours
after start of infusion. On all other days of the in-house period, standard breakfast, lunch, 
dinner and snack will be provided at the times deemed convenient by the clinical site.
5.3.2
Caffeine, Alcohol, and Tobacco
Use of caffeine, alcohol and tobacco will be restricted as follows:

The consumption of foods and beverages containing caffeine (e.g., tea, coffee and 
caffeinated soft drinks) will not be permitted from 24 hours before dosing until the 
end of the residential period (Day 10). During the period when participants are not 
resident in the unit, caffeine containing beverages must be no more than three cups 
per day, and methylxanthine containing drinks (e.g. cola) must be less than 1 L per 
day.


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
Consumption of alcohol will not be allowed from 48 hours before dosing until the 
end of the residential period (Day 10) and should be limited to a maximum of 
2 drinks/day (1 drink 14 g of pure alcohol, i.e., 12 fl oz of regular beer or 5 fl oz of 
wine or 1.5 fl oz of distilled spirits) during out-clinic period until follow-up.

The use of tobacco will not be permitted from 48 hours before dosing until the end of 
the residential period (Day 10) and should be limited to a maximum of 5 cigarettes a 
day or equivalent amount of tobacco during the out-clinic time until follow-up.
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 96 hours before the screening visit, 
laboratory safety tests and 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) will 
not be re-screened unless agreed with the Sponsor. However, safety tests can be 
repeated once during screening period in the case of a borderline result, at the discretion 
of the Investigator. A repeat of a screening safety test is not considered a re-screening. 
5.5
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment using clinical database and 
IEC/IRB approved newspaper/radio/social-media advertisements prior to consenting to 
take place in 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.
All investigational medicinal products (IMPs) required for completion of this study
(RO7126209 and matching placebo) will be provided by the Sponsor. 
Study drug (RO7126209 or matching placebo) will be administered to the participants at 
the study center by investigational staff on the morning of Day 1.


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6.1
TREATMENTS ADMINISTERED
Table 6 summarizes the treatments administered.
Table 6
Summary of Treatments Administered
Study Treatment 
Name:
RO7126209
Placebo
IMP and NIMP
IMP
IMP
Dose Formulation:
liquid concentrate for infusion 
liquid concentrate for infusion 
Unit Dose 
Strength(s)/Dosage 
Level(s):
Dose:
Dose level 1: 0.1 mg/kg
See Section 4.1.1 for
dose-escalation information and 
Pharmacy Manual for details.
N/A
Route of 
Administration:
IV infusion
IV infusion
Packaging and 
Labeling:
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 6.6 or Section 7, respectively.
Please see the RO7126209 IB and pharmacy manual 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.
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.


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
Report any deviations or product complaints to the Study Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization 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.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment 
On Day 1, participant will be randomized to receive placebo or active treatment. The 
randomization numbers will be generated by the Sponsor or its designee.
The randomized treatment assignment will be allocated from the list sequentially to 
participants in the order in which they are enrolled.
The Investigator or designee will enter the corresponding participant number for 
allocation to the dose group/cohort in the appropriate place on each participant’s eCRF.
The randomization list will be made available to the pharmacist preparing the study 
treatment, to the individual responsible for PK sample bioanalysis, to the Clinical 
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and to statisticians or programmers at Roche. Likewise, the pharmacometrician will be 
unblinded. PK and safety 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.
6.3.2
Blinding
This is a Participant and Observer-Blinded Study.
Participants will be randomized to placebo or active treatment in each dose cohort/level. 
The randomization numbers will be generated by the Sponsor or its designee. This study 
is observer-blinded. This means that the participant, the Investigator(s), and all 
individuals in direct contact with the participant at the investigative site will be blinded, 
except the Pharmacist handling the study treatment. Members of the Sponsor’s project 
and study teams who do not have direct contact with the participant may be unblinded at 
the Clinical Pharmacologist’s discretion.
To allow informed recommendations or decisions regarding the dose-selection in this 
study, an integrated assessment of the safety, tolerability and available 
pharmacokinetics will be made prior to each dose-decision. The Clinical Pharmacologist 
or Clinical Pharmacology Scientist may share mean reports (e.g., tabular summaries or 
mean graphs by treatment group) with other individuals (e.g., drug safety physician, 
principal Investigator), involved in the dose decision process, but should not disclose 
individual treatment assignment.
If required, unblinded data (individual as well as at group level) may also be presented to 
the Drug Safety Committee or other experts of the Sponsor.
Single-participant emergency unblinding
If unblinding is necessary for immediate participant management (e.g., in the case of a 
SAE for which participant management might be affected by knowledge of treatment 
assignment), the Investigator will be able to break the treatment code. The Investigator 
is not required to contact the Medical Monitor prior to breaking the treatment code; 
however, the treatment code should not be broken except in emergency situations.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs that are considered by the Investigator to be related to 
study treatment. The Sponsor must be notified before the blind is broken unless 
identification of the study treatment is required for medical emergency in which the 
knowledge of the specific blinded treatment will affect the immediate management of the 
participant’s conditions (e.g., antidote is 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 and the name of all the person(s) who had to be unblinded in 
the source documentation and eCRF, as applicable.


