Clinical trial NCT04475848
Conditions: Autistic Disorder Autism Spectrum Disorder Child Development Disorders, Pervasive Mental Disorders Neurodevelopmental Disorders
Keywords: Autism Spectrum Disorder
Sponsor: Hoffmann-La Roche
Start date: 2020-07-15; Completion date: 2022-02-06
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect (FE) of RO6953958 following oral administration in healthy male participants. Part 3 (Drug-drug interaction (DDI)) will assess the safety, tolerability, and effect of RO6953958 on the PK of the cytochrome P450 (CYP) 3A substrate midazolam.

Detailed description:

Arms: arm 1: There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of RO6953958 while fasted. Participants in the fed (FE) cohort will return to receive the same single oral dose of RO6953958 repeated in the fed state. arm 2: There will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed. arm 3: A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 once daily (QD) for 10 days. arm 4: A maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of palcebo QD for 10 days. arm 5: RO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD).

Participants will also be administered midazolam.
Interventions: intervention 1: RO6953958 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg).

Part 2: The starting dose is planned to be 45 mg.

Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD). intervention 2: Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg.

Part 2: The starting dose is planned to be 45 mg. intervention 3: Midazolam will be administered as single intervenous (IV) bolus injection of 100 micrograms (ug) on Day 1 and Day 13, and as single oral dose of 300 ug on Day 2 and Day 14.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: A Randomized, Investigator- /Subject- Blind, Single- and Multiple-
Ascending Dose, Placebo-Controlled Study to Investigate Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of 
RO6953958 (Including RO6953958 Effect on Midazolam) Following 
Oral Administration in Healthy Male Participants 
NCT Number: NCT04475848  
Document Date: Protocol Version 7: 05-November-2021 


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.
RO6953958 —F. Hoffmann-La Roche Ltd
Protocol BP41695, Version 7
PROTOCOL
TITLE:
A RANDOMIZED, INVESTIGATOR- /SUBJECT-
BLIND, SINGLE- AND MULTIPLE-ASCENDING 
DOSE, PLACEBO-CONTROLLED STUDY TO 
INVESTIGATE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS
AND FOOD EFFECT OF RO6953958 (INCLUDING 
RO6953958 EFFECT ON MIDAZOLAM) 
FOLLOWING ORAL ADMINISTRATION IN HEALTHY 
MALE PARTICIPANTS
PROTOCOL NUMBER:
BP41695
VERSION:
7
EUDRACT NUMBER:
2019-004486-41
IND NUMBER:
Not applicable
TEST PRODUCT:
RO6953958
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 13 December 2019
DATE AMENDED:
Version 2: 28 February 2020
Version 3: 26 May 2020
Version 4: 06 Nov 2020
Version 5: 02 February 2021
Version 6: 19 April 2021
Version 7: See electronic date stamp below
Company Signatory
Approver's Name
Title
Date and Time (UTC)
05-Nov-2021 10:46:36


RO6953958—F. Hoffmann-La Roche Ltd
2/Protocol BP41695, Version 7
PROTOCOL ACCEPTANCE FORM
TITLE:
A RANDOMIZED, INVESTIGATOR- /SUBJECT-
BLIND, SINGLE- AND MULTIPLE-ASCENDING 
DOSE, PLACEBO-CONTROLLED STUDY TO 
INVESTIGATE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS 
AND FOOD EFFECT OF RO6953958 (INCLUDING 
RO6953958 EFFECT ON MIDAZOLAM) 
FOLLOWING ORAL ADMINISTRATION IN HEALTHY 
MALE PARTICIPANTS
PROTOCOL NUMBER:
BP41695
VERSION NUMBER:
7
EUDRACT NUMBER:
2019-004486-41
IND NUMBER:
Not applicable
TEST PRODUCT:
RO6953958
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.


RO6953958—F. Hoffmann-La Roche Ltd
3/Protocol BP41695, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol BP41695 has been amended to include an additional study part (Part 3 
Drug-drug interaction [DDI]) to assess the effect of RO6953958 on the pharmacokinetics
of the cytochrome P450 (CYP) 3A substrate midazolam. Changes to the protocol, along 
with a rationale for each change, are summarized below:

Addition of Study Part 3 (DDI)
–
The study title has been updated.
–
Figure 2 has been added to Section 1.2 (Schematic of Study Design).
–
Tables have been added to Section 1.3 (Schedule of Activities) (Table 5 overall 
schedule, Tables 6 and 7, detailed schedules).
–
Section 2.1 (Study Rationale) has been updated to include Part 3 DDI 
–
Section 3 (Objectives) has been updated to include Part 3 objectives.
–
Section 4.1 (Study Design) has been updated to include Part 3 overall design.
–
Section 4.1.3 (Part 3 DDI) has been added to include Part 3 study design.
–
Section 4.1.4 (Length of study) has been updated to include the duration and 
activities of Part 3.
–
Section 4.2.7 (Rationale for Drug-Drug Interaction Evaluation and the Use of 
Midazolam) has been added to provide background for microdosing with 
midazolam.
–
Section 4.2.8 (Rationale for Measuring 4-Hydroxycholesterol/Cholesterol 
Ratio) has been added to provide background for using the 
4-hydroxycholesterol/cholesterol ratio in plasma as an endogenous marker for 
hepatic CYP3A4 inhibition. Section 8.7.14 was added to cover the blood 
samples required for this analysis.
–
Section 4.3.2 (Part 3 Dose Justification) has been updated to include dose 
justifications for RO6953958 and midazolam.
–
Section 5.2 (Exclusion criteria), Criterion #20 was added to account for use of 
midazolam.
–
Section 6 (Treatment) and 6.1 (Treatment administered) were updated to 
include midazolam as non-investigational medicinal product (NIMP).
–
Section 6.3.1 (Method of Treatment Assignment) was updated to include 
enrolment details for Part 3.
–
Section 8.5 (PK) was updated to include plasma concentration determination of
midazolam.
–
Section 9.2.2 (Part 3 Drug-Drug Interaction) was added to include sample size 
determination in Part 3.


RO6953958—F. Hoffmann-La Roche Ltd
4/Protocol BP41695, Version 7
–
Section 9.4.3.1 (Pharmacokinetic Parameters) has been updated to include 
Part 3 PK parameters.
–
Section 9.4.3.2 (Statistical Analysis Methods) has been updated to include 
Part 3. 

Further changes:
–
Dose escalation: Figure 1, Table 11, and Table 12 have been updated to reflect 
the actual doses given in the ongoing study (Part 1 and Part 2).
–
Section 2.1 (Study Rationale), Section 2.2.1 (background on indication), and 
Section 2.2.2 (Background on RO6953958) have been updated to align with the 
most recent Investigator’s Brochure, now referring to “neurodevelopmental 
disorders” (NDDs) as an indication instead of “autism spectrum disorder (ASD) 
and autism-related sleep disorders”. Section 4.2.2 (Rationale for Study 
Population) has been updated accordingly. The requirement to exclude 
participants with sleep disorder from study Part 2 has been removed from 
exclusion criterion #31. 
–
Section 2.2.2.2 (Preliminary Blinded Safety and Pharmacokinetic and Safety 
Data Observed in Part 1 and Part 2) has been updated to include new 
participant data.
–
Because the theoretical risk of blood pressure decrease has not been fully 
evaluated, Section 2.3 (Benefit/Risk Assessment) has been updated to indicate 
that care should be taken by participants not to stand up abruptly or without 
using the support of a stable object following dosing with RO6953958.
–
Section 8.7.1.1 (Clinical genotyping) was updated to include additional 
genotyping assessments.
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RO6953958—F. Hoffmann-La Roche Ltd
5/Protocol BP41695, Version 7
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL AMENDMENT, VERSION 7: RATIONALE...................................... 3
1.
PROTOCOL SUMMARY............................................................................. 14
1.1
Synopsis................................................................................ 14
1.2
Schematic of Study Design.................................................... 26
1.3
Schedule of Activities ............................................................ 26
2.
INTRODUCTION ........................................................................................ 47
2.1
Study Rationale ..................................................................... 47
2.2
Background ........................................................................... 47
2.2.1
Background on Neurodevelopmental Disorders .................... 47
2.2.2
Background on RO6953958 .................................................. 48
2.2.2.1
Safety Information from Drugs of the Same Class................. 51
2.2.2.2
Preliminary Pharmacokinetic and Safety Data 
Observed in Part 1 and Part 2 ............................................... 52
2.3
Benefit/Risk Assessment....................................................... 56
3.
OBJECTIVES AND ENDPOINTS ............................................................... 59
4.
STUDY DESIGN......................................................................................... 62
4.1
Overall Design ....................................................................... 62
4.1.1
Part 1 (SAD/FE)..................................................................... 63
4.1.2
Part 2 (MAD).......................................................................... 64
4.1.3
Part 3 (DDI) ........................................................................... 65
4.1.4
Length of the Study ............................................................... 66
4.1.5
Dose-Escalation Decision Criteria ......................................... 66
4.1.5.1
Data Requirements for Dose-Escalation Decision 
for Sentinel Group and Dose Groups in Part 1 ...................... 67
4.1.5.2
Decision Criteria to Progress from Part 1 to Part 
2 ............................................................................................ 68
4.1.5.3
Data Requirements for Dose-Escalation Decision 
Criteria for Part 2 ................................................................... 68
4.1.5.4
Decision to Expand Cohorts in Part 2 Based on 
Review of Sleep Biomarkers.................................................. 68
4.1.6
Stopping Rules ...................................................................... 69


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6/Protocol BP41695, Version 7
4.1.6.1
Stopping Rules for the Study................................................. 69
4.1.6.2
Stopping Rules for Individuals ............................................... 69
4.1.6.3
Stopping Rules after Dosing of the Sentinel 
Group in Part 1 (all Dose Levels)........................................... 70
4.1.6.4
Dose-Escalation and Study Cohort Stopping 
Rules in Part 1 and Part 2...................................................... 70
4.1.7
Communication Strategy for Preceding from the 
Sentinel Group and each Dose Groups in Parts 1 
and 2...................................................................................... 70
4.2
Scientific Rationale for Study Design..................................... 71
4.2.1
Rationale for Number of Dosing Days and 
Regimen in Part 2.................................................................. 71
4.2.2
Rationale for Study Population .............................................. 71
4.2.3
Rationale for Control Group................................................... 72
4.2.4
Rationale for Orthostatic Challenge....................................... 72
4.2.5
Rationale for PD/Biomarker Assessments............................. 72
4.2.6
Rationale for CSF sampling................................................... 72
4.2.7
Rationale for Drug-Drug Interaction Study Design 
and the Use of Midazolam..................................................... 73
4.2.8
Rationale for Measuring 
4-Hydroxycholesterol/Cholesterol Ratio............................... 74
4.3
Justification for Dose ............................................................. 74
4.3.1
Starting Dose......................................................................... 74
4.3.2
Part 3 Dose Justification........................................................ 75
4.3.3
Maximum Exposure/Dose...................................................... 76
4.4
End of Study Definition .......................................................... 77
5.
STUDY POPULATION................................................................................ 77
5.1
Inclusion Criteria.................................................................... 77
5.2
Exclusion Criteria................................................................... 78
5.3
Lifestyle Considerations......................................................... 81
5.3.1
Meals and Dietary Restrictions.............................................. 81
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 82
5.3.3
Activity ................................................................................... 82
5.4
Screen Failures ..................................................................... 82
5.5
Recruitment Procedures........................................................ 82


RO6953958—F. Hoffmann-La Roche Ltd
7/Protocol BP41695, Version 7
6.
TREATMENTS............................................................................................ 83
6.1
Treatments Administered....................................................... 83
6.2
Preparation/Handling/Storage/Accountability ........................ 86
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 87
6.3.1
Method of Treatment Assignment.......................................... 87
6.3.2
Blinding and Emergency Unblinding...................................... 88
6.4
Treatment Compliance .......................................................... 89
6.5
Concomitant Therapy ............................................................ 89
6.5.1
Permitted Therapy................................................................. 89
6.5.2
Prohibited Therapy ................................................................ 90
6.6
Dose Modification.................................................................. 90
6.7
Treatment after the End of the Study..................................... 91
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 91
7.1
Discontinuation of Study Treatment....................................... 91
7.2
Participant Discontinuation/Withdrawal from the 
Study and Participant Replacement ...................................... 92
7.3
Lost to Follow-Up................................................................... 92
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 93
8.1
Efficacy Assessments............................................................ 93
8.2
Safety Assessments .............................................................. 93
8.2.1
Physical Examinations........................................................... 93
8.2.2
Vital Signs.............................................................................. 94
8.2.2.1
Orthostatic Challenge Testing ............................................... 94
8.2.3
Electrocardiograms................................................................ 94
8.2.3.1
Holter ECG Monitoring........................................................... 95
8.2.4
Clinical Safety Laboratory Assessments................................ 97
8.2.5
Suicidal Risk Monitoring ........................................................ 98
8.2.6
Medical History and Demographic Data ................................ 99
8.3
Adverse Events and Serious Adverse Events ....................... 99
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 99


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8/Protocol BP41695, Version 7
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ................................................................... 100
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ................................................................... 100
8.3.3.1
Investigator Follow-Up......................................................... 100
8.3.3.2
Sponsor Follow-Up .............................................................. 100
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ................................................................... 101
8.3.4.1
Emergency Medical Contacts.............................................. 101
8.3.5
Pregnancy ........................................................................... 101
8.3.6
Non-Serious Adverse Events of Special Interest................. 101
8.4
Treatment of Overdose........................................................ 102
8.5
Pharmacokinetics ................................................................ 102
8.6
Immunogenicity Assessments ............................................. 104
8.7
Pharmacodynamics and Biomarker Analyses ..................... 104
8.7.1
Genetic and Genomic Analyses .......................................... 104
8.7.1.1
Clinical Genotyping.............................................................. 104
8.7.2
Pittsburgh Sleep Quality Index ............................................ 104
8.7.3
Patient-Reported Outcomes Measurement 
Information System Sleep Questionnaires........................... 104
8.7.4
Karolinska Sleepiness Scale (KSS)..................................... 105
8.7.5
Epworth Sleepiness Scale (ESS) ........................................ 105
8.7.6
Morningness-Eveningness Questionnaire (MEQ)................ 105
8.7.7
Sleep Mat ............................................................................ 105
8.7.8
Polysomnography................................................................ 106
8.7.9
Platelet Aggregation Assay.................................................. 106
8.7.10
Facial Expression Recognition Task.................................... 106
8.7.11
Circadian Sleep Biomarkers ................................................ 106
8.7.12
Core Body Temperature Assessment.................................. 106
8.7.13
Wake EEG........................................................................... 107
8.7.14
4-Hydroxycholesterol and Total Cholesterol...................... 107
8.8
Pharmacodynamics and Biomarker Samples...................... 107
8.9
Samples for Research Biosample Repository ..................... 107
8.9.1
Overview of the Research Biosample Repository................ 107