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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.
6.5
CONCOMITANT THERAPY
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
approved dietary and herbal supplements, nutritional supplements) used by a participant 
within 30 days of 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 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 adverse events should be 
recorded on the Adverse Event eCRF.
6.5.1
Permitted Therapy
All medications (prescription and OTC) taken within 30 days of study screening and for 
the duration of the study will be recorded on the appropriate eCRF.
Acetaminophen is allowed up to a maximum dose of 2 g/day up to 48 hours prior to
dosing, not to exceed 4 g total during the week prior to dosing. 
Additionally, local anesthetic is permitted during the lumbar puncture
 
.
6.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 14 days or 5 half-lives (whichever is 
longer) prior to study drug administration until follow-up, with the exception of 


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medications to treat adverse events unless the rationale for the exception is discussed 
and clearly documented between the investigator, the medical and safety monitor and 
the Sponsor. 
Use of the following therapies is prohibited during the study:

 

Vaccination is prohibited within two months prior to Day 1.

 
 

Use of all other concomitant medications, herbal preparations (whether as teas or 
formulations), including prescription, and over-the-counter drugs is prohibited from 
14 days, prior to Day 1 of the trial (dosing day), or five times the elimination half-life 
of the medications, whichever is longer, until follow-up.
6.6
DOSE MODIFICATION
The decision to escalate to the next dose level will be made jointly by the Sponsor study 
team, the Investigator and any other person the Investigator or Clinical Pharmacologist 
considers necessary to assist with the decision as described in Section 4.1.3.
Based on emergent safety (e.g. infusion-related reactions), the duration of the infusion 
may be modified. 
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO7126209 or other study interventions 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 (e.g., participants 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.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
Not applicable as this is a single dose administration study.


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In case of an IRR or for any other safety reason, infusion might be stopped or performed 
at a lower rate (see Section 8.3.7). 
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.
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 be used as part of the overall research data.
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 Schedule of Activities (SoA: Section 1.3) and Section 8.10.4 for data to be collected 
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.


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Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time points are summarized in the 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 
be utilized for screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time-frame defined in the SoA.
8.1
EFFICACY ASSESSMENTS
Efficacy parameters will not be evaluated in this study.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol-specified safety laboratory assessments; measurement of 
protocol-specified vital signs; ECGs; 
, MRI; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study.
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the
cardiovascular, respiratory, gastrointestinal, dermatological, 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.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
At subsequent visits (or 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 adverse events on the Adverse Event eCRF.


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8.2.3
Vital Signs
Vital signs including temperature (oral), pulse rate, respiratory rate, and blood pressure 
will be assessed. They will be taken before blood collection and will be measured at the 
time point specified in the SoA tables (Section 1.3).
Single 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 non-infusion 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 in a room at comfortable temperature and 
without distractions (e.g., television, cell phones), with the healthy participant’s arm 
unconstrained by clothing or other material.
Where the clinical significance of abnormal vital signs measurement at screening is 
considered uncertain, screening vital signs assessment may be repeated once during 
the screening period at the discretion of the Investigator to confirm eligibility.
8.2.4
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 
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 2 minutes 
apart. The full set of triplicates should be completed in less than 5 minutes. The average 
of the three readings will be used to determine ECG intervals (e.g., PR, QRS, QT and 
QTc).
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 


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appropriate to repeat abnormal ECGs to rule out improper lead placement potentially 
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 or loaded electronically. QTcF (Fridericia’s correction) and RR 
will be calculated automatically, and recorded on the eCRF or loaded electronically. 
Changes in T‑wave and U‑wave morphology and overall ECG interpretation will be 
documented on the eCRF or loaded electronically. T-wave information will be captured 
as normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal.
Where the clinical significance of abnormal ECG recordings at screening is considered 
uncertain, screening ECG assessment may be repeated once during the screening 
period at the discretion of the Investigator to confirm eligibility.
8.2.5
Clinical Safety Laboratory Assessments
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 (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. 
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 eCRF.


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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 at screening 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.
 
 
 
8.2.6
MRI
Brain MRI using at least a 1.5-Tesla machine will be performed for the eligible 
participants at screening to exclude microbleeds, lacunar infarcts, and space-occupying 
lesions (see Section 5.2, Exclusion criteria) and will include fluid-attenuated inversion 
recovery (FLAIR) sequence and T2*/gradient echo sequence (GRE). On Days 7 and 57 
post dose brain MRI will be performed to confirm absence of brain side effects 
(e.g., inflammation). In case of clinical findings, CE-MRI may be performed.
Additional brain MRIs must be performed following the onset of a serious CNS adverse 
event or following a clinically significant worsening of a CNS adverse event. The results 
should be documented on the appropriate adverse event page and serious adverse 
event form (if applicable). 
MRI data (e.g., images) may be shared with the Sponsor.
 