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9/Protocol BP41695, Version 7
8.9.2
Sample Collection................................................................ 108
8.10
Medical Resource Utilization and Health 
Economics........................................................................... 109
8.11
Timing of Study Assessments ............................................. 109
8.11.1
Screening and Pretreatment Assessments.......................... 109
8.11.2
Assessments during Treatment........................................... 109
8.11.3
Assessments at Study Completion/Early 
Termination Visit.................................................................. 109
8.11.4
Follow-Up Assessments ...................................................... 110
8.11.5
Assessments at Unscheduled Visits.................................... 110
9.
STATISTICAL CONSIDERATIONS .......................................................... 110
9.1
Statistical Hypotheses ......................................................... 110
9.2
Sample Size Determination ................................................. 110
9.2.1
Part 1 (Single Ascending Doses) and Part 2 
(Multiple Ascending Doses)................................................. 110
9.2.2
Part 3 (Drug-Drug Interaction) ............................................. 110
9.3
Populations for Analyses ..................................................... 111
9.4
Statistical Analyses.............................................................. 111
9.4.1
Demographics and Baseline Characteristics ....................... 111
9.4.2
Safety Analyses................................................................... 111
9.4.3
Pharmacokinetic Analyses................................................... 112
9.4.3.1
Pharmacokinetic Parameters............................................... 112
9.4.3.2
Statistical Analysis Methods ................................................ 113
9.4.4
Cardiodynamic Electrocardiogram (ECG) 
Assessment......................................................................... 115
9.4.5
Pharmacodynamic Analyses ............................................... 116
9.5
Summaries of Conduct of Study.......................................... 116
10. REFERENCES ......................................................................................... 117
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.................................................................................. 121
LIST OF TABLES
Table 1
Overall Schedule of Activities – Part 1........................................ 27


RO6953958—F. Hoffmann-La Roche Ltd
10/Protocol BP41695, Version 7
Table 2
Detailed Schedule of Activities – Part 1 ...................................... 29
Table 3
Overall Schedule of Activities – Part 2........................................ 31
Table 4
Detailed Schedule of Activities – Part 2 ...................................... 35
Table 5
Overall Schedule of Activities – Part 3........................................ 43
Table 6
Detailed Schedule of Activities on Day 1 and Day 13 – Part 3.... 45
Table 7
Detailed Schedule of Activities on Day 2 (Day 3 for 
RO6953958 PK Profile) and Day 14 – Part 3.............................. 46
Table 8
Summary of pharmacokinetic parameters for RO6953958 
and its metabolites (RO7045755 [M1] and RO7021594 [M3]) 
following single doses of 5, 15, 45, 90, 180, and 360 mg 
under fasted and fed conditions.................................................. 53
Table 9
Summary of Pharmacokinetic Parameters for RO6953958 
and the Metabolites RO7045755 (M1) and RO7021594 (M3) 
on Day 1 and Day 10 Following Multiple Oral Doses of 45 
mg and 140 mg for 10 Days Under Fed Conditions.................... 55
Table 10
Objectives and Endpoints ........................................................... 60
Table 11
Confirmed and Tentative Dose Escalation in the SAD (Part 
1)................................................................................................. 64
Table 12
Confirmed and Tentative Dose Escalation in the MAD (Part 
2)................................................................................................. 65
Table 13
Estimated Margins of Safety for Entry-Into-Human Starting 
and Therapeutic Dose................................................................. 75
Table 14
Summary of Treatments Administered........................................ 84
Table 15
T-Wave Morphology and U-Wave Presence Categories 
(Assessed Manually)................................................................... 97
Table 16
Analysis Populations................................................................. 111
Table 17
Safety Statistical Analysis Methods .......................................... 112
LIST OF FIGURES
Figure 1
Overview of Study Design for Part 1 and Part 2.......................... 26
Figure 2
Overview of Study Design for Part 3........................................... 26
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations......... 122
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting........................................................... 130
Appendix 3
Procedures for Recording Adverse Events ............................... 138
Appendix 4
Clinical Laboratory Tests .......................................................... 142
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 145


RO6953958—F. Hoffmann-La Roche Ltd
11/Protocol BP41695, Version 7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
4HC
4-hydroxycholesterol
AE
Adverse event
ALT
Alanine aminotransferase
AR
Accumulation ratio
ASD
Autism Spectrum Disorder
AST
Aspartate aminotransferase
AUC
Area under the curve
AUCinf
Area under the concentration–time curve from Time 0 
to infinity
AUC0-24
Area under the plasma concentration–time curve from 
0 to 24 hours
BCRP
Breast cancer resistance protein
BID
Twice daily
C-SSRS
Columbia Suicide Severity Rating Scale
CI
Confidence interval
Cmax
Maximum observed concentration
CNS
Central nervous system
COVID-19
Corona virus pandemic: the name designation refers to 
COVI for the acronym of coronavirus, D for the word 
disease, and 19 for the year of the outbreak.
CSF
Cerebrospinal Fluid
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of variation
CYP
Cytochrome P450
DDI
Drug-drug interaction
DRF
Dose-range finding
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EFD
Embryo-fetal development
ESS
Epworth Sleepiness Scale
EU
European Union
FDA
Food and Drug Administration
FE
Food effect
FERT
Facial Emotion Recognition Task


RO6953958—F. Hoffmann-La Roche Ltd
12/Protocol BP41695, Version 7
Abbreviation
Definition
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HED
human equivalent dose
hERG
Human ether à go-go
HIV
Human immunodeficiency virus
HR
Heart rate
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IV
Intravenous
Kb
Dissociation constant
KSS
Karolinska Sleepiness Scale
LPLO
Last participant, last observation
M1
RO7045755
M3
RO7021594
MAD
Multiple-ascending dose
MEQ
Morningness–eveningness Questionnaire
MFD
Maximum feasible dose
MHRA
Medicines and Healthcare products Regulatory Agency
NCI
National Cancer Institute
NDD
Neurodevelopmental disorder
NIMP
Non-investigational product
NOAEL
No-observed-adverse-effect level
NSAESI
Non-serious adverse event of special interest
OATP
Organic anion-transporting polypeptide
OTC
Over-the-counter
PAA
Platelet aggregation assay
PAD
Pharmacologically active dose
PD
Pharmacodynamic(s)
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)


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Abbreviation
Definition
PR 
PR interval of the ECG
PROMIS
Patient-Reported Outcomes Measurement Information 
System
PSG
Polysomnography
PSQI
Pittsburgh Sleep Quality Index
QD
Once daily
QRS
QRS interval of the ECG
QT
QT interval of the ECG
QTc
Corrected QT interval
QTcF
Corrected QT interval using the Fridericia’s formula
RBR
Research biosample repository
REC
Research Ethics Committee
RR
RR interval of the ECG
SAD
Single-ascending dose
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SE
Sleep efficiency
SMS
Smith-Magenis syndrome
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
tmax
Time of maximum concentration observed
ULN
Upper limit of normal
US
United States
V
Volume
V/F
Apparent volume of distribution
Vss
Volume of distribution under steady-state conditions
WOCBP
Women of childbearing potential


RO6953958—F. Hoffmann-La Roche Ltd
14/Protocol BP41695, Version 7
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A RANDOMIZED, INVESTIGATOR- /SUBJECT-BLIND, SINGLE-
AND MULTIPLE-ASCENDING DOSE, PLACEBO-CONTROLLED 
STUDY TO INVESTIGATE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, PHARMACODYNAMICS AND FOOD 
EFFECT OF RO6953958 (INCLUDING RO6953958 EFFECT ON 
MIDAZOLAM) FOLLOWING ORAL ADMINISTRATION IN 
HEALTHY MALE PARTICIPANTS
SHORT TITLE
A Randomized, SAD/MAD/DDI, Placebo-Controlled Study for 
Safety, Tolerability, PK, PD, and Food Effect following 
RO6953958 Administration in Healthy Participants
PROTOCOL NUMBER:
BP41695
VERSION:
7
TEST PRODUCT:
RO6953958
PHASE:
I
RATIONALE
RO6953958 is a potent and selective human vasopressin V1a receptor antagonist that blocks 
the activation of the V1a G protein-coupled receptor. Evidence from mouse studies implicates 
V1a receptor antagonism in the accelerated resynchronization of circadian rhythm. 
RO6953958 is highly potent on the human V1a receptor (dissociation constant [Kb] = 0.22 nM) 
and may provide a novel and first approach to treat circadian disturbances and social deficits in 
neurodevelopmental disorders (NDDs). This is the first study with RO6953958 in humans, 
designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) 
of single- and multiple-ascending doses (MAD), food effect (FE), and drug-drug interaction 
(DDI) potential following oral administration to healthy male participants. The study results will 
support further clinical development of RO6953958.


RO6953958—F. Hoffmann-La Roche Ltd
15/Protocol BP41695, Version 7
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Parts 1, 2, 
and 3

To assess the safety and 
tolerability of single- and 
multiple-ascending doses 
of RO6953958 alone and 
in combination with 
midazolam (Part 3 only) in 
healthy participants

Incidence and severity of AEs. 
Changes in vital signs, physical 
findings, ECG parameters (12-lead 
safety in all parts and 24-hour 
Holter in Part 1 and Part 2 only), 
and clinical laboratory results 
during and following RO6953958
administration

Change in suicide risk (using 
Columbia Suicide Severity Rating 
Scale) in Part 2 and 3 only
Secondary
Parts 1, 2, 
and 3

To investigate the PK of 
RO6953958 and its 
metabolites RO7021594 
and RO7045755 following 
single and multiple doses
of RO6953958 alone and 
in combination with 
midazolam (Part 3 only)

To investigate the dose 
proportionality of 
RO6953958

PK concentrations and PK 
parameters of RO6953958 and its 
metabolites RO7021594 and 
RO7045755
Part 1

To assess the effect of food 
on the PK of a single dose 
of RO6953958

PK concentrations and PK 
parameters of RO6953958 and its 
metabolites RO7021594 and 
RO7045755 in fasted and fed state
Part 3

To investigate the effect of 
RO6953958 on the PK of 
the cytochrome P450 
(CYP) 3A substrate 
midazolam

PK concentrations and parameters 
of midazolam
OVERALL DESIGN
The study is a three-part design. Part 1 (single-ascending dose [SAD]) of this study will examine 
safety and tolerability, and characterize PK and PD effect by evaluating the Karolinska 
sleepiness scale (KSS). Part 1 will also evaluate FE after RO6953958 administration at the 
dose(s) proposed for clinical use. In Part 2 (multiple-ascending dose [MAD]) the safety, 
tolerability, PK and PD effects by evaluating cortisol, melatonin, and sleep parameters of multiple 
doses of RO6953958 will be evaluated in fed conditions, based on preliminary PK data in Part 1. 
In addition, the concentration of RO6953958 and its metabolites will be measured in CSF.


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The doses in Part 2 will be determined based on review of the Part 1 data. Ascending doses are 
planned in order to establish the safety and tolerability at low dose levels before proceeding to 
higher dose levels. Dose levels may be adjusted (increased, decreased, or repeated), or 
intermediate doses may be used depending on the emerging safety and PK data at each dose 
level.
In Part 3, the safety, tolerability, and effect of RO6953958 on the pharmacokinetics of the 
cytochrome P450 (CYP) 3A substrate midazolam will be assessed by evaluating PK parameters 
of midazolam. In addition, concentrations of 4-hydroxycholesterol and total cholesterol will 
be measured and the 4-hydroxycholesterol/cholesterol ratio will be calculated as an 
endogenous marker of CYP3A activity.
Study Design
Part 1 (SAD/FE)
Part 1 will be a randomized, investigator-/subject-blind, placebo-controlled SAD study with a 
parallel design and sentinel dosing, to explore the safety, tolerability, PK, and PD of single doses 
of orally administered RO6953958 in the fasted state and using one cohort to administer 
RO6953958 in the fed state.
Participants will be recruited in seven sequential cohorts. In each cohort, participants will receive 
either a single oral dose of RO6953958 or placebo while fasted. Participants in the FE cohort 
(90 mg) will return to receive the same dose repeated in the fed state. Each participant in the 
selected cohort will receive a single dose of RO6953958 30 minutes after starting a standardized 
high fat, high calorie breakfast. If participants are not willing to complete the fed part, additional 
participants will be recruited to ensure that a minimum number of participants complete food 
effect investigations (6 on active treatment and 2 on placebo in each period).
The starting dose of 5 mg is anticipated to be safe and have minimal pharmacological effects. 
Subsequent doses will be selected during study conduct based on emerging safety and PK data. 
In all cohorts, sentinel dosing will be employed to allow for an evaluation of safety data by the 
Investigator up to 23 hours after the start of treatment before subsequent participants are dosed. 
There will be at least 1 week between each dose level in order to permit adequate time for 
collation and review of emerging data before the next dose is administered. After review of the 
PK exposures in Cohort 1 and in the case that the observed exposure (maximum observed 
concentration [Cmax] and area under the concentration–time curve from Time 0 to infinity [AUCinf])
of the first dose in humans is significantly below the predicted concentrations, the dose of 
Cohort 2 may be adjusted by a greater than 3.3-fold increase in order to reach the expected 
exposure level for the original starting dose (with the same maximum increase of 3.3-fold 
multiples thereafter for further dose-escalation steps).
Part 2 (MAD)
Part 2 will be a randomized, Investigator- /subject-blind, placebo-controlled MAD study with the 
purpose of evaluating the safety, tolerability, PK, and PD of multiple doses of orally administered 
RO6953958. Participants from Part 1 cannot participate in Part 2.
Part 2 will explore the safety, tolerability, PK, and PD of multiple doses of RO6953958. The 
starting dose for Part 2 is 45 mg RO6953958 once daily (QD), established on the basis of safety 
and PK data in Part 1. The first dosing in Part 2 will only commence once safety is confirmed on
the basis of dosing in Part 1 that allows at least 4-times’ coverage (e.g., start 40 mg MAD once 
safety confirmed at a dose of 160 mg or higher in SAD). A maximum of five dose levels are 
anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive 
either a multiple oral dose of RO6953958 or placebo once daily for 10 days (active to placebo 
ratio 3:1). The treatment period may be extended to 14 days in subsequent cohorts depending 
on emerging data.
In addition, a lumbar puncture for CSF sampling will be performed in all participants in each 
cohort on Day 7 or alternatively Day 6 or 8. In a cohort, CSF sampling will be done predose in 4 
participants and approximately 5 to 7 h after dosing of RO6953958 (around Tmax of the M3 
metabolite) in the other 4 participants for determination of RO6953958, M3 (RO7021594) and 
M1 (RO7045755) concentrations in CSF. A corresponding blood sample will be taken at the 
same time point. The time point of CSF sampling in a participant may be adjusted with emerging 