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8.2.8
Medical History and Demographic Data
Medical history includes clinically significant diseases and all medications (e.g., 
prescription drugs, OTC drugs, herbal or homeopathic remedies, nutritional supplements) 
used by the participant within 30 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 serious adverse event (SAE) can be found in Appendix 2. 
The non-serious adverse events 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 Section 8.3.7. 
The Investigator and any qualified designees are responsible for ensuring that all 
adverse events (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 adverse events are provided in Appendix 3.
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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Clinic staff will seek information on adverse events at each study day. All adverse events, 
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, 
all adverse events caused by a protocol-mandated intervention should be reported (e.g., 
adverse events related to invasive procedures such as lumbar puncture). If the adverse 
event meets the criteria for serious adverse event (see Section 2 from Appendix 2 ), it 
should be reported immediately.
After initiation of study treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until the last follow-up visit (574 days after dosing).
Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period of 57 days 4 days after dosing.
However, if the Investigator learns of any SAE (including a death) or other adverse 
events 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 
adverse event 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 serious adverse events 
considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant’s medical record to facilitate source 


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data 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 serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow-up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case.
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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (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 IB 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. Medical Monitors’ contact details will be available on a 
separate list generated by the study management team.


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8.3.5
Pregnancy
Male participants will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
574 days after dosing. 
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:

Cases of an elevated ALT or 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
Management of Specific Adverse Events
IRRs as defined by Kang and Saif (2007) are “any signs or symptoms experienced by 
patients during the infusion of pharmacologic or biologic agents or any event occurring 
on the first day of drug administration”. IRRs are common adverse drug reactions (ADRs)
reported with the use of biologic therapies. IRRs are usually reported with the first or 
second infusion of a therapeutic monoclonal antibody and tend to be dose-related. Such 
reactions typically occur during or shortly after an infusion or within 24 hours after study 
drug infusion. IRRs is a basket term including other terms such as anaphylaxis, 
anaphylactoid reactions, complement activation-related pseudoallergy (CARPA) and
cytokine release syndrome. Combinations of IRR types may occur in the same patient
(Doesseger  et al 2015).
IRR symptoms may be indistinguishable from an anaphylaxis Type 1 hypersensitivity 
reaction (i.e., flushing, rash, respiratory difficulty, hypotension, tachycardia); however, 


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hypersensitivity reactions (IgE-mediated) generally do not occur with the first exposure 
to a biologic therapy.
Anaphylactoid reactions may occur with the first exposure to an antigen and may be 
clinically indistinguishable from anaphylaxis. Unlike anaphylactic reactions, 
anaphylactoid reactions are milder upon repeated administration. 
CARPA typically occurs within minutes after starting the infusion. However, it may be 
delayed, particularly in premedicated patients. The most frequent symptoms being 
flushing, rash, dyspnea, chest pain, back pain and subjective distress.
Cytokines release syndrome (CRS) can present as with a variety of symptoms ranging 
from mild, flu-like symptoms (fever, fatigue, headache, rash, arthralgia, and myalgia) to 
more severe cases characterized by hypotension as well as high fever and can progress 
to an uncontrolled systemic inflammatory response with vasopressor-requiring 
circulatory shock, vascular leakage, disseminated intravascular coagulation, and multi-
organ system failure. Laboratory abnormalities that are common in patients with CRS 
include cytopenias, elevated creatinine and liver enzymes, deranged coagulation 
parameters, and a high C-reactive protein (CRP) (Shimabukuro-Vornhagen et al 2018).
Figure 2 describes the process for the overall evaluation of AEs to determine whether an 
AE is an IRR.


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Figure 2
Evaluation and Reporting of Infusion Related Reaction (IRR)


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Figure 2
Evaluation and Reporting of Infusion Related Reaction (IRR) (cont.)
1. Source: Lee et al 2014. 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the NCI CTCAE (v5), which can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
2. Note:  High-Dose Vasopressor (duration #3 hours) in table below
Pressor
Dose
Norepinephrine monotherapy
#20 mcg/min
Dopamine monotherapy 
#10 mcg/kg/min
Phenylephrine monotherapy
#200 mcg/min
Epinephrine monotherapy
#10 mcg/min
If on vasopressin
Vasopressin + norepinephrine equivalent of #10 mcg/min a
If on combination vasopressors (not vasopressin)
Norepinephrine equivalent of # 20 mcg/min a
Source: Russell et al 2008. 
mcg −microgram; min −minute; VASST −Vasopressin and Septic Shock Trial. 
a VASST vasopressor equivalent equation: norepinephrine equivalent dose −[norepinephrine (mcg/min)] ∗[dopamine (mcg/kg/min)] ∗
[phenylephrine (mcg/min) /10].


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Specific management steps for IRRs and hypersensitivity reactions of different severity 
are provided in Table 7. The participant should be monitored until complete resolution of 
the symptoms and treated as clinically indicated.
A blood sample will be taken in all participants at baseline (predose Day 1) and 6 hours 
post dose (the timing might be adjusted based on emerging data)
 
In case a Grade3 
IRR occurs, blood samples for the assessment 
 
 will be collected and analysed along with the paired baseline sample. The 
baseline and 6-hour (timing might be adjusted based on emerging data) post dose 
samples of all participants will be analysed to assess the relationship between dose, 
cytokine release and occurrence of IRRs as appropriate. Guidelines for managing 
infusion-related reactions with onset after infusion but within 24-hour window in 
presented in Table 8


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Table 7
Guidelines for Managing Infusion-Related Reactions with onset 
during infusion
Event
Action to Be Taken
Grade 1
Stop or slow down study drug infusion to 50% of the initial rate. 
Assess vital signs. Clinical observation for improvement/resolution 
of symptoms. No treatment is needed. 
Grade 2
Stop study drug infusion. Perform serial vital signs assessment 
every 15 minutes, supportive therapy (fluids [Normal Saline or 
Lactated Ringers], supplemental oxygen, diphenhydramine 
2550mg PO or IV Q6h for rash, acetaminophen 650 mg PO [or 
minimum recommended adult dose of paracetamol]) Q6h. ADA 
and PK levels should be drawn. If symptoms resolve completely 
during the visit, infusion may resume at 50% of the previous 
infusion rate. 
Grade 3
Stop study drug infusion. Perform serial vital signs assessment as 
dictated by the patient’s clinical symptoms, supportive therapy 
(fluids [Normal Saline or Lactated Ringers], supplemental oxygen, 
diphenhydramine 2550mg PO or IV for rash, acetaminophen 
650 mg PO [or minimum recommended adult dose of 
paracetamol], methylprednisolone 125 mg IV). Labs: 
 within 3 hours of the event and 
to be repeated in 4872 hours post event. ADA and PK levels 
should be drawn.
Grade 4
Stop study drug infusion. Perform serial vital signs assessment 
every 5 minutes, supportive therapy (fluids [Normal Saline or 
Lactated Ringers], supplemental oxygen/ intubation and ventilatory 
support, diphenhydramine 2550 mg PO or IV for rash, 
acetaminophen 650 mg PO [or minimum recommended adult dose 
of paracetamol], methylprednisolone 125 mg IV). Labs:
 within 3 hours of the event and 
to be repeated in 4872 hours post event. ADA and PK levels 
should be drawn. 
Anaphylaxis
Stop study drug infusion. Assess vital signs every 5 minutes. 
Administer IV fluids (Normal saline or Lactated Ringers), 
supplemental oxygen/ventilatory support, for systemic symptoms 
(angioedema, bronchospasm) epinephrine 1:1000, 0.3 mL 
subcutaneous (may be repeated in 20 minutes; in patients on beta 
blockers, glucagon administration may be needed), 
diphenhydramine 2550 mg IV, methylprednisolone 125 mg IV). 
Labs:
 within 3 hours 
of the event and to be repeated in 4872 hours post-event. 
Discontinue participants from the study. ADA and PK levels should 
be drawn (See Lieberman et al 2015 for anaphylaxis guidance). 


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Table 8
Guidelines for Managing Infusion-Related Reactions with onset 
after infusion but within 24-hour window
Event
Action to Be Taken
Grade 1

Treat symptomatically as indicated, including antihistamines, 
antipyretics, and/or analgesics as needed.

Treat fever and neutropenia if present.

Monitor fluid balance; administer IV fluids as clinically 
indicated.
Grade 2 

Follow all Grade 1 recommendations. 

Monitor cardiac and other organ function closely. 

Hemodynamic support as indicated. 

Oxygen for hypoxia.

Admit to ICU as appropriate. 

If no improvement within 24 hours: 
Notify Medical Monitor. 
Consider administering tocilizumab 8 mg/kg e IV as a 
single dose.

ADA and PK levels should be drawn.
Grade 3

Notify Medical Monitor.

Cardiopulmonary and organ function monitoring in Intensive 
Care Unit.

Hemodynamic support as indicated.

Oxygen for hypoxia.

Other supportive care as clinically indicated (e.g., fever and 
neutropenia, infection).

Administer tocilizumab 8 mg/kg IV.
–
If no clinical improvement within 24 hours:
Administer repeat dose of tocilizumab 8 mg/kg.
Consider initiating IV corticosteroids (e.g., 
methylprednisolone [2 mg/kg/day] or dexamethasone 10 
mg for neurologic symptoms).