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PK or CSF samples from preceding cohorts. In addition, these results might also lead to the 
conclusion to stop CSF sampling in subsequent cohorts.
The dose may be adjusted during the treatment period depending on the safety and/or PK 
observations. In addition, a different dosing regimen may be explored if warranted based on the 
safety and/or PK profile of RO6953958 (e.g., twice daily or exploration of titration). The starting 
dose in Part 2 Cohort 1 selected based on the safety and PK from Part 1 is 45 mg RO6953958 
QD. Based on the outcome of Part 1, RO6953958 will be administered under fed conditions (a 
standard breakfast). Subsequent doses in Part 2 will be based on emerging safety and PK data.
Additionally, the timing of dosing may be changed for additional participants in a cohort at a 
specific dose level, in order to explore the effect of time of dosing on the pharmacokinetics. A 
decision to include additional participants dosed in the evening at a specific dose level would 
only be made following review of the safety and PK following morning administration at the 
chosen dose level. CSF sampling would not be done in participants who are administered the 
dose in the evening.
Part 3 (DDI)
Part 3 will be a single-center, non-randomized, open-label, five-treatment, fixed sequence 
crossover study with the purpose of evaluating the safety and tolerability of RO6953958 alone 
and in combination with midazolam and to assess the effect of RO6953958 on the PK of the 
CYP3A substrate midazolam. In addition, the effect of RO6953958 treatment on an 
endogenous marker of CYP3A activity will be assessed.
RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at 
the maximum dose QD that was tested in the ongoing Part 2 (MAD). Midazolam will be 
administered as single IV bolus injection of 100 g on Day 1 and Day 13, and as single oral 
dose of 300 g on Day 2 and Day 14.
Treatment Groups and Duration
The following confirmed and tentative dose levels are planned for Part 1 and 2:

SAD Cohort 1: 5 mg RO6953958 or matching placebo

SAD Cohort 2: 15 mg RO6953958 or matching placebo

SAD Cohort 3: 45 mg RO6953958 or matching placebo

SAD Cohort 4: 90 mg RO6953958 or matching placebo and FE*

SAD Cohort 5: 180 mg RO6953958 or matching placebo 

SAD Cohort 6: 360 mg RO6953958 or matching placebo

SAD Cohort 7:  RO6953958 or matching placebo** – dose to be determined

MAD Cohort 1: 45 mg RO6953958 or matching placebo

MAD Cohort 2: 140 mg RO6953958 or matching placebo

MAD Cohort 3: 210 mg RO6953958 or matching placebo 

MAD Cohort 4: RO6953958 or matching placebo – dose to be determined

MAD Cohort 5: RO6953958 or matching placebo – dose to be determined
* Cohort 4 will return to receive the same dose in the fed state (a single dose of RO6953958 or 
placebo 30 minutes after starting a standardized high fat, high calorie breakfast).
** Cohort 7 may run pending emerging data review from the MAD. Timing of dosing of
RO6953958 may be in the evening instead of the morning, and dosing may be done under 
different food condition (fed vs fasted).
Part 3 (DDI): 

RO6953958 - maximum dose QD tested in Part 2 – to be given QD for 12 days (Day 3 
through Day 14) 

midazolam - 100 g – two single IV doses on Day 1 and Day 13 

midazolam - 300 g – two single oral doses on Day 2 and Day 14


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The investigational medicinal products (IMPs) for this study are RO6953958 capsules 2.5 mg, 
10 mg, and 80 mg; and matching placebo. Midazolam is a non-investigational product.
Dose-Escalation Decision Criteria
The dose-escalation decision will be made by the Roche Clinical Pharmacologist, the Principal 
Investigator, and appropriate personnel as required. The dose will not be escalated further if the 
tolerability, safety, or PK at the preceding dose level is not acceptable as judged by the Principal 
Investigator and the Clinical Pharmacologist. After review of the safety and PK data and 
discussion between the Roche Clinical Pharmacologist and the Principal Investigator, the same 
dose or regimen or a lower dose within the tolerated dose range may be given again in 
subsequent treatments to increase data within the tolerated dose range.
Dose escalation in Part 1 and Part 2 for all participants will be stopped if any of the predefined 
stopping rules are met in participants receiving RO6953958. However, the same or a lower dose 
may be administered after the discussion between the Sponsor’s Clinical Pharmacologist and 
the Investigator. Additionally, dosing will be stopped if any of the stopping rules applies during 
the conduct of the study and applies to an individual participant during the study.
Participants who prematurely discontinued from the study may be replaced to ensure adequate 
numbers (at least 6 participants; 4 on RO6953958) of evaluable participants for each dose 
escalation step.
Dose escalation is dependent on the safety and PK data at each dose level. Dose-level 
increments will be no more than 3.3-fold and may be adjusted downwards, or doses may be 
repeated if safety or PK concerns emerge from ongoing results. In the case that the observed 
exposure at the first SAD dose level (Cohort 1) is significantly below the predicted human 
exposure, a dose increment higher than 3.3-fold may be given subsequently at the second dose 
level (Cohort 2) to achieve the predicted exposure for the starting dose (with the same dose-
escalation multiples thereafter).
Due to the exploratory nature of this clinical study, its conduct can be discontinued before the 
last foreseen dose level has been investigated. This will not constitute a premature termination 
of the study.
Stopping Rules
Stopping Rules for the Study
The trial will be stopped if the following criteria are met:

A serious adverse reaction (i.e., a serious adverse event [SAE] considered as, at least,
possibly related to the IMP administration) in one participant or 

Severe adverse reactions (i.e., severe non-serious adverse events considered as, at least, 
possibly related to the IMP administration) in two participants in the same cohort.
Following an internal safety review, if it is appropriate to restart the trial, a substantial 
amendment will be submitted to the Medicines and Healthcare products Regulatory Agency 
(MHRA) and Research Ethics Committee (REC). The trial will not restart until the amendment 
has been approved by the MHRA and REC.
Stopping Rules for Individuals
Dosing will be stopped at any time during the study in a given participant receiving RO6953958 if 
one of the following circumstances occurs:

SAE considered related to study treatment.

Alanine aminotransferase (ALT) 5 upper limit of normal (ULN).

ALT 3 ULN and total bilirubin 2 ULN or international normalized ratio (INR) 1.5 (if a 
participant meets this withdrawal criterion, serum bilirubin fractionation should be 
performed).

ALT 3ULN if associated with the appearance or worsening of rash or hepatitis symptoms 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia). Participants who have ALT 3ULN and5ULN, total bilirubin2ULN or 


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INR1.5, and who do not exhibit hepatitis symptoms or rash can continue in the study (and 
continue receiving trial medication) as long as they can be monitored at least weekly until 
abnormal results are within the reference range or close to pretreatment values.
If a dose administration is suspended to allow for additional safety assessments, but no safety 
concerns are raised to prevent continued dosing in the judgment of the Investigator, dosing may 
resume at the next planned dosing date. A missed dose will not be made up (applicable to Part 2
[MAD] only).
Stopping Rules after Dosing of the Sentinel Group in Part 1 (all Dose Levels)
At all dose levels in Part 1, in order to avoid simultaneous exposure of all the participants, only 
2 participants (sentinel group; composed of 1 participant on active treatment and 1 on placebo) 
will be dosed first prior to dosing further participants at the same dose level. If the safety and 
tolerability data (AEs, electrocardiograms [ECG], vital signs, and clinical laboratory test results) 
of the first 23 hours following dosing for the initial 2 participants are acceptable in the judgment 
of the Investigator, 6 additional participants (5 on active treatment and 1 on placebo) will be 
dosed at the same dose level at least 24 hours after the sentinel group. Dosing will be stopped 
after the sentinel group if one of the following circumstances occurs in the participant receiving 
RO6953958, unless it is determined by the Investigator that the occurrence is not related to the 
administration of the study drug:

One SAE

Any other findings that, at the joint discretion of the Sponsor’s Clinical Pharmacologist, the 
Medical and Safety monitor and the Investigator, indicate that the dosing should be stopped
Dose-Escalation and Study Cohort Stopping Rules in Part 1 and Part 2
Dose-escalation will be stopped and treatment within an ongoing cohort will be stopped in Part 1 
and/or Part 2 if one of the following circumstances occurs in participants receiving RO6953958 
within the same dose level, unless it is determined by the Investigator that the occurrence is not 
related to the administration of the study drug:

SAE considered to be related to study drug in 1 participant receiving RO6953958

Severe non-serious AEs considered to be related to study drug in 2 or more participants 
receiving RO6953958 in the same cohort

Clinical significant RO6953958-related laboratory abnormalities of the same type in 2 or 
more participants

Clinical significant RO6953958-related changes in vital signs or ECGs of the same type in 2 
or more participants

If maximum individual exposure is anticipated to exceed the predicted Cmax (approximately 
3500 ng/mL) and AUC (35,000 ngh/mL) at the next planned dose level based on PK from 
previous dose cohorts or maximum feasible dose level of 800 mg once daily (QD) is 
achieved

Any other findings that, at the joint discretion of the Sponsor’s study team and the 
Investigator, indicate that the dosing should be stopped
Length of Study
Part 1 (SAD/FE)
The total duration of the study for each participant in each cohort will be up to 7 weeks 
(14 weeks if the participant is part of the FE cohort) divided as follows: 

Screening: Up to 4 weeks


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
In-clinic period: Days -2 to 5.

Treatment period: Day 1 

Washout period between each treatment (FE cohort only): Approximately 21 days. This 
might be adjusted/extended based on PK data from Part 1 or to await safety information 
from the subsequent dose level to provide adequate safety coverage for the fed part.

Safety follow-up: 7 to 14 days after the last dose.
Part 2 (MAD)
The total duration of the study for each participant will be up to 8 weeks divided as follows:

Screening: Up to 4 weeks.

In-clinic period: 16 days (Days -21 to 14; 2 baseline days, 10 dosing days, 6 follow-up days).

Treatment period: Days 1 to 10 (possibly to Day 14).

Safety follow-up: 7 to 14 days after last dose.
Part 3 (DDI)
The total duration of the study for each participant will be up to 8 weeks approximately 
divided as follows:

Screening: Up to 4 weeks.

In-clinic period: 19 days (Days -1 to 18; 1 baseline day, 14 dosing days, 4 follow-up 
days).

Five treatment periods: Days 1 to 14 (Days 1 and 2 midazolam, Days 3 through 14 
RO6953958, Days 13 and 14 midazolam).

Safety follow-up: 7 to 14 days after the final dose of RO6953958.
End of Study
A participant is considered to have completed the study if the participant has completed all
phases of the study including the last scheduled procedure.
The end of the study is defined as the date when the last participant, last observation (LPLO) 
occurs. LPLO is expected to occur approximately 2 weeks after the last participant last dose in 
Part 3.
PARTICIPANT POPULATION
The participants in this study will be healthy male volunteers between 18 to 55 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.
Able and willing to provide written informed consent and to comply with the study protocol 
according to International Council on Harmonisation (ICH) and local regulations.
                                           
1 Participants may be admitted on Day-3 to ensure severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) testing can be reported prior to dosing.


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Age
2.
Participants must be 18 to 55 years of age, inclusive, at the time of signing the informed 
consent form.
Type of Participants and Disease Characteristics
3.
Healthy, as judged by the Investigator. Healthy status will be defined as the absence of 
evidence of any active or chronic disease following a detailed medical and surgical history, a 
complete physical examination, vital signs, 12-lead ECG, hematology, blood chemistry, 
serology, and urinalysis.
Weight
4.
Body mass index (BMI) within the range 18 to 31 kg/m2 (inclusive).
Sleep (Part 2 MAD Only)
Habitual sleep pattern
5.
Participants must be prepared to collect a sleep log and wear an actigraphy device the week 
before participation in the study. Participants must also have scored 5 or less on the
Pittsburgh Sleep Quality Index (PSQI), less than 13 on the Epworth sleepiness scale (ESS),
and not be considered an extreme morning or evening type according to the morningness–
eveningness questionnaire (MEQ) at screening to be eligible.
Sex
6.
Male participants
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for male enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. Periodic abstinence and withdrawal are not 
acceptable methods of contraception.
During the treatment period and for at least 14 days after the last dose of study drug, agreement 
to:

Remain abstinent (refrain from heterosexual intercourse) or use a condom with a female 
partner of childbearing potential, or pregnant female partner, to avoid exposing the embryo.

Refrain from donating sperm for at least 14 days after last dose.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Any condition or disease detected during the medical interview/physical examination that 
would render the participant unsuitable for the study, place the participant at undue risk, or 
interfere with the ability of the participant to complete the study, as determined by the 
Investigator.


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2.
History or evidence of any medical condition potentially altering the absorption, metabolism,
or elimination of drugs. This includes a surgical history of the gastrointestinal tract affecting 
gastric motility or altering the gastrointestinal tract.
3.
History of any clinically significant gastrointestinal, renal, hepatic, bronchopulmonary, 
neurological, psychiatric, cardiovascular, endocrinological, hematological, or allergic 
disease, sleep disorders (Part 2 [MAD] only), unexplained syncope (within 12 months prior to 
screening), metabolic disorder, cancer, or cirrhosis.
4.
Use of any psychoactive medication, or medications known to have effects on central 
nervous system (CNS), or blood flow taken within 4 weeks prior to the first dosing (or within 
5 times the elimination half-life of the medication) prior to the first dosing (whichever is 
longer).
5.
History of convulsions (other than benign febrile convulsions of childhood), including 
epilepsy, or personal history of significant cerebral trauma or CNS infections (e.g., 
meningitis).
6.
History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic reactions.
7.
Any major illness within 1 month before the screening examination or any febrile illness 
within 1 week prior to screening and up to the first study drug administration.
8.
Abnormal blood pressure, defined as confirmed (based on the average of 3 consecutive 
measurements) systolic blood pressure (SBP) greater than 140 or less than 90 mmHg, and 
diastolic blood pressure (DBP) greater than 90 or less than 50 mmHg.
9.
Presence of orthostatic hypotension at screening. Orthostatic hypotension is defined as 
decrease by 20 mmHg in SBP and/or 10 mmHg in DBP after erection from a supine position 
and/or clinical presyncopal/syncopal AE during test.
10. Abnormal pulse rate, defined as confirmed (based on the average of 3 consecutive 
measurements) resting pulse rate greater than 100 or less than 40 bpm.
11. History or presence of clinically significant ECG abnormalities before study treatment 
administration (e.g., PQ/PR interval 220 ms, QT interval corrected using Fridericia’s 
formula [QTcF] 450 ms) or cardiovascular disease (e.g., cardiac insufficiency, coronary 
artery disease, cardiomyopathy, congestive heart failure, family history of congenital long QT 
syndrome, family history of sudden death).
12. Clinically significant abnormalities in laboratory test results (including hepatic and renal 
panels, complete blood count, chemistry panel, and urinalysis). In the case of uncertain or 
questionable results, tests performed during screening may be repeated before 
randomization to confirm eligibility.
13. ALT and/or bilirubin 1.5 ULN (isolated bilirubin 1.5 ULN is acceptable if bilirubin is 
fractionated and direct bilirubin 35%).
14. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the 
exception of Gilbert's syndrome or asymptomatic gallstones).
15. Participants who, in the Investigator's judgment, pose a suicidal or homicidal risk, or any 
participant with a history of suicidal or homicidal attempts.