Labs: 
 within 3 
hours of the event and to be repeated in 48 - 72 hours post 
event. ADA and PK levels should be drawn.
Grade 4

Follow all Grade 3 management guidelines
Labs: 
 within 3 hours 
of the event and to be repeated in 4872 hours post event. ADA 
and PK levels should be drawn.
In case of signs/symptoms of IRR in the sentinel cohort, IRR risk mitigation steps may 
be implemented in the remaining participants of the dose level and the higher dose 
levels. The same approach will applied in case of signs/symptoms of IRRs in the 


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participants enrolled in the main cohort at a certain dose level for the higher dose levels.
In order to reduce the occurrence and potential impact of IRRs, slower infusion time may 
be applied to all participants of the cohort (and the cohorts at higher dose level), after 
discussion and approval by the medical monitor. 
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 adverse event unless it results in untoward medical effects (see 
Sections 5 and 5.2 of Appendix 2 for further details).
In the event of an overdose, 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 blood samples for PK analysis according to the schedule of assessments if 
not medically contraindicated.
4.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the CRF.
8.5
LUMBAR PUNCTURES
 lumbar punctures per participant will be performed at the times indicated in the SoA 
(see Section 1.3) to collect CSF, performed by a qualified physician. Atraumatic needles 
will be used, the liquid will be sampled in a free flowing manner, which will take about 
5 minutes. For details please see the Laboratory Manual
CSF Samples will be aliquoted per time point for the measurement of RO7126209 
(Section 8.6.1), 
 
Details on processes for collection and shipment of these samples can be found in 
Sample Handling Manual.
8.6
PHARMACOKINETICS
As a general note, any volume of blood or CSF samples remaining after the specified 
analyses may be used for assay development/validation of exploratory assays and 
experiments. In addition, blood samples may be used to measure levels of total binding 
competent gantenerumab, characterize drug molecule integrity and potential soluble 
target interference. If performed, the results will be reported in a separate report to the 
CSR.


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Any changes in the timing or addition of time-points for any planned study assessments 
must be documented and approved by the relevant study team member and then, 
archived in the Sponsor and site study files, but this will not constitute a protocol
amendment. 
Placebo-treated participants may not be analysed in the first instance, but retained for 
subsequent analysis if appropriate.
The PK blood and CSF samples will be destroyed 6 months after the release of final 
bioanalytical report at the CRO performing the analysis or shipped to Roche. In the latter 
case the samples may be stored up to 2 years after the date of final CSR. Details on 
sampling procedures, sample storage and shipment are given in the sample 
documentation.
8.6.1
Plasma 
Mandatory blood samples to evaluate concentrations of RO7126209 in plasma will be
collected as outlined in the SoA (see Section 1.3). 
Blood samples must not be taken from the same arm as IV drug administration on Day 1.
The date and time of each sample collection will be recorded in the eCRF.
Plasma concentrations of RO7126209 will be measured by a specific and validated 
 method. PK parameters will be estimated using standard non-compartmental 
methods.
During the course of the study, number of samples and PK sampling time-points may be 
modified on the basis of emerging data to ensure the pharmacokinetics of RO7126209 
can be adequately characterized.
8.6.2
Cerebrospinal Fluid
CSF samples will be collected at the timepoints outlined in the SoA (Section 1.3) and as 
described in Section 8.5. 
RO7126209 CSF concentrations will be measured by a specific and validated 
 
method. CSF pharmacokinetic data will not be required for dose escalation decision.
8.7
IMMUNOGENICITY ASSESSMENTS 
As RO7126209 is a bispecific monoclonal antibody there is a risk that ADA against 
RO7126209 could develop, potentially reducing its efficacy and/or potentially resulting in 
symptomatic hypersensitivity reaction, including immune-complex reactions. Antibodies 
to RO7126209 will be evaluated in blood samples collected from all participants 
according to the SoA (Section 1.3). ADA data will not be required for dose escalation 
decisions.




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8.8.2
Clinical Genotyping
 
 
 
 
 
APOE ε4:
In case of occurrence of ARIA, a whole blood sample will be obtained for DNA 
extraction. These participants will be evaluated for APOE ε4 genotype in order to identify 
their status with respect to their known risk factors for ARIA. 
Data arising from these analyses will be subject to the same confidentiality as the rest of 
the study.
The residual blood will be destroyed within 5 years after the date of final closure of the 
final CSR.
Details on processes for collection and shipment of these samples can be found in the 
Sample Handling Manual.
8.9
HEALTH ECONOMICS 
Health Economics/Medical Resource Utilization and Health Economics parameters will 
not be evaluated in this study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Order of Assessments
At timepoints where more than one assessment is required, the following sequence 
should be followed as applicable, and priority will be given to the PK blood sample being 
taken at the scheduled time: (1) ECGs; (2) Vital signs; (3) Respiratory rate; (4) PK blood 
sampling; (5) Laboratory safety tests and other blood sampling (anti-RO7126209 
antibodies); (6) CSF sampling; (7) others.
8.10.2
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 Forms 
(ICFs) for enrolled participant and for participants who are not subsequently enrolled will 
be maintained at the study site.


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All screening, and all pre-treatment assessments (related to entry criteria), 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 at the time points indicated 
in the SoA Section 1.3), unless otherwise specified.
8.10.3
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). 
8.10.4
Assessments at Study Completion/Early Termination Visit
Participants who complete the study or discontinue from the study early (as described in 
Section 4.1.4 and Section 7) will be asked to return to the clinic 57± 4 days after the 
dose of study drug for a follow‑up visit (see Section 1.3 and Section 8.10.5).
8.10.5
Follow-Up Assessments
Assessments at the follow-up/early termination visit will be performed as indicated in the
SoA (see Section 1.3). After the study completion/early termination visit, adverse events 
should be followed as outlined in Sections 8.3.1 and 8.3.3.
9.
STATISTICAL CONSIDERATIONS
9.1
SAMPLE SIZE DETERMINATION
The maximum number of participants to be randomized was chosen based on practical 
clinical judgment. Thirty-six participants are expected to be enrolled in this study.
Additional participants will be enrolled in 
 with the maximum number of participants not 
exceeding 60. A minimum of 4 active treatment and 2 placebo participants will be 
included in the first two dose levels. Starting at dose level 3 a minimum of 6 active 
treatment and 2 placebo participants will be included.


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The number of participants may be adapted during the study to characterize precisely 
the safety and PK profile of RO7126209.
The current planned study design and sample size complies with standard safety review 
rules applied in single ascending dose studies.
9.2
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 9.
Table 9
Analysis Populations
Population
Description
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
All participants who have received active (RO7126209) 
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.
Immunogenicity
Participants who had at least one predose or at least one post
dose ADA assessment will be included and analyzed 
according to the treatment they actually received. The 
relationship between ADA status and safety, PK, and 
biomarker endpoints will be analyzed and reported 
descriptively via subgroup analyses.
9.3
STATISTICAL ANALYSES
9.3.1
Demographics and Baseline Characteristics
Demographic and other baseline characteristics of the safety analysis population will be 
listed and summarized with descriptive statistics.
9.3.2
Safety Analyses
All safety analyses will be based on the safety analysis population.


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Table 10 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.
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 utilizing 
a mapped term and appropriate drug dictionary level.
Concomitant medications will be presented in summary tables and listings.
9.3.3
Pharmacokinetic Analyses
All PK Analyses will be carried out on the PK analysis population. 
9.3.3.1
Plasma Pharmacokinetic Parameters
Plasma PK parameters of RO7126209 will be read directly from the plasma 
concentration versus time profiles or calculated by using standard non-compartmental 
methods. 
Pharmacokinetic parameters of RO7126209 will include (if appropriate):

Cend: observed plasma concentration at the end of the infusion

AUC0-24h: Area under the plasma concentration versus time curve from zero to 24 h 
postdose

AUC0-168h: Area under the plasma concentration versus time curve from zero to 168h 
postdose

AUC0-last: Area under the plasma concentration versus time curve from zero to the 
last measurable concentration

AUC0-inf: Area under the plasma concentration versus time curve extrapolated to 
infinity


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
z: Terminal rate constant calculated by linear regression of the log-transformed 
terminal part of the concentration time curve

T1/2: Apparent terminal half-life, computed as ln(2)/z

CL : the total body clearance calculated as Dose/AUC

V: Volume of distribution at steady-state, estimated based on iv data using the 
following formula V = MRT *CL, where MRT is the mean residence time and CL 
total body clearance. Mean residence time is calculated as follows : 
MRT = (AUMC0-inf / AUC0-inf) - tinfusion/2, where tinfusion is the infusion duration
9.3.3.2
CSF Pharmacokinetic Parameters
Population pharmacokinetic analyses using non-linear mixed effects modeling will be
performed to analyze the plasma and the CSF concentration data of RO7126209 
following IV administration.
The results of this analysis will be reported in a document separate from the clinical 
study report.
9.3.3.3
Statistical Analyses
The following statistical analysis on the PK parameters (AUC0-, [or if it cannot properly 
be determined AUC0-t or AUC0last] and Cmax) will be performed after completion of the 
study to explore dose-proportionality. The following linear model will be applied to the 
log-transformed, dose-normalized pharmacokinetic study variables:
,…,M)
,
,…,N; j=
,
(i=
y
ij
j
ij
2
1
2
1
   
~





where is the number of different doses, N is the total number of participants, denotes 
the general mean of the transformed variables, j is the effect of dose j and j is the 
residual error for participant i in the dose level j. The residual errors are assumed to be
independent and identically distributed following a normal distribution with zero mean 
and variance 2.
Least square means with corresponding 90% confidence intervals (CI) will be derived for 
each dose level and plotted to evaluate if there are obvious trends for normalized PK 
parameters of decreasing/increasing with dose.
The following hypothesis will be tested (in an exploratory sense) for the primary 
pharmacokinetic parameters:
H0: There is no deviation from dose-proportionality (i.e., 1 2 …M)
versus
H1 : There is a deviation from dose-proportionality (1 ≠2 for some i, j).
All p values will be interpreted in an exploratory sense only.