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16. Known active or any major episode of infection within 4 weeks prior to the start of drug 
administration.
17. Participants who test positive for acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
on admission to the study site should not be enrolled. 
Prior/Concomitant Therapy
18. Have used or intend to use over-the-counter or prescription medication including herbal 
medications within 30 days prior to dosing
19. Participants likely to need concomitant medication during the study period (including for 
dental conditions).
20. Part 3 (DDI) only - History of hypersensitivity to benzodiazepines (including midazolam) 
or its formulation ingredients.
Prior/Concurrent Clinical Study Experience
21. Participation in an investigational drug or device study within 3 months before admission to 
this study or more than 4 times a year.
Diagnostic Assessments
22. Positive test for drugs of abuse or alcohol.
23. Positive test for human immunodeficiency virus (HIV) antibody at screening.
24. Positive result on hepatitis B virus or hepatitis C virus (HCV), presence of hepatitis B surface 
antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months
prior to starting study treatment.
Other Exclusions
25. Dietary restrictions that would prohibit the consumption of standardized meals.
26. Inability or unwillingness to fully consume standardized breakfast at Day 1 (for Part 1, FE 
cohort).
27. Consumption of any prohibited medications and food/beverages before study start and 
during the study.
28. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of drug of 
abuse or previous history of or treatment for a dependence disorder.
29. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy 
that, in the opinion of the Investigator, contraindicates the participation in the study.
30. Participants who are smokers for at least 90 days prior to screening.
31. Part 2 (MAD) only – Participants who have issues sleeping or who have travelled across 2 or 
more time zones in the month prior to screening. 
32. Part 2 (MAD) only – Participants who cannot produce sufficient saliva for study 
assessments.


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33. Participants who have donated more than 500 mL of blood or blood products or had 
significant blood loss within 3 months prior to screening.
34. Participants under judicial supervision, guardianship, or curatorship.
For participants with planned lumbar punctures, the following additional exclusion criteria 
apply:
35. Have a history of clinically significant back pain, back pathology, and/or back injury (e.g. 
degenerative disease, spinal deformity, or spinal surgery) that may predispose to 
complications from, or technical difficulty with, lumbar puncture, 
36. Have criteria that would preclude a lumbar puncture, such as local infection at the site of the 
lumbar puncture, clinically significant coagulation parameter abnormalities, or treatment with 
an anticoagulant or with antiplatelet agents within 6 weeks prior to the day of lumbar 
puncture, 
37. Have a clinically significant hypersensitivity to local anesthetics that may be used for lumbar 
puncture (e.g. lidocaine).
NUMBER OF PARTICIPANTS
Part 1 (SAD)
Fifty-six participants will be randomized, 8 per cohort. For all dose levels, a sentinel group of 
2 participants will be randomized as 1 on active treatment and 1 on placebo and the remaining 
participants will be randomized as 5 on active treatment and 1 on placebo at the same dose 
level at least 24 hours later. If participants in the FE cohort do not agree to perform the fed part, 
additional participants will be recruited.
Part 2 (MAD)
Up to 80 participants will be randomized with a minimum of 6 active treatment and 2 placebo 
participants in each dose level with the option to expand up to a maximum of 12 active treatment 
and 4 placebo participants per dose level. All dose levels will be assigned to active treatment or 
placebo using a 3:1 ratio.
Part 3 (DDI)
Sixteen participants will be enrolled to have at least 12 participants complete study Part 3. All 
participants will receive active treatment.
CONCOMITANT MEDICATIONS
As a general rule, no concomitant medication or vaccine will be permitted, with the exception of
COVID-19 vaccines and medications to treat AEs, unless the rationale for exception is discussed 
and clearly documented between the Investigator and the Sponsor. Participants are allowed to 
receive a dose of COVID-19 vaccine at least 21 days prior to the first dose of study treatment or 
a dose of COVID-19 vaccine at least 10 days after last dose of study treatment.
Use of the following therapies is prohibited during the study and for at least 30 days, or at least 
5 half-lives of the medication, prior to initiation of study treatment (whichever is longer), unless 
otherwise specified below:

Any prescribed or OTC medication (including herbal products, vitamin, mineral, dietary 
supplements, melatonin, and melatonin agonists).


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
Any known inhibitor of cytochrome P450 (CYP) 3A4 or CYP2C19 taken within 4 weeks prior
to start of administration of study drug (Day 1) or within 5 times the elimination half-life of 
the medication prior to start of study drug intake (whichever is longer), including but not 
limited to the following drugs: ritonavir, troleandomycin, telaprevir, danoprevir, elvitegravir, 
saquinavir, lopinavir, indinavir, nelfinavir, boceprevir, voriconazole, mifepristone, 
posaconazole, telithromycin, ketoconazole, itraconazole, fluconazole, erythromycin, 
clarithromycin, mibefradil, ceritinib, ribociclib, idelalisib, conivaptan, nefazodone, diltiazem, 
verapamil, cimetidine, fluvoxamine, fluoxetine, ASP8477, and ticlopidine.

Any known inducer of CYP3A4 or CYP2C19 taken within 4 weeks prior to start of 
administration of study treatment (Day 1), including but not limited to the following drugs: 
rifampicin, rifabutin, glucocorticoids, carbamazepine, oxcarbazepine, phenytoin, 
phenobarbital, St. John’s Wort extract, mitotane, avasimibe, rifapentine, ivosidenib, 
carbamazepine, lumacaftor, apalutamide, enzalutamide, and ritonavir.

Use of drugs acting on platelets such as aspirin, clopidogrel, dipyridamole, ticlopidine, or 
with anticoagulant effect like heparin or warfarin.


RO6953958—F. Hoffmann-La Roche Ltd
26/Protocol BP41695, Version 7
1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design for Part 1 and Part 2
BID = twice daily; MAD = multiple-ascending dose; QD = once daily; RO = RO6953958;
SAD = single-ascending dose.
Figure 2
Overview of Study Design for Part 3
Screening 
Visit
In-Clinic Period
Ambulatory 
Visits
Final 
Follow-up
Visit
Day -28 
to Day -2
Day -1 to Day 18; 
1 baseline day (Day -1), 14 dosing days (see below), 
4 follow-up days (Day 15 to Day 18)
Day 19 to 
Day 20
Day 21 to 
Day 28 
5 Treatment periods:

Day 1 – IV midazolam microdosing (100 g)

Day 2 – oral midazolam microdosing (300 g)

Days 3 to 14 – RO6953958 QD (maximum dose QD 
tested in Part 2)

Day 13 – RO6953958 in combination with a single 
100 g IV dose of midazolam (RO6953958 plus IV 
midazolam)

Day 14 – RO6953958 in combination with a single 
300 g oral dose of midazolam (RO6953958 plus oral 
midazolam)
Within 7 to 
14 days after 
the final dose 
of RO6953958
IV = intravenous; QD = once daily.
1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities is provided in Table 1 and Table 2 for Part 1, in Table 3
and Table 4 for Part 2, and in Table 5, Table 6, and Table 7 for Part 3.


RO6953958—F. Hoffmann-La Roche Ltd
27/Protocol BP41695, Version 7
Table 1
Overall Schedule of Activities – Part 1
Day
Screening up to Day -28
Day -2o
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 8
Follow Up Visit (7-14 days)
Assessments
Informed Consent
x
Demography
x
Medical History
x
Physical Examination
x
a
x
i
x
i
x
a
In-house Period
x
x
x
x
x
x
x
Vital Signs b
x
j
x
3
j
1
x
x
ECG-12 lead (triplicate) c
x
x
3
1
x
x
Holter ECG monitoring d e
x
x
Serology
x
Urine Alcohol Test
x
x
x
Urine Drugs of Abuse
x
x
x
Urinalysis
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
Coagulation
x
x
Randomizatione
x
Administration of Study Medication f
x
Standard Meal g
x
x
x
x
x
x
x
PK Sample plasma k
10
x
x
x
x
x
x
x
Urine PK Sample h,k
x
x
x
PAA blood sampling l,m
x
x
Karolinska Sleepiness Scale (KSS) m
6
x
x
SARS-CoV-2 testing
x
Sleep mat n
x
Clinical Genotyping
x
e
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
Previous and Concomitant Treatments
x
x
x
x
x
x
x
x
x
x
x


RO6953958—F. Hoffmann-La Roche Ltd
28/Protocol BP41695, Version 7
Table 1
Overall Schedule of Activities – Part 1 (cont.)
a. Full physical examination including body weight and height at screening when body mass index (BMI) will be derived.
b. Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. Temperature will be recorded at screening, Day 1 
predose, and follow-up.
c. Triplicate 12-lead ECGs will be measured after the participant has rested in a supine position for at least 10 minutes (see detailed Table 2).
d. Holter ECG data will be extracted at timepoints specified in Table 2. The participants should be at rest and in a supine position for at least 
10 minutes prior to and remain in a supine position for at least 5 more minutes after the specified ECG extraction timepoints. When ECG 
extractions coincide with safety ECGs, vital signs assessment, and blood draws, procedures should be carried out in said order.
e. In first period only of FE cohort.
f. RO6953958 will be administered orally with approximately 240 mL water in the morning of Day 1. Water will be allowed ad libitum until 1 hour 
prior to dosing and from 1 hour postdosing. At higher dose levels, twice-daily dosing may be required.
g. Participants will stay fasted overnight (at least 10 hours) before dosing and remain fasted until lunch 4 hours postdose. Dinner will be provided 
approximately 8 hours postdose. Participants in the food-effect cohort will receive (in addition to lunch and dinner) a high fat, high calorie 
breakfast 30 minutes before drug intake. Three standard meals (breakfast, lunch, and dinner) will be served on Days 2, 3, and 4.
h. Bladder must be completely emptied at the time of study drug administration. Urine sample collection intervals are detailed in Table 2.
i. Brief, targeted physical exam.
j. Orthostatic challenge: Participants will rest in the supine position for 10 minutes and then quickly stand up and remain standing for 3 minutes. 
Pulse rate and blood pressure will be measured 3 times after the participant has rested in the supine position for 10 minutes (i.e., at 8, 9, and 
10 minutes) and again after around 3 minutes in standing position to compare this with the latest supine measurements (Section 8.2.2.1).
k. Schedule of blood and urine samples may be modified to better characterize PK profile after analysis of emerging PK data from previous doses.
l. PAA – platelet aggregation assay.
m. The timing of PD measurements may be adapted based on emerging PK data.
n. Four participants will have sleep mat data collected overnight for testing purposes only.
o. Participants will be admitted on Day-2 to ensure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing can be reported prior to 
dosing.


RO6953958—F. Hoffmann-La Roche Ltd
29/Protocol BP41695, Version 7
Table 2
Detailed Schedule of Activities – Part 1
Vital 
Signs a
ECG-12 
lead b
Holter ECG 
time points 
for extraction 
c i
Standard 
Meal f
Karolinska 
Sleepiness 
Scale (KSS) 
h
PK 
Sample
Urine PK 
Sample d
PAA blood 
sampling 
g,h
Clinical 
Genotyping
Day -1
x
x
x
x
Predose
x e
x
3
x f
x
x
x i
0h
30 min
x
x
1h
x
x
x
x
2 h
x j
x
x
x
3h
x
x
x
4h
x
5h
x
x
x
6h
x
x
7h
x
x
x
x
x
x
8h
x
10h
x
x
12h
x
x
x
12 to 24h
Day 2
24h
x
x
x
x
x
x
Day 3
48h
x
x
x
Day 4
72h
x
x
Day 5
96h
x
x
x
x
Day 6
120 h
x
Day 8
168 h
x
Day 10
216 h
x
24 to 48h
4 to 12h
0 to 4h
Day
Scheduled 
Time (h)
Day 1


RO6953958—F. Hoffmann-La Roche Ltd
30/Protocol BP41695, Version 7
Table 2
Detailed Schedule of Activities – Part 1 (cont.)
a. Vital signs will include blood pressure, pulse rate, respiratory rate and (at selected timepoints) body temperature. Vital sign measurements will be 
taken after the participant has rested in a supine position for at least 5 minutes.
b. Triplicate 12-lead ECG will be collected after the participant has rested in a supine position for at least 10 minutes.
c. Participants should be at rest and in a supine position for at least 10 minutes prior to and remain in a supine position for at least 5 more minutes 
after the specified ECG extraction timepoints. Three readings will be taken as a baseline at predose on Day 1.
d. Participants will be asked to empty their bladder before dosing. Then, all urine voided up to 48 hours postdose will be collected in four lots.
e. Body temperature to be recorded.
f. Participants will stay fasted overnight (at least 10 hours) before dosing and remain fasted until lunch 4 hours postdose. Dinner will be provided 
approximately 8 hours postdose. Participants in the food-effect cohort will receive (in addition to lunch and dinner) a high fat, high calorie 
breakfast 30 minutes before drug intake. Three standard meals (breakfast, lunch, and dinner) will be served on Days 2, 3, and 4.
g. PAA – platelet aggregation assay.
h. The timing of PD measurements may be adapted based on emerging PK data.
i. In first period only for FE cohort.
j. Orthostatic challenge: Participants will rest in the supine position for 10 minutes and then quickly stand up and remain standing for 3 minutes. 
Pulse rate and blood pressure will be measured 3 times after the participant has rested in the supine position for 10 minutes (i.e., at 8, 9, and 
10 minutes) and again after around 3 minutes in standing position to compare this with the latest supine measurements.


RO6953958—F. Hoffmann-La Roche Ltd
31/Protocol BP41695, Version 7
Table 3
Overall Schedule of Activities – Part 2
Day
Screening up 
to Day -28
Day -2q
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 17
Follow Up Visit 
(7-14 days)
Assessments
Informed Consent
x
Demography
x
Medical History
x
Physical Examination
x
a
x
f
x
f
x
f
x
a
In-house Period e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Discharge from Unit
x
Vital Signs b
x
j
x
x
3
j
x
x
x
x
x
x
j
x
x
3
x
x
x
x
x
ECG-12 lead c
x
x
x
3
x
x
3
x
x
x
Holter ECG monitoring d
x
x
x
x
Serology
x
x
Urine Alcohol  Test
x
x
x
Urine Drugs of Abuse
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
Coagulation r
x
x r
x r
x r
x
x
Randomisation
x


RO6953958—F. Hoffmann-La Roche Ltd
32/Protocol BP41695, Version 7
Table 3
Overall Schedule of Activities – Part 2 (cont.)
Day
Screening up 
to Day -28
Day -2q
Day -1
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 17
Follow Up Visit 
(7-14 days)
Assessments
Administration of Study Medication l
x
x
x
x
x
x
x
x
x
x
Standard Meals
x
x
x
m
x
x
x
x
x
x
x
x
xm
x
x
x
x
PK Sample g
10u
x
x
x
x
x
x
x
x
10u
x
x
x
x
x
x
x
Urine PK Sample g, h
x
x
x
x
x
CSF Sampling r
x r
x r
x r
Cortisolo
10
10
10
10
DLMOn
11
11
11
11
Epworth Sleepiness Scale
x
Morningness-Eveningness Questionnaire 
(MEQ)
x
Actigraphy and Sleep log
x 
i
Pittsburgh Sleep Quality Index 
x
Promis Sleep Questionnaires k
x
x
x
Karolinska Sleepiness Scale (KSS)
6
6
6
6
6
Facial Expression Recognition Task (FERT)
x
x
x
Polysomnography and sleep mat p
x
x
x
x
x
Core body temperature assessment s
x s
x s
x s
x s
x s
Wake EEG t
x t
x t
x t
C-SSRS
x
x
x
x
x
x
Clinical Genotyping
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Previous and Concomitant Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


RO6953958—F. Hoffmann-La Roche Ltd
33/Protocol BP41695, Version 7
Table 3
Overall Schedule of Activities – Part 2 (cont.)
a. Full physical examination including body weight and height at screening when body mass index (BMI) will be derived.
b. Vital signs will include blood pressure, pulse rate, respiratory rate, and at selected timepoints on Day 1 and Day 10 for body temperature.
c. Triplicate 12‑lead ECGs will be collected after the participant has rested in a supine position for at least 10 minutes (see Detailed Table 4).
d. Holter monitoring will be measured from predose on Day 1 to 24 hours postdosing on the morning of Day 2. Holter ECG data will be extracted at 
timepoints specified in Table 4. The participants should be at rest and in a supine position for at least 10 minutes prior to and remain in a supine 
position for at least 5 more minutes after the specified ECG extraction timepoints.
e. Dim lighting protocol to be applied before bedtime (lights out at 11:00 pm) starting 1 hour before melatonin sampling begins; participants should 
be recumbent (not supine), with no napping during days where this protocol is applied.
f. Brief, targeted physical exam.
g. Schedule of blood and urine samples may be modified to better characterize the PK profile. Timing of blood draw will be determined after 
analysis of the SAD and the PK data review from the previous cohort in MAD as appropriate.
h. Urine sample collection interval are detailed in Table 4.
i. Sleep log will be collected and actigraphy watch will be worn during the week prior to admission to unit.
j. Orthostatic challenge: Participants will rest in the supine position for 10 minutes and then quickly stand up and remain standing for 3 minutes. 
Pulse rate and blood pressure will be measured 3 times after the participant has rested in the supine position for 10 minutes (i.e., at 8, 9, and 
10 minutes) and again after around 3 minutes in standing position to compare this with the latest supine measurements.
k. PROMIS Sleep Disturbance and PROMIS Sleep-Related Impairment short forms (8 items).
l. RO6953958 administered under fasted conditions depending on data from Part 1. In case fed conditions are applied, the dose will be 
administered with breakfast. A dose level may have a different timing of daily drug administration (evening vs morning) in additional participants.
m. The same food conditions (in terms of meal constitution and time of administration) will apply on Day 1 and on Day 10.
n. DLMO –dim light melatonin onset. Melatonin in saliva and serum to be collected every 30 mins between 6 p.m. and 11 p.m under dim light 
conditions. Timings and number of samples (to a maximum of 12 samples per matrix) may be adjusted based on DLMO protocol.
o. Cortisol in serum to be collected every 15 minutes for an hour after waking up, then every 30 minutes up until 3.5 hours after waking. Leftover 
samples will be used for additional melatonin testing.
p. Polysomnography and sleep mat overnight on Day -2 (habituation), Day -1 (baseline), Day 1 and Day 9 (on drug), and Day 12 (off drug).
q. Participants may be admitted on Day-3 to ensure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing can be reported prior 
to dosing.
r. An additional PK blood sample is also taken on either Day 6, 7 or 8 to coincide with CSF sampling, as well as a coagulation sample which should 
be measured on the day prior to CSF sampling e.g., Day 5, 6 or 7.  Timing of CSF sampling may be adapted based on emerging PK data.


RO6953958—F. Hoffmann-La Roche Ltd
34/Protocol BP41695, Version 7
Table 3
Overall Schedule of Activities – Part 2 (cont.)
s. Apply vest and swallow the equivital pill for measuring the core body temperature prior to the DLMO or equivalent time if no assessment. 
Remove vest after last cortisol sampling the day after or equivalent time if no assessment.
t. Wake EEG is performed on Day-1 (baseline) and Day 5 (or alternatively on Day 6) at approximately 2 pm for 30 min.
u. Leftover PK samples collected on Day 1 and Day 10 will be used for additional cortisol testing.


RO6953958—F. Hoffmann-La Roche Ltd
35/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2
Day
Scheduled Time 
(h)
Vital Signs a
ECG-12 
lead b
Holter ECG time 
points for 
extraction e,o
Urinalysis
Blood 
Chemistry
Hematology
Coagulation
Administration of 
Study Medication c
Standard 
Meals h,i
PK 
Sample d
Urine PK 
Sample d, n
Day -2q
x
x
x
x
x
x
Predose -24
x
1h
2h
x 
3h
4h
x
5h
6h
7h
8h
x
10h
12h
Predose
x 
l
x
3
x
u
0h
x
30 min
x
x
u
1h
x
x
u
2h
x 
m
x
x
x
u
3h
x
x
u
4h
x
5h
x
x
u
6h
x
x
u
7h
x
x
x
x
u
8h
x
10h
x
x
u
12h
x
x
u
Predose
x
x
x
x
x
x
0h
x
1h
3h
5h
6h
7h
12h
Predose
x
x
0h
x
2h
x
Day -1
4 to 12h
0 to 4h
Day 2
Day 3
Day 1
x
12 to 24h


RO6953958—F. Hoffmann-La Roche Ltd
36/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
Day
Scheduled Time 
(h)
Vital Signs a
ECG-12 
lead b
Holter ECG time 
points for 
extraction e,o
Urinalysis
Blood 
Chemistry
Hematology
Coagulation
Administration of 
Study Medication c
Standard 
Meals h,i
PK 
Sample d
Urine PK 
Sample d, n
Predose
x
x
0h
x
Predose
x 
x
x
x
x r
x
0h
x
2h
5h 
6 h
Predose
x 
x r
x
0h
x
2h
x
5h
6h 
7h
Predose
x r
x
0h
x
2h
x m
5 h
7 h
Predose
x 
x
0h
x
5 h
7 h
Predose
x 
x
x
x
x
0h
x
6h
12h
Day 9
Day 8
xr
Day 6
xr
xr
Day 4
Day 5
Day 7
x


RO6953958—F. Hoffmann-La Roche Ltd
37/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
Day
Scheduled Time 
(h)
Vital Signs a
ECG-12 
lead b
Holter ECG time 
points for 
extraction e,o
Urinalysis
Blood 
Chemistry
Hematology
Coagulation
Administration of 
Study Medication c
Standard 
Meals h,i
PK 
Sample d
Urine PK 
Sample d, n
Predose
x l
x
x
xu
0h
x
30 min
x
x
u
1 h
x
xu
2h
x
x
x
x
u
3h
x
xu
4h
x
5h
x
xu
6h
x
xu
7h
x
x
x
x
u
8h
x
10h
x
xu
12h
x
xu
12 to 24h
Day 11
24h
x
x
x
x
Day 12
48h
x
x
x
x
x 
x
x
Day 13
72h
x
x
x
Day 14
96h
x
x
x
x
x p
x
x
Day 15
120 h
x
Day 17
168 h
x
Day 19
216 h
x
4 to 12h
0 to 4h
24 to 48h
Day 10


RO6953958—F. Hoffmann-La Roche Ltd
38/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
Day
Scheduled Time 
(h)
CSF Sample
Clinical 
Genotyping
Cortisol k
DLMO j
Promis Sleep 
Questionnaires f
Karolinska 
Sleepiness Scale 
(KSS)
Polysomnography and 
sleep mat g
Core Body Temperatures
Wake EEGt
Facial Expression 
Recognition Task 
(FERT)
CSSRS
Day -2q
11
x
x
Predose -24
x
x
x
0h
1h
x
x
2h
3h
x
4h
5h
x
x
6h
7h
x
8h
10h
12h
x
x
x
Predose
x
x
0h
30 min
1h
x
x
2h
3h
x
4h
5h
x
6h
7h
x
8h
10h
12h
x
x
x
Predose
x
0h
1h
x
3h
x
5h
x
6h
7h
x
12h
x
Predose
0h
2h
11
10
Day -1
Day 2
Day 3
Day 1
10


RO6953958—F. Hoffmann-La Roche Ltd
39/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
Day
Scheduled Time 
(h)
CSF Sample
Clinical 
Genotyping
Cortisol k
DLMO j
Promis Sleep 
Questionnaires f
Karolinska 
Sleepiness Scale 
(KSS)
Polysomnography and 
sleep mat g
Core Body 
Temperatures
Wake EEGt
Facial Expression 
Recognition Task 
(FERT)
CSSRS
Predose
0h
Predose
0h
2h
5h 
x
6 h
Predose
x r
0h
2h
5h
x
6h 
7h
Predose
x r
x
0h
2h
5 h
7 h
Predose
x r
0h
5 h
7 h
Predose
0h
6h
12h
11
x
x
Day 9
Day 8
Day 6
xr
xr
xr
Day 4
Day 5
Day 7


RO6953958—F. Hoffmann-La Roche Ltd
40/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
Day
Scheduled Time 
(h)
CSF Sample
Clinical 
Genotyping
Cortisol k
DLMO j
Promis Sleep 
Questionnaires f
Karolinska 
Sleepiness Scale 
(KSS)
Polysomnography and 
sleep mat g
Core Body 
Temperatures
Wake EEGt
Facial Expression 
Recognition Task 
(FERT)
CSSRS
Predose
x
0h
30 min
1 h
x
x
2h
3h
x
4h
5h
x
6h
7h
x
8h
10h
12h
x
Day 11
24h
Day 12
48h
11
x
x
x
Day 13
72h
10
6 as above
x
Day 14
96h
x
x
Day 15
120 h
Day 17
168 h
Day 19
216 h
10
Day 10


RO6953958—F. Hoffmann-La Roche Ltd
41/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
a. Vital signs will include blood pressure, pulse rate, respiratory rate, and (at selected timepoints) body temperature. Vital sign measurements will 
be taken after the participant has rested in a supine position for at least 5 minutes.
b. Triplicate 12‑lead ECG will be collected after the participant has rested in a supine position for at least 10 minutes.
c. RO6953958 will be given orally with water from Day 1 to Day 10, once daily in the morning. A dose level may have a different timing of daily drug 
administration (evening vs morning) in additional participants.
d. Schedule of blood and urine samples may be modified to better characterize the PK profile. Timing of blood draw will be determined after 
analysis of the SAD and the PK data review from the previous cohort in MAD as appropriate.
e. 3 timepoints at predose.
f. PROMIS Sleep Disturbance and PROMIS Sleep-Related Impairment short forms (8 items).
g. Polysomnography and sleep mat overnight on Day -2 (habituation), Day -1 (baseline), Day 1 and Day 9 (on drug), and Day 12 (off drug).
h. RO6953958 administered under fasted conditions depending on data from Part 1. In case fed conditions are applied, the dose will be 
administered with breakfast.
i. The same food conditions (in terms of meal constitution and time of administration) will apply on Day 1 and on Day 10.
j. DLMO – dim light melatonin onset. Melatonin in saliva and serum to be collected every 30 minutes between 6 p.m. and 11 p.m under dim light 
conditions. Timings and number of samples (to a maximum of 12 samples per matrix) may be adjusted based on DLMO protocol.
k. Cortisol in serum to be collected every 15 minutes for an hour after waking up, then every 30 minutes up until 3.5 hours after waking. Leftover
samples will be used for additional melatonin testing.
l. Body temperature will be measured at predose on Day 1 and Day 10. 
m. Orthostatic challenge: Participants will rest in the supine position for 10 minutes and then quickly stand up and remain standing for 3 minutes. 
Pulse rate and blood pressure will be measured 3 times after the participant has rested in the supine position for 10 minutes (i.e. at 8, 9, and 
10 minutes) and again after around 3 minutes in standing position to compare this with the latest supine measurements.
n. Participants will be asked to empty their bladder before dosing on Day 1 and Day 10. Then, all urine voided during 24 hours postdose on Day 1 
and up to 48 hours on Day 10 will be collected.
o. Participants should be at rest and in a supine position for at least 10 minutes prior to and remain in a supine position for at least 5 more minutes 
after the specified ECG extraction timepoints. When ECG extractions coincide with safety ECGs, vital signs assessment and blood draws, 
procedures should be carried out in said order.
p. Coagulation should also be measured.
q. Participants may be admitted on Day-3 to ensure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing can be reported prior 
to dosing.


RO6953958—F. Hoffmann-La Roche Ltd
42/Protocol BP41695, Version 7
Table 4
Detailed Schedule of Activities – Part 2 (cont.)
r. Sample will be taken pre-dose in 4 participants per cohort and at 6 hours after dosing (allowed time window was between 5 to 7 hours after 
dosing) in 4 participants in each cohort (i.e., one CSF sample per participant per cohort). At the same timepoint an additional PK sample is 
taken. As an alternative to Day 7, CSF sampling and PK sampling can also be performed on Day 6 or Day 8 at predose or 6 hours after dosing 
(allowed time window was between 5 to 7 hours after dosing). Coagulation sample to be taken a day prior to CSF sampling. Timing of CSF 
sampling may be adapted based on emerging PK data.
s. Apply vest and swallow the equivital pill for measuring the core body temperature prior to the DLMO. Remove vest after last cortisol sampling the 
day after.
t. Wake EEG is performed on Day-1 (baseline) and Day 5 (alternatively on Day 6) at 2 pm for 30 min.
u. Leftover PK samples collected on Day 1 and Day 10 will be used for additional cortisol testing.


RO6953958—F. Hoffmann-La Roche Ltd
43/Protocol BP41695, Version 7
Table 5
Overall Schedule of Activities – Part 3
Day relative to first Dose Midazolam
Screening up to 
Day -28
Baseline 
Day -1
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
Final Follow-up 
Visit 
c
Informed Consent
x
Demography
x
Medical History 
x
Inclusion/Exclusion Criteria Review
x
x
Physical Examination 
a
x
x
x
x
x
Admission to Unit
x
In-house Period
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Discharge from Unit
x
Ambulatory Visit
x
x
x
x
Vital Signs 
b
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG-12 Lead 
d
x
x
x
x
x
x
x
x
x
x
x
x
x
Serology
x
SARS-CoV-2 PCR Test
e
x
Urine Alcohol Test
f
x
x
x
Urine Drugs of Abuse 
f
x
x
x
Urinalysis
x
x
x
x
x
x
x
x
x
Blood Chemistry
x
x
x
x
x
x
x
x
x
Hematology
x
x
x
x
x
x
x
x
x
Coagulation
x
x
x
Administration of RO6953958 
g
x
x
x
x
x
x
x
x
x
x
x
x
Oral Administration of Midazolam 
h
x
x
IV Administration of Midazolam
h
x
x
Standard Meal 
i
x
x
x
x
Clinical Genotyping
x
PK Sample RO6953958, M1, and M3
10
x
j
x
j
x
j
x
j
x
j
x
j
10
x
x
x
x
x
x
x
PK Sample Midazolam 
k
14
13
x
14
13
x
4β -hydroxycholesterol Sampling 
l
x
x
x
x
x
x
x
x
Previous and Concomitant Treatments
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events 
m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
C-SSRS
x
x
x
x
x
x


RO6953958—F. Hoffmann-La Roche Ltd
44/Protocol BP41695, Version 7
Table 5
Overall Schedule of Activities – (cont.)
BMI = body mass index; C-SSRS = Columbia Suicide Severity Scale; ECG = electrocardiogram; IV = intravenous; M1 = RO7045755; 
M3 = RO7021594; PCR=polymerase chain reaction; PK=pharmacokinetic; QD = once daily. 
a.
Full physical examination including body weight at Screening and Follow-up; height at Screening when BMI will be derived. All other 
visits will include only a brief, targeted physical examination.
b.
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. Temperature will be recorded at Screening, 
Day 1 (predose), and Follow-up. All measurements will be taken after the participant has rested in a supine position for at least 5 
minutes.
c.
The final follow-up visit is 7 to 14 days after the last dosing of RO6953958.
d.
Triplicate 12lead ECGs will be collected after the participant has rested in a supine position for at least 10 minutes.
e.
Sampling of nasal and throat mucosal cells. If deemed necessary, additional tests may be conducted during the study.
f.
At indicated visits and any other time at the discretion of the Investigator.
g.
On Days 3 to 14, a single oral dose of RO6953958 (highest safe QD dose tested in Part 2) will be given in the morning under fed 
conditions with water.
h.
Midazolam will be administered in the morning as a bolus injection on Days 1 and 13 or orally (liquid) on Days 2 and 14.
i.
See details of mealtimes in Table 6 and Table 7.
j.
Predose PK samples only to be taken on Days 4, 6, 8, 10, 12, and 13; full PK profile to be taken on Days 3 and 14 (see Table 7 for 
details) through to the follow-up visit.
k.
See details for midazolam PK sampling in Table 6 and Table 7.
l.
Sample taken predose relative to RO6953958 and midazolam dosing on dosing days.
m.
Adverse events and use of concomitant medication during outpatient periods to be captured at the next study centre visit or from 
spontaneous reports.