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9.3.4
Bayesian Analysis to Support Dose-Escalation 
Recommendations
A Bayesian CRM model will be used to inform decisions about the dose of RO7126209 
to be given to the next cohort, based on the accumulating data for safety (measured by 
the occurrence of dose-limiting events [DLEs]) and PK. A DLE will be defined as any 
treatment-related adverse reaction (e.g., AE, laboratory abnormality, change in vital 
signs, ECG) occurring within 8 days after dosing, that would prevent another drug 
administration at the same dose level in a given participant.
Following the accumulation of safety and PK data for each cohort of participants, a CRM 
model will recommend doses which:
1. Limit to ≤ 20% the probability of a DLE rate ≥ 30% (Estimation of the highest dose 
D1, such that: Prob(DLE rate at D1 30%) 20%).
2. Limit the probability of exceeding a predicted mean maximum exposure level 
(MEL) to 20%. (Estimation of D2, such that Prob{Cmax(D2) CMEL } 20%).
24.
If D1 or D2 is less than the default increment, min(D1, D2) will be selected, otherwise the 
default increment.
The CRM method uses the data of the last and all previous cohorts. All calculations will 
be performed using a Bayesian framework with the priors properly predefined.
However, clinical judgment will always override model estimates in the dose selection 
process.
Simulations were performed to examine the operating characteristics of the CRM model 
across some dose-response profiles for safety (DLEs) (Appendix 6).
9.3.5
Immunogenicity Analyses 
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any 
treatment (Shankar et al 2014).
The numbers and proportions of ADA-positive participants and ADA-negative
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence 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).


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
Participants 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 
will be analyzed and reported descriptively via subgroup analyses.
9.3.6
Pharmacokinetic / Safety Relationships 
Exploratory investigation of the relationship between plasma exposure of RO7126209 
and safety measurements may be performed. 
9.4
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.
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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 EU/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 or their 
legally authorized representative 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 (HIPAA) requirements, where applicable, 


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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 or the 
participant’s legally authorized representative.
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative 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 or the 
participant’s legally authorized representative. 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.
Each Consent Form may also include participant 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 participant 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.
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 


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names or any information which would make the participant identifiable will not be 
transferred. 
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.
Study data may be submitted to government or other health research databases or
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
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., LPLV)
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.


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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.
2.1.2.
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.
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.
2.1.3.
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.


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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 unless 
local regulations or institutional policies require a longer retention period. 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.
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.
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 patients 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.


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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.
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.
3.
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.
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:

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 (see Appendix 3, Section 4).

Exacerbation of a chronic or intermittent preexisting 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).
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.

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 preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.


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2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a 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 preexisting 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.

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 


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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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 Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing adverse event severity). 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as grade 1, grade 2, grade 3, grade 4, grade 5, according 
National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE 
(v5) ); the event itself may be of relatively minor medical significance (such as grade 3
headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event.


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Table 1
Adverse Event Severity Grading Scale
Severity
Description
Grade 1
mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
Grade 2
moderate; minimal, local, or non-invasive intervention indicated; or limiting age 
appropriate instrumental activities of daily livinga
Grade 3
severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c
Grade 4
life-threatening consequences or urgent intervention indicated.
Grade 5
death related to adverse eventd
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the NCI CTCAE (v5), which can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referenc
e_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.
d Grade 4 and 5 events must be reported as serious adverse events.
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.

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.


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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)
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.


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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 AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, 
adverse events and 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.
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.


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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 RO7126209 or matching 
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 RO7126209 or matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as Special Situations. Special situations should be recorded as 
described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details.


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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}:

RO7126209 IB
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.
INFUSION-RELATED REACTIONS
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study treatment infusion should be captured as a diagnosis 
(e.g., infusion-related reaction or anaphylactic reaction) on the Adverse Event eCRF. If 
possible, avoid ambiguous terms such as “systemic reaction”. Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF. If a 
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 Infusion-Related 
Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS 
For adverse events other than infusion-related reactions (see Section 1.1), a diagnosis 
(if known) should be recorded on the Adverse Event eCRF rather than individual signs 
and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, 
and elevated transaminases). However, if a constellation of signs and/or symptoms 
cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded on the Adverse Event eCRF. If a 
diagnosis is subsequently established, all previously reported adverse events based on 
signs and symptoms should be nullified and replaced by one adverse event report based 
on the single diagnosis, with a starting date that corresponds to the starting date of the 
first symptom of the eventual diagnosis.
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 ULN associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 


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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.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.


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
Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF 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.
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. 
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”).
9.
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


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
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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
Definition of Laboratory Abnormalities
For all laboratory parameters included in this analysis, 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 these laboratory parameters. 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. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.

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.
2
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 study 
treatment.
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 


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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.
3
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 embryofetal 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 or therapeutic abortion not associated with an underlying maternal or 
embryofetal 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.
4
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a 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).