RO6953958—F. Hoffmann-La Roche Ltd
45/Protocol BP41695, Version 7
Table 6
Detailed Schedule of Activities on Day 1 and Day 13 – Part 3
ECG = electrocardiogram; h = hour; IV = intravenous, min = minute; M1 = RO7045755; M3 = RO7021594; PK = pharmacokinetic.
a.
Standardized meals at -2.5 hours predose and at approximately 2 and 8 hours postdose relative to midazolam dosing. PK sampling should 
be performed before providing meals.
b.
On Day 13 only.
c.
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. Temperature will be recorded at Screening, 
Day 1 (predose), and Follow-up. All measurements will be taken after the participant has rested in a supine position for at least 
5 minutes. Perform vital signs assessment prior to PK sampling 
d.
On Day 13 only, RO6953958 will be administered orally 30 minutes after starting a standardized breakfast (2 hours prior to midazolam 
dosing).
e.
Midazolam will be administered in the morning as a bolus injection on Days 1 and 13 (2 hours after RO6953958 dosing).
~3
2.5
2
0.5
0
5 min
0.25
0.5
0.75
1
1.5
2
2.5
3
4
6
8
10
Standard Meal 
a
x
x
x
PK Sample RO6953958, M1 and M3 
b
x
ECG-12 lead
x
Vital signs 
c
x
x
x
Administration of RO6953958 
d
x
PK Sample midazolam
x
x
x
x
x
x
x
x
x
x
x
x
x
x
4β -hydroxycholesterol sampling 
x
IV Administration of midazolam 
e
x
Procedure
Time prior to IV midazolam dosing (h)
Time post IV midazolam dosing (h)


RO6953958—F. Hoffmann-La Roche Ltd
46/Protocol BP41695, Version 7
Table 7
Detailed Schedule of Activities on Day 2 (Day 3 for RO6953958 PK Profile) and Day 14 – Part 3
ECG = electrocardiogram, min = minute; h = hour; M1 = RO7045755; M3 = RO7021594; PK = pharmacokinetics.
a.
Vital signs will include blood pressure, pulse rate, respiratory rate, and body temperature. Temperature will be recorded at Screening, 
Day 1 (predose), and Follow-up. All measurements will be taken after the participant has rested in a supine position for at least 
5 minutes. Perform vital signs prior to PK sampling.
b.
Standardized meals at -2 hours predose and at approximately 2 and 8 hours postdose relative to midazolam dosing. PK sampling should 
be performed before providing meals.
c.
Full PK profile for RO6953958 on Days 3 and 14 only. On Day 3, PK sample times will be relative to RO6953958 administration.
d.
On Day 14 only, RO6953958 will be administered orally 30 minutes after starting a standardized breakfast (1.5 hours prior to 
midazolam dosing).
e.
Midazolam will be administered orally on Days 2 and 14 (1.5 hours after RO6953958 dosing).
2
1.5
1
0.5
0
0.25
0.5
0.75
1
1.5
2
2.5
3
3.5
4
4.5
5.5
6
8
8.5
10
10.5
ECG-12 lead
x
Vital signs a
x
x
x
Standard Meal b
x
x
x
PK Sample RO6953958, M1 and M3 c
x
x
x
x
x
x
x
x
x
x
PK Sample midazolam 
x
x
x
x
x
x
x
x
x
x
x
x
x
4β -hydroxycholesterol sampling 
x
Administration of RO6953958
 d
x
Oral Administration of midazolam
 e
x
Procedure
Time pre oral midazolam dosing (h)
Time post oral midazolam dosing (h)


RO6953958—F. Hoffmann-La Roche Ltd 
47/Protocol BP41695, Version 7 
2.
INTRODUCTION
There have been no clinical studies with RO6953958 to date. The planned Phase I study 
BP41695 in healthy male volunteers will be the first study conducted in humans. 
2.1 
STUDY RATIONALE 
RO6953958 is a potent and selective human vasopressin V1a receptor antagonist that 
blocks the activation of the V1a G protein-coupled receptor. Evidence from mouse 
studies implicates a V1a receptor antagonism in the accelerated resynchronization of 
circadian rhythm. RO6953958 is highly potent on the human V1a receptor (dissociation 
constant [Kb] = 0.22 nM) and may provide a novel and first approach to treat circadian 
disturbances and social deficits in neurodevelopmental disorders (NDDs). This is the 
first study with RO6953958 in humans, designed to assess the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple-ascending 
doses (MAD), food effect (FE), and drug-drug interaction (DDI) potential following oral 
administration to healthy male participants. The study results will support further clinical 
development of RO6953958. 
The rationale for the study design is provided in Section 4.2. 
2.2 
BACKGROUND 
2.2.1 
Background on Neurodevelopmental Disorders 
NDDs are defined as a group of disorders caused by changes in early brain 
development, resulting in behavioral and cognitive alterations in sensory and motor 
systems, speech, and language (van Loo and Martens 2007). The prevalence of these 
disorders has been estimated to be approximately 1 in 6 children (approximately 17%) 
between the ages of 3 to 17 years in the United States (with the most common, 
attention-deficit/hyperactivity disorder [affecting between 8.5%–9.5% of children] and 
Autism Spectrum Disorder [ASD; between 1.1%−2.5% children, or 1%−2% of the 
world population]) (Elsabbagh et al 2012; Baio et al 2018; Xu et al 2019; Zablotsky 
et al 2019). Up to 80% of children with NDDs are reported to have disrupted sleep 
(Grigg−Damberger and Ralls 2013), with associated deleterious effects on daytime 
behaviors, cognition, physical and/or emotional outcomes and on their overall 
development and caregiver burden (Stores 2001; Schreck et al 2004; Jan et al 2008; 
Annaz et al 2011; Taylor et al 2012). Furthermore, greater sleep difficulties in children 
with ASD are associated with greater impairment in core deficits of the disorder 
compared to ASD in children with less sleep difficulty (Cohen 2017; MacDuffie et al 
2020; Yavuz−Kodat 2020), suggesting that improving sleep is an important approach to 
treatment of NDDs. 
Sleep disorders in children with NDDs are often multifactorial in etiology, including 
medical, neurologic, and psychiatric co-morbidities. However, some specific conditions 
such as Smith-Magenis syndrome (SMS), ASD, Prader-Willi, Angelman, and Rett 
syndromes are associated with specific dysfunctions in circadian rhythms (Potocki et al 


RO6953958—F. Hoffmann-La Roche Ltd
48/Protocol BP41695, Version 7
2000; De Leersnyder 2001; Tordjman 2005; Melke et al 2008; Powell and LaSalle 
2015).
Abnormalities in the vasopressin systems have also been investigated in psychiatric 
disorders (Iovino et al 2018) and NDDs (Francis et al 2014) that are characterized by 
the presence of social deficits. Moreover, disturbed sleep-wake patterns have also been 
described in a number of psychiatric disorders and NDDs including ASD (Pinato et al 
2019), SMS, Prader-Willi, Angelman, and Rett syndromes (Powell and LaSalle 2015). 
Based on current literature and nonclinical observations, V1a receptor antagonism has 
the potential to offer therapeutic benefit for a wide range of NDDs and psychiatric 
disorders that involve circadian rhythm sleep-wake disturbances.
There are three known receptors of the nine amino acid vasopressin peptide. These G 
protein-coupled receptors are called vasopressin 1a (V1a), vasopressin 1b (V1b), and 
vasopressin 2 (V2) receptors. V1a and V1b are coupled to Gq protein and stimulate 
intracellular calcium release. V2 is coupled to Gs protein alpha-subunit (Gs) and 
stimulates cyclic adenosine monophosphate formation. A very closely related peptide 
receptor is the oxytocin receptor, which is also coupled to Gq. The V1a, V1b, and 
oxytocin receptors are expressed in limbic areas of the brain, including the 
hypothalamus, septum, ventral tegmental area, hippocampus, and amygdala (Loup et al 
1991; Ostrowski et al 1994; Ostrowski 1998). These areas are known to be involved in 
emotional processes and play a critical role in affective disorders and the regulation of 
social behavior. The V1a receptor is also expressed in a high number of neurons of the 
dorsal SCN, which plays an important role in keeping the endogenous circadian clock 
synchronized to the light/dark rhythm (Tsuji et al 2017).
In the periphery, V1a receptors are expressed in platelets and vascular smooth muscles, 
mediating vasopressin-induced platelet aggregation and vasoconstriction, respectively. 
V1a receptors expressed in the medulla of adrenals may be involved in the release of 
catecholamines. V1a receptors expressed in dorsal root ganglia and peripheral nerves 
have been claimed to mediate analgesic effects of oxytocin and vasopressin 
(Schorscher-Pectu et al 2010). Renal expression of V1a receptors has been suggested 
to be involved in mediating the renal effects of aldosterone and their luminal expression 
in the renal tubules in sodium excretion. However, the quantitative relevance of such 
effects in humans is not known. In clinical studies with another V1a receptor antagonist 
(balovaptan) developed by the Sponsor for social and communication deficits in ASD, 
no relevant changes in blood pressure, heart rate, blood sodium and potassium levels, or 
changes in bleeding risk were observed. V2 receptors are mainly expressed in the 
kidneys where they mediate the anti-diuretic effects of vasopressin.
2.2.2
Background on RO6953958
The human vasopressin V1a receptor is a Gq protein coupled receptor and RO6953958 
was found to be a potent and selective human V1a antagonist. In vitro, RO6953958 
exhibited an inhibition constant of 0.5 nM for the human V1a receptor, with at least 


RO6953958—F. Hoffmann-La Roche Ltd
49/Protocol BP41695, Version 7
6000-fold binding selectivity over 133 other receptors, enzymes, and ion channels 
including the related human vasopressin V2 and V1b receptors, as well as the human 
oxytocin receptor. In functional assays of calcium fluxes using fluorescent imaging 
(fluorometric imaging plate reader), RO6953958 showed antagonist activity at the 
human V1a with a dissociation constant (Kb) of 0.22 nM. The dissociation half-life of 
RO6953958 from the human V1a receptor is 102 minutes at room temperature.
Metabolites M1 (RO7045755) and M3 (RO7021594) were also shown to inhibit the 
human V1a receptor in a functional assay, with Kb values of 24 nM and 0.75 nM, 
respectively.
In an ex vivo functional assay, RO6953958 was shown to inhibit V1a-mediated 
vasopressin-induced platelet aggregation in human whole blood, with a Kb of 12 nM. 
This value is consistent with the dissociation constant measured in vitro (Kb = 0.22 nM), 
taking into account the measured human plasma free fraction of 1.7%, and it 
demonstrates that RO6953958 can inhibit the native V1a receptor.
In a mouse circadian study, wild-type mice subjected to a 6hour-phase advance of the 
light/dark cycle resynchronized significantly faster to the new cycle after one 
intraperitoneal administration of 60 mg/kg RO6953958 than vehicle-treated mice. This 
indicates that RO6953958 has the potential to resynchronize circadian rhythms, which 
may improve sleep-wake patterns that are known to be dysregulated in patients with 
NDDs.
The PK properties of RO6953958 were assessed in rats, cynomolgus monkeys, dogs,
and minipigs. RO6953958 was well absorbed in all of these species following oral
administration. In rats and cynomolgus monkeys, RO6953958 displayed a low systemic 
clearance, whereas in dogs and minipigs the systemic clearance was medium to high. 
The volume of distribution under steady-state conditions (Vss) was low to moderate in all 
of the species tested. RO6953958 has low intrinsic clearance in vitro and a moderate 
plasma protein binding across species, including humans. This results in a low to 
moderate predicted systemic clearance in humans. Cerebrospinal fluid (CSF) exposures 
in rats indicated RO6953958 has good brain penetration, consistent with weak 
P-glycoprotein (P-gp) substrate properties. RO6953958 is cleared in vitro and in animal 
species primarily by oxidative metabolism. After single dose intravenous (IV) 
administration in rats, less than 1% of the administered dose was found in urine and 
feces as parent compound, suggesting that the renal clearance plays a minor role in 
RO6953958 elimination in rats. 
The primary steps in RO6953958 oxidation by human liver microsomes or human 
hepatocytes mainly result in the generation of metabolites M1 (N-oxide), M2, and M3 
(phenol), with minor secondary metabolites also identified (secondary oxidation products 
and glucuronides). RO6953958 is a substrate for human cytochrome P450 (CYP) 3A4 
and CYP2C19. RO6953958 is an inhibitor (CYP2C19, 2C8, 3A4) and inducer (CYP2B6, 
2C8, 3A4) of the major human CYP enzymes in vitro. However, based on anticipated 


RO6953958—F. Hoffmann-La Roche Ltd
50/Protocol BP41695, Version 7
human dose and target exposures, it is unlikely that co-administration with RO6953958 
will alter the pharmacokinetics of other drugs whose disposition is influenced by CYP 
metabolism, with the possible exception of CYP3A4 depending on the clinical dose. 
Requirement for clinical DDI studies will be refined upon availability of data from this 
ongoing Phase I study (BP41695). RO6953958 is highly permeable and displays no 
substrate interaction with human P-gp.
In vitro studies have shown that RO6953958 does not significantly inhibit P-gp at the 
digoxin binding site, nor does it significantly inhibit the breast cancer resistance protein 
(BCRP) efflux transporter. In addition, RO6953958 does not significantly inhibit the 
organic anion-transporting polypeptides (OATP) 1B1 or OATP1B3, the organic anion 
transporter OAT1, or the multidrug and toxin extrusion transporter MATE2-K. 
However, it can inhibit OAT3, the organic cation transporter OCT2 and MATE1 at 
high-substrate concentrations. The relevance of this finding will be evaluated further 
once the clinical dose for Phase II studies has been defined. 
The DDI potential of M1 and M3, the major circulating metabolites identified so far, 
was also assessed. No perpetrator DDI risk potential due to enzymes or transporters 
was observed for M1 in vitro. At high concentrations only (i.e., substrate 
concentrations not considered to be clinically relevant), M3 was found to be an in vitro 
reversible inhibitor of CYP2C8, CYP3A4, and UGT1A1 and also an inhibitor of OAT3. 
M3 did not significantly inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OCT2, 
MATE1, or MATE2-K.
The nonclinical safety program was conducted in rats and cynomolgus monkeys, which 
are pharmacologically relevant species.
RO6953958 was administered in the 13-week Good Laboratory Practice (GLP) toxicity 
study in rats at doses up to 500 mg/kg/day in males and up to 250 mg/kg/day in females, 
the highest doses administered, with no adverse effects. The 
no-observed-adverse-effect level (NOAEL) for this study was 500 mg/kg/day in males 
and 250 mg/kg/day in females. 
RO6953958 was administered in the 13-week GLP toxicity study in male and female 
cynomolgus monkeys at doses up to 600 mg/kg/day, which was the maximum feasible 
dose (MFD) with no adverse effects. 
Cardiovascular safety of RO6953958 and M3 was assessed in vitro in human ether à 
go-go (hERG) cardiac ion channel assays. Based on the results of these studies, 
RO6953958 and M3 are not expected to affect hERG cardiac ion channels at the 
intended clinical dose. No in vivo cardiovascular effects were observed in cynomolgus 
monkeys after single or repeat dosing up to 600 mg/kg/day, which was the highest dose 
evaluated.


RO6953958—F. Hoffmann-La Roche Ltd
51/Protocol BP41695, Version 7
GLP safety pharmacology studies were conducted in rats to assess central nervous 
system (CNS) and respiratory function. No effects on the CNS were observed at doses 
up to 500 mg/kg in males and 250 mg/kg in females using the functional observation 
battery and nerve conduction velocity evaluations included in the GLP 13-week oral 
gavage toxicity study in rats. These were the highest doses evaluated. No effects in 
respiratory function were observed after a single dose of 500 mg/kg, which was the 
highest dose administered.
The in vitro and in vivo mutagenicity assays did not reveal any indication of genotoxic 
potential for RO6953958 or M3. No teratogenic effects were observed at the highest 
doses tested in the rat embryo-fetal development (EFD), rabbit EFD, or rat dose-range 
finding (DRF) juvenile studies. The NOAEL was 250 mg/kg/day in the rat EFD study 
and 300 mg/kg/day in the rabbit EFD study. The NOAEL was 500 mg/kg/day for males 
and 250 mg/kg/day for females in the rat DRF juvenile study.
A detailed description of the chemistry, pharmacology, and safety of RO6953958 is 
provided in the RO6953958 Investigator’s Brochure.
2.2.2.1
Safety Information from Drugs of the Same Class
Safety information from a selective V1a receptor antagonist is available for balovaptan 
(RO5285119) which was in Phase II/Phase III clinical development for treatment of core 
symptoms of ASD. However, further development of balovaptan has been stopped 
based on the planned futility analysis of one of the Phase III studies in adults with ASD 
and final results in a Phase II study in children and adolescents with ASD. Balovaptan 
was considered to be safe and well tolerated in both studies.
No adverse event (AE) pattern thought to be causally linked to the blockade of the V1a 
receptor has been identified as of now.
Animal toxicities noted with balovaptan emerged at plasma levels higher than required to 
block the V1a receptor and are considered to be related to the chemical structure of 
balovaptan and its metabolite(s) and not target-related (RO5285119 [balovaptan] 
Investigator’s Brochure). As RO6953958 is chemically distinct from balovaptan and 
from balovaptan’s major metabolite in animals, the animal toxicities observed with 
balovaptan are considered irrelevant for RO6953958. Indeed, the available 13-week 
GLP toxicology results with RO6953958 in rats and monkeys did not reveal toxicities 
found in animals with balovaptan.
Additionally, the effects of a single, 20-mg IV dose of RO5028442, another V1a receptor 
antagonist, was assessed in a multicenter, randomized, double-blind, 
placebo-controlled, crossover study in 19 high functioning male participants with ASD
Single doses of 20 mg, associated with a predicted 90% receptor occupancy at Ctrough, 
were well tolerated (Umbricht et al 2017).


RO6953958—F. Hoffmann-La Roche Ltd
52/Protocol BP41695, Version 7
Therefore, no particular target-related safety concerns are expected for this novel target 
of V1a receptors RO6953958 in this proposed entry-into-human study.
Taken together, safety experience from other V1aR receptor antagonists does not point 
to a safety alert related to mode of action and no relevant toxicities were observed in 
13-week GLP toxicology animal studies with RO6953958 indicating a particular 
non-target related safety risk.
2.2.2.2
Preliminary Pharmacokinetic and Safety Data Observed in Part 
1 and Part 2
At the time of writing version 7 of this protocol, 64 male participants (active and placebo
3:1) had been enrolled in Study BP41695. In Part 1 (SAD) 48 participants received 
single oral doses of 5 mg, 15 mg, 45 mg, 90 mg, 180 mg, and 360 mg respectively, with 
6 participants on active, and 2 on placebo at each dose level. Subjects receiving 90 mg 
returned around 4 weeks later for another dose of 90 mg under fed conditions. In the 
ongoing Part 2 (MAD) of the study, a further 16 male participants (active and placebo 
3:1) have been dosed with 45 mg and 140 mg QD for 10 days, with 6 participants on 
active, and 2 on placebo at each dose level. On 12 Jul 2021, a new cohort was started 
within the MAD part with a dose of 210 mg QD for 10 days. This cohort is currently 
ongoing.
Clinical Pharmacology
A full PK data set was available for Part 1 (SAD) of this study. A preliminary PK 
parameter summary based on the available PK data of RO6953958 and its metabolites 
(RO7045755 and RO7021594) is presented in Table 8.
Following single oral doses ranging from 5 mg to 360 mg in the fasted state, 
RO6953958 was rapidly absorbed with a median Tmax of between 1-2 h postdose. A later 
Tmax for the metabolites, RO7045755 and RO7021594, was observed with median 
values of approximately 2 h which was further delayed to between 4 - 7h for 45 to 
360 mg, respectively. The Cmax of RO6953958 increased in a less than dose proportional 
manner, for single doses of 5, 15, 45, 90 180, and 360 mg. However, the AUCinf of 
RO6953958 appears to increase with dose for 5, 15, 45, 90, 180, and 360 mg, 
respectively in a relatively dose-proportional manner. The metabolites RO7045755 and 
RO7021594 show a similar trend with dose for Cmax and AUCinf. In terms of overall 
exposure compared to parent (RO6953958), RO7021594 is approximately 7-fold higher 
than RO6953958 whilst RO7045755 is comparable to RO6953958 after a single dose.
When 90 mg RO6953958 was administered with a high fat breakfast, the Cmax of 
RO6953958 increased 2-fold compared to fasted conditions, whereas AUCinf remained 
similar (Table 8). This trend was also observed for both metabolites (RO7045755 and 
RO7021594).


RO6953958—F. Hoffmann-La Roche Ltd
53/Protocol BP41695, Version 7
Urinary excretion of RO6953958 after single dosing was quantifiable in urine, however, 
the fraction excreted was very small and generally less than 1% of the dose 
administered (range: 0.27% to 0.64%). Excretion of M3 was comparable to parent, 
however, M1 urinary excretion was around 10-fold higher.
Table 8
Summary of pharmacokinetic parameters for RO6953958 and its 
metabolites (RO7045755 [M1] and RO7021594 [M3]) following 
single doses of 5, 15, 45, 90, 180, and 360 mg under fasted and 
fed conditions
* For all Tmax values the median is reported, not the geometric mean.
In the ongoing Part 2 (MAD) of this study, oral doses of 45 mg and 140 mg were 
administered for 10 days QD under fed conditions. Table 9 provides a summary of the 
available results for PK parameters on Day 1 and 10 for RO6953958 and the 
metabolites RO7045755 (M1) and RO7021594 (M3) 
Based on the half-lives of RO6953958, M1, and M3 - with M3 showing the longest 
geometric mean half-life ranging between 15.0 and 29.5 hours - steady state is expected 
to have been reached by Day 10. RO6953958 was rapidly absorbed with a tmax of 
approximately 2 hours postdose. The total AUC from 0 to next dose (AUCtau) for 
RO6953958 increased in a mostly dose-proportional fashion over the two doses. 
However, a less than dose-proportional increase in Cmax on both Day 1 and 10 was 
Tmax*
Cmax
AUCINF_obs Tmax
Cmax
AUCINF_obs Tmax
Cmax
AUCINF_obs
(hr)
(ng/ml)
(hr*ng/ml)
(hr)
(ng/ml)
(hr*ng/ml)
(hr)
(ng/ml)
(hr*ng/ml)
RO6953958 5MG
Geometric Mean
1
70.3
206
2
61.3
1490
2
31.9
238
Fasted
Geometric CV%
31.4
39.7
45
37.7
33
64
Min
0.5
49.5
132
1
35
1030
1
21.2
105
Max
2
99.7
401
3
127
2820
3
43.4
518
RO6953958 15MG
Geometric Mean
1
150
676
2
187
5130
2
77.3
740
Fasted
Geometric CV%
34.2
52.2
41
49.9
25.2
49
Min
0.5
106
317
2
122
3220
1
59.9
423
Max
2.12
250
1180
6
375
11400
6
119
1400
RO6953958 45MG
Geometric Mean
2
299
1780
5.5
480
12600
4
169
1700
Fasted
Geometric CV%
50
26.2
76
90.5
36.9
35.5
Min
1
135
1180
5
224
4420
2.02
108
1010
Max
3
525
2530
7
1180
33200
6
248
2500
RO6953958 90MG
Geometric Mean
2
451
5120
6.51
490
21100
5
272
5120
Fasted
Geometric CV%
30.7
46.5
18.8
42
32.5
32.2
Min
1
324
2720
5
388
12000
3
194
3190
Max
2.02
704
7890
10
597
37100
6
473
7170
RO6953958 90MG
Geometric Mean
4
932
5410
5.5
819
21600
5
491
5770
Fed
Geometric CV%
34.6
39.3
21.2
40.1
29.1
33.2
Min
2
618
3020
3
606
12700
2
311
3730
Max
5
1450
7780
10
1120
36500
7
662
8140
RO6953958 180MG Geometric Mean
2
618
9710
6.5
1230
74600
4
305
6900
Fasted
Geometric CV%
47.4
31.3
67.2
79.6
71.1
62.4
Min
1
365
6760
2
625
35900
2
107
2940
Max
5
1110
16400
48
2890
179000
7.05
630
14500
RO6953958 360MG Geometric Mean
2
866
15200
7.01
1280
79100
5.01
481
11700
Fasted
Geometric CV%
39.5
78.7
28.3
46.9
42.4
87.8
Min
0.5
460
5930
5
856
43600
3
265
3040
Max
3
1220
30300
24.1
1950
156000
10
817
25600
Dose and fed status
Analyte
RO6953958
RO7021594
RO7045755


RO6953958—F. Hoffmann-La Roche Ltd
54/Protocol BP41695, Version 7
evident, suggesting solubility-limited absorption. The accumulation ratios (AR) from 
Day 1 to Day 10 were ~1 for both Cmax and AUCtau for the parent compound 
(RO6953958) and M1, whereas they were ranging from 1.6-1.9 for M3. 
For M3, AUCtau was approximately 4.6- and 8-fold higher than the parent compound, on 
Days 1 and 10, respectively; while exposure levels of M1 were 0.7-fold of the parent 
compound on both Days 1 and 10, for both doses administered. 


RO6953958—F. Hoffmann-La Roche Ltd
55/Protocol BP41695, Version 7
Table 9
Summary of Pharmacokinetic Parameters for RO6953958 and the Metabolites RO7045755 (M1) and 
RO7021594 (M3) on Day 1 and Day 10 Following Multiple Oral Doses of 45 mg and 140 mg for 
10 Days Under Fed Conditions
Analyte
RO6953958
RO7021594 (M3)
RO7045755 (M1)
Dose
(mg)
Day
n=6
tmax*
(hr)
Cmax
(ng/ml)
AR Cmax
AUCtau
(hr*ng/ml)
AR AUCtau
t1/2
(hr)
tmax*
(hr)
Cmax
(ng/ml)
AR Cmax
AUCtau
(hr*ng/ml)
AR AUCtau
t1/2
(hr)
MPR_Cmax
MPR_ 
AUCtau
tmax*
(hr)
Cmax
(ng/ml)
AR Cmax
AUCtau
(hr*ng/ml)
AR AUCtau
t1/2
(hr)
MPR_ Cmax
MPR_
AUCtau
45
1
Geomean
2.53
469
1830
2.54
5.00
677
9040
15.0
1.39
4.75
4.00
171
1450
3.87
0.350 0.761
GM CV%
21.9
38.7
44.7
45.9
33.1
47.9
43.8
13.6
77.7
72.5
28.5
43.0
74.1
44.6
32.3
36.2
Min
2.00
268
833
1.52
3.00
455
5910
11.8
0.726
2.67
3.00
97.3
485
2.15
0.227 0.465
Max
3.00
798
2810
3.80
6.03
1330
17700
17.0
3.46
11.9
5.00
266
2450
6.01
0.542
1.12
45
10
Geomean
2.02
490
1.05
2010
1.10
3.32
5.02
1100
1.63
16400
1.81
29.5
2.16
7.85
3.01
194
1.13
1550
1.07
4.32
0.380 0.744
GM CV%
41.8
25.0
19.0
38.4
8.41
41.9
39.2
41.4
12.1
47.9
13.9
34.6
50.7
69.3
35.3
44.9
10.0
79.7
8.13
50.3
37.3
40.1
Min
1.00
384
0.876
1000
1.01
1.96
2.08
704
1.45
9440
1.60
18.4
1.09
4.19
2.08
98.8
1.01
500
0.989
2.13
0.248 0.436
Max
3.00
699
1.43
2840
1.24
4.72
5.05
1930
1.94
31000
2.28
44.8
3.91
17.0
5.02
306
1.31
2540
1.21
7.48
0.654
1.05
140
1
Geomean
2.01
1190
5820
5.81
3.02
1790
27400
19.9
1.45
4.53
3.02
452
3980
6.07
0.366 0.658
GM CV%
36.9
43.5
64.0
17.5
52.4
66.7
69.6
72.0
99.3
93.8
26.7
31.5
70.8
45.8
35.6
46.5
Min
1.00
720
3330
4.40
3.00
887
13300
11.6
0.444
1.68
3.00
332
1760
3.34
0.248 0.367
Max
3.02
1920
12900
7.16
10.0
3490
67800
50.0
3.34
11.0
5.00
779
8500
12.4
0.639
1.14
140
10
Geomean
2.04
1250
1.05
6060
1.04
7.28
4.00
3180
1.77
51500
1.88
26.4
2.46
8.17
3.04
456
1.01
4290
1.08
6.71
0.352 0.681
GM CV%
41.2
49.7
24.0
58.0
15.9
46.4
40.5
76.7
32.2
85.4
19.9
32.1
110
101
26.5
68.3
45.2
97.2
23.4
42.8
29.4
52.4
Min
1.02
616
0.706
2850
0.858
3.22
3.00
1360
1.21
22000
1.54
15.9
0.719
2.59
3.00
186
0.560
1390
0.791
3.56
0.239 0.359
Max
3.00
2310
1.40
11600
1.25
11.4
7.00
9710
2.78
181000
2.67
37.2
6.87
19.8
5.00
1020
2.09
11900
1.55
11.2
0.527
1.15
AR = accumulation ratio; Geomean = Geometric Mean; GM CV% = geometric coefficient of variation; Max = maximum; Min = minimum; MPR = metabolite 
to parent ratio; * = Median for tmax.