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Appendix 6
Statistical Details and Simulation of the Operating 
Characteristics of the Planned Design for Supporting the Dose-
Escalation Recommendations
Statistical Models
Details on the statistical models, methods and algorithms as well as scenarios for 
evaluating the operating characteristics of the CRM designs are given below.
Model for safety analysis
The relationship between the dose and the probability of observing a DLE will be 
described by the following two-parameter logistic regression model:
where p is the probability of observing a DLE at a given dose, α is the log of the odds for 
p at the reference dose (, here equals to 0.3 mg) and β is the slope of the curve. 
(detailed discussion about this model parameterization can be found in 
[Neuenschwander B.,Branson M., Gsponer T. Critical Aspects of the Bayesian Approach 
to Phase I Cancer Trials. Stat Med, 2008; 27:2420-2439.])
Since the model will be estimated using a Bayesian framework, priors need to be 
specified for α and β. Neuenschwander’s ‘minimally informative prior’ will be used 
(Neuenschwander, 2008). This prior was built on the assumption that the starting dose 
(0.1 mg/kg) is safe (probability that DLE rate > 0.2 is less than 0.05) and with 10.8 mg/kg,
the probability of DLE rate > 0.35 is 0.6.
The resulting bivariate distribution that will be used is:
Figure 1 shows the graph of the chosen prior with 95%-credible interval.


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Figure 1. Prior for safety analysis.
Simulations for the operating characteristics
Simulations were performed to examine the operating characteristics of the CRM model 
across some dose-response profiles for safety (DLEs). 
For the simulation, the following settings were made:

Maximum number of cohorts: 6

Cohort size: For the first 3 dose levels, 4+2 and the last 3 dose levels 6+2

Decision criterion for safety: prob(DLE rate 30%) 0.2

The dose grid is (in mg/kg) 0.1 0.2 0.3 0.4 0.5 0.6  0.7  0.8  0.9  1.2  1.5  1.8  2.1
2.4  2.7  3.0  3.6  4.2  4.8  5.4  6.0  6.6  7.2  7.8  8.4 9.0  9.6 10.2 10.8
0
25
50
75
100
0
3
6
9
Dose level [mg/kg]
Probability of DLT [%]
Type
Estimate
95% Credible Interval
Prior for safety


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The simulations were based on a hypothetical ‘simulation truth’. Three scenarios based 
on a logistic regression models, an ‘optimistic’, a ‘realistic’ and a ‘pessimistic’ one, were 
chosen. The doses, where a DLE probability of 0.3 is achieved under these scenarios 
are 12 mg/kg, 4 mg/kg, and 2 mg/kg, respectively. Figure 2 below shows a graphical 
display of these parameters.
Figure 2. Simulation truths for evaluating operating characteristics for safety.
ß
Results from the simulations
The first table (Table 1) shows what the next recommended dose is for all possible 
number of DLEs observed, assuming no DLEs are observed until the current dose 
level.


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Table 1: Examination of the chosen safety decision algorithm.
dose
DLTs
next Dose
0.1
0
0.300
0.1
1
0.200
0.1
2
0.001
0.1
3
0.001
0.3
0
0.900
0.3
1
0.700
0.3
2
0.300
0.3
3
0.100
0.9
0
2.700
0.9
1
1.200
0.9
2
0.600
0.9
3
0.400
2.7
0
5.400
2.7
1
4.800
2.7
2
2.100
2.7
3
1.200
5.4
0
10.800
5.4
1
9.600
5.4
2
6.600
5.4
3
3.600
The next table (Table 2) displays operating characteristics based on 1000 simulations for 
the three scenarios described in the previous section. Dmax, denotes the highest dose 
such that: Prob(DLE rate at Dmax > 30%) < 20%).


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Table 2: Operating characteristics; means and Intervals corresponding to 10 and 90 % 
quantiles.
Scenario
Proportions of DLEs on 
active 
[%]
Dose most often 
chosen as Dmax
Observed DLE rate at . 
Dmax  [%]
optimistic
7.3(2.8,12.3ß)
4.4 mg/kg
11.7
realistic
9.2(4.8,11.9)
1.6 mg/kg
8.3
pessimistic
13.3(9.5,16.7)
0.8 mg/kg
13.1
Remarks and Conclusions
The proposed CRM design shows a good protection against overdosing and gives 
reasonable estimates for the mean of the doses as selected as Dmax. The results in
Table 1have to be interpreted with caution for the lowest doses. 


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Appendix 7 Equivalent Visual Acuity Measurements
Snellen Visual Acuity
4 meters
6 meters
20 feet
Decimal 
fraction
LogMAR
4/40
6/60
20/200
0.10
+1.0
4/32
6/48
20/160
0.125
+0.9
4/25
6/38
20/125
0.16
+0.8
4/20
6/30
20/100
0.20
+0.7
4/16
6/24
20/80
0.25
+0.6
4/12.5
6/20
20/63
0.32
+0.5
4/10
6/15
20/50
0.40
+0.4
4/8
6/12
20/40
0.50
+0.3
4/6.3
6/10
20/32
0.63
+0.2
4/5
6/7.5
20/25
0.80
+0.1
4/4
6/6
20/20
1.00
+0.0
4/3.2
6/5
20/16
1.25
-0.1
4/2.5
6/3.75
20/12.5
1.60
-0.2
4/2
6/3
20/10
2.00
-0.3