RO6953958—F. Hoffmann-La Roche Ltd
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Safety
A total of 48 healthy male participants enrolled in the SAD part received single, oral 
doses of 5, 15, 45, 90, 180, and 360 mg with 6 participants on RO6953958 and 2 on 
placebo at each dose level. There were no deaths or serious adverse events (SAEs) 
reported. The majority of the AEs were mild and self-limited (resolved within 
24 hours), with no dose-limiting AEs or dose-limiting toxicities observed. There were 
no clinically significant changes in vital signs, laboratory tests, or ECGs including 
QTc and PR interval. Oral administration of RO6953958 at single doses has been 
generally safe and well tolerated and no dose relationship was observed for any of the 
reported AEs. 
In the SAD part (Part 1), a total of 22 treatment-emergent AEs (TEAEs) were recorded 
for 17 participants, of which 15 received RO6953958 and 2 received placebo. Of the 
22 TEAEs, 15 were considered to be related to study drug administration by the 
Principal Investigator. The majority of AEs involved the system organ class of nervous 
system disorders. The most commonly reported AEs were headache (n = 5) and 
somnolence (n = 3); these events were reported by participants who received 5, 15, 90, 
or 360 mg RO6953958. Sixteen TEAEs were reported with mild intensity, including all of 
the somnolence events. Six of the AEs were reported with moderate intensity: ear 
infection, sore throat, headache, presyncope and syncope in participants who received 
either15 mg RO6953958 or placebo. Back pain was reported by a participant who 
received 180 mg RO6953958.
In the ongoing, and still-blinded MAD part (Part 2), an additional 16 participants have 
been enrolled who received 45 mg or 140 mg for 10 days QD with 6 participants on 
active and 2 on placebo at each dose level. There have been no deaths or SAEs reported 
and no clinically significant changes in vital signs, laboratory tests, or ECG including 
QTc and PR interval. On 12 July 2021, a new cohort in MAD with the dose of 210 mg 
QD for 10 days started and is currently ongoing. So far, a similar AE profile has been 
observed in Part 2 as that in Part 1 of the study.
A detailed description of the chemistry, pharmacology, and safety of RO6953958 is 
provided in the Investigator’s Brochure.
2.3
BENEFIT/RISK ASSESSMENT
For this first study with RO6953958 in humans, healthy male participants aged 18 to 55 
(inclusive) were chosen because of the absence of potentially confounding disease 
processes, which will lead to a clearer and more consistent assessment of drug 
disposition and biological activity. In addition, healthy participants are unlikely to require 
concomitant medication that could interfere with the study drug or its PD effects. Female 
participants have been excluded as nonclinical teratogenicity studies have not been 
conducted to date and not to expose female participants to undue risk.


RO6953958—F. Hoffmann-La Roche Ltd
57/Protocol BP41695, Version 7
In the single-ascending dose (SAD) part (Part 1), in order to avoid simultaneous 
exposure of all participants on the same day, a sentinel group at each dose level will be 
dosed first with 2 participants randomized; 1 on the active treatment and 1 on placebo. If 
the safety and tolerability from the first 2 participants are acceptable in the judgment of 
the Investigator 23 hours after dosing, the remaining participants (randomized as 5 on
the active treatment and 1 on placebo) will be dosed at the same dose level at least 
24 hours later. Ascending doses are planned in order to establish the safety and 
tolerability at low dose levels before proceeding to higher dose levels. Dose levels may 
be adjusted (increased, decreased, or repeated) or intermediate doses may be used 
depending on the emerging safety and PK data at each dose level. In order to ensure
safety of the participants, the effects of each dose level including safety and PK will be 
reviewed carefully before escalating to the next dose level. Criteria and stopping rules 
for dose-escalation decisions are detailed in Section 4.1.5 and Section 4.1.7. No 
therapeutic benefit is anticipated for participants of this study, as is common for most 
Phase I studies involving healthy participants. The evaluation of potential risks of 
RO6953958 in humans is based primarily on available data from nonclinical toxicology, 
safety pharmacology studies documented class risks from other drugs developed in 
house that bind V1a receptors as antagonists (balovaptan and RO5028442; see 
Section 2.2.2.1) and preliminary blinded safety data from Part 1 of the study
(Section 2.2.2.2).
To ensure the safety of participants, safety monitoring/assessments covering broadly the 
various organ systems have been implemented, while nonclinical studies do not 
mandate a particular dedicated safety measure. During the conduct of the study,
participants will be hospitalized at the clinical research unit for the entire treatment 
duration and for at least 48 hours after the last dose. Safety and tolerability will be 
monitored closely throughout the study. Tolerability will be assessed by recorded AEs. In 
addition, any cardiovascular changes will be monitored with extensive and repeated 
measurements of vital signs (blood pressure [BP] and pulse rate), triplicate 12-lead and 
Holter electrocardiograms (ECGs) (in Part 1, no Holter ECG for the fed part in the FE 
cohort; in Part 3 no Holter ECG), and laboratory safety parameters, which will be 
recorded in all parts of the study. In addition, RO6953958 concentrations will be 
measured in plasma and urine on specific days, and plasma PK concentrations will be 
used to support dose escalation. Furthermore, CSF sampling by lumbar puncture will be 
performed in Part 2 of the study in all participants per cohort to support dose selection 
for future clinical studies.
To ensure the safety of study participants and staff and minimise their risk of COVID-19 
infection, appropriate trial and site specific COVID-19 risk mitigation measures will be 
implemented as required per local and site regulations. 
Additionally, a risk assessment was conducted to determine whether there is any impact 
of the COVID-19 vaccines on the benefit/risk assessment of this study protocol including 
but not limited to the healthy population under study and study treatment being 


RO6953958—F. Hoffmann-La Roche Ltd
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evaluated. Based on this assessment, in order not to delay study participant from 
receiving a COVID-19 vaccination when it is offered to them, participants are allowed to 
receive a dose of the vaccine 21 days prior to the first dose of study treatment or a dose 
of the vaccine at least 10 days after the last dose of study treatment. The existing safety 
monitoring and management guidelines, as well as the risk minimization measures 
outlined in the clinical protocol, are considered appropriate to support administration of 
COVID-19 vaccines.
Following the FDA guidance on estimating the maximum safe starting dose in adult 
healthy volunteers (U.S. FDA 2005), a maximum starting dose of 240 mg was calculated 
without taking into consideration the pharmacologically active dose (PAD). However, as 
the dose of 240 mg daily is anticipated to be within the estimated therapeutic dose range
in humans (10 mg to 160 mg twice daily [BID]) which is to be explored during Part 1, a 
starting dose of 5 mg has been selected (Section 4.3). An alternative approach is a 
starting dose offering the possibility to assess safety of dose levels that are below the 
anticipated therapeutic PAD range in humans based on PK/PD (EMA 2017). A 5-mg 
starting dose is expected to be safe and associated with no or only minimal PD effect(s). 
The conservative and careful selection of the starting dose ensures safety margins of 
more than 565- and 975-fold on the basis of free concentrations for Cmax and area under 
the curve (AUC) against the NOAEL of cynomolgus monkey. Furthermore, subsequent 
dose-escalation-decision criteria include a maximum individual exposure that does not 
exceed a predicted exposure for Cmax of approximately 3500 ng/mL and/or AUC0-24 of 
35,000 ngh/mL.
In Part 1, dose escalation will be stopped if the subsequent dose is predicted to result in 
maximum individual exposures that would exceed a Cmax of approximately 3500 ng/mL 
and/or AUC0-24 of 35,000 ng·h/mL or the MFD of 10 dose units of 80 mg (800 mg) QD. A 
Cmax of approximately 3500 ng/mL AUC0-24 of 35,000 ng·h/mL has a 9-fold safety margin 
below the NOAEL (based on free concentrations) reported for cynomolgus monkey. The 
maximum dose in Part 2 (MAD) will not exceed maximum individual total and peak
exposures observed in Part 1 or doses tested in Part 1 (SAD). Part 1 of the study will 
also investigate the effect of food on the PK of RO6953958 to establish the appropriate 
timing of dosing relative to food intake for Part 2 and subsequent studies. The dose for 
the FE is to be performed at the anticipated therapeutic dose tested in Part 1 but may be 
adjusted based on the review of the PK data.
In addition to the potential risks associated with study drug administration, other potential 
risks include discomfort from planned study procedures such as CSF sampling. CSF 
sampling by lumbar puncture carries a risk of post-puncture headache, and, although 
rare, a potential risk of spinal infection or hemorrhage. These risks will be minimized by 
careful selection of the participants and by having an experienced anesthesiologist 
perform the lumbar punctures. The rationale for CSF sampling in this study can be found 
in Section 4.2.6.


RO6953958—F. Hoffmann-La Roche Ltd
59/Protocol BP41695, Version 7
For Part 3, please refer to Section 4.2.7 for rationale of midazolam and its associated 
risks.
Furthermore, additional safety measures are required during the assessment of the core 
body temperature. After the core body temperature pill (capsule sensor) is swallowed
and until the device has left the body, magnetic resonance imaging (MRI) is strongly 
forbidden. In order to make sure that this is not overlooked it is recommended to affix an 
MRI warning wrist band to the participant with the instruction to wear it until the sensor 
has left the body. It is recommended to swallow the capsule sensor with water or any 
other suitable liquid to avoid choking. In rare instances, the capsule sensor may become 
lodged in the intestines. Participants are therefore asked to report any gastrointestinal 
discomfort following ingestion of the capsule, such as nausea, vomiting or pain 
immediately.
The administration of RO6953958 is anticipated to be safe and well-tolerated following 
single and multiple oral dose administration based on available nonclinical data and 
under the study conditions described above and outlined in Section 1.2 and Section 4. 
However, because the theoretical risk of blood pressure decrease has not been fully 
evaluated, care should be taken by participants not to stand up abruptly, or without 
using the support of a stable object following dosing with RO6953958.The potential 
risks for any healthy participants due to the treatment of RO6953958 or study-related 
procedures are considered minimal and outweighed by the potential to develop a new 
treatment for ASD and autism-related sleep disorders. More detailed information about 
the known and expected benefits in the context of potential risks and reasonably 
expected AEs of RO6953958 is provided in the RO6953958 Investigator’s Brochure.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 10.


RO6953958—F. Hoffmann-La Roche Ltd
60/Protocol BP41695, Version 7
Table 10 Objectives and Endpoints
Objectives
Endpoints
Primary
Parts 1, 2, 
and 3

To assess the safety and 
tolerability of single- and 
multiple-ascending doses 
of RO6953958 alone and 
in combination with 
midazolam (Part 3 only) in 
healthy participants

Incidence and severity of AEs. 
Changes in vital signs, physical 
findings, ECG parameters (12-lead 
safety in all parts and 24-hour 
Holter in Part 1 and Part 2 only), 
and clinical laboratory results 
during and following RO6953958
administration

Change in suicide risk (using 
Columbia Suicide Severity Rating 
Scale) in Part 2 only
Secondary
Parts 1, 2, 
and 3

To investigate the PK of 
RO6953958 and its 
metabolites RO7021594 
and RO7045755 following 
single and multiple doses
of RO6953958 alone and 
in combination with 
midazolam (Part 3 only)

To investigate the dose 
proportionality of 
RO6953958

PK concentrations and PK 
parameters of RO6953958 and its 
metabolites RO7021594 and 
RO7045755
Part 1

To assess the effect of food 
on the PK of a single dose 
of RO6953958

PK concentrations and PK 
parameters of RO6953958 and its 
metabolites RO7021594 and 
RO7045755 in fasted and fed state
Part 3

To investigate the effect of 
RO6953958 on the PK of 
the cytochrome P450 
(CYP) 3A substrate 
midazolam

PK concentrations and parameters 
of midazolam


RO6953958—F. Hoffmann-La Roche Ltd
61/Protocol BP41695, Version 7
Table 10 Objectives and Endpoints (cont.)
Objectives
Endpoints
Exploratory
Parts 1, 2, 
and 3

To screen for the presence 
of RO6953958 derived 
metabolites 

To assess the relative 
abundance and PK 
parameters of any 
metabolite as appropriate

PK concentrations of RO6953958
derived metabolites, if appropriate 

PK parameters of RO6953958
derived metabolites, if appropriate
Parts 1, 2, 
and 3

To investigate whether 
genetic variants (e.g., at
drug-metabolizing enzymes
transporters, receptors)
affect the PK, PD, and/or
safety of RO6953958

Clinical genotyping data
Part 1 and 2

Optional cardiodynamic
ECG assessment:
To evaluate the effect of 
RO6953958 on ECG 
parameters, including 
Concentration-QTc (C-QT) 
analysis

Change-from-baseline heart rate
(HR), PR, QRS and QTcF (HR, 
PR, QRS and QTcF)

Placebo-corrected HR, PR, 
QRS and QTcF(HR, PR, 
QRS and QTcF)

Categorical outliers for HR, QTcF, 
PR, and QRS

Frequency of treatment emergent 
changes of T-wave morphology 
and U-wave presence
Part 2

To investigate the effect of 
RO6953958 on sleep and 
circadian rhythm

PD parameters including sleep 
quality questionnaires (PROMIS 
Sleep Disturbance and 
Sleep-Related Impairment), 
sleepiness scale (KSS), melatonin
onset and offset, cortisol, 
polysomnography (PSG) and sleep 
mat-derived sleep parameters, 
nocturnal core body temperature, 
wake EEG and FERT


RO6953958—F. Hoffmann-La Roche Ltd
62/Protocol BP41695, Version 7
Table 10 Objectives and Endpoints (cont.)
Objectives
Endpoints
Exploratory
Part 2

To determine cerebrospinal 
fluid (CSF) concentrations 
of RO6953958 and its 
metabolites RO7021594 
and RO7045755 following 
multiple doses

CSF concentrations of RO6953958 
and its metabolites RO7021594 
and RO7045755
Part 3

To evaluate the 
endogenous biomarker 
4-hydroxycholesterol 
(4HC)/cholesterol ratio 
for the assessment of 
CYP3A activity following 
oral administration of 
RO6953958

Plasma concentrations and percent 
change from baseline of 4HC and 
total cholesterol, and the 
4βHC/cholesterol ratio
4.
STUDY DESIGN
4.1
OVERALL DESIGN
An overview of the study design is provided in Section 1.2.
The study is a three-part design:
Part 1 (SAD) of this study will examine safety and tolerability, and characterize PK and 
PD effect by evaluating the Karolinska sleepiness scale (KSS). Part 1 will also evaluate 
FE after RO6953958 administration at the dose(s) proposed for clinical use. 
In Part 2 (multiple-ascending dose [MAD]) the safety, tolerability, PK, and PD effects by 
evaluating cortisol, melatonin, and sleep parameters of multiple doses of RO6953958 
will be evaluated in fed conditions, based on preliminary PK data in Part 1. In addition, 
concentrations of RO6953958 and its metabolites will be measured in CSF. The doses 
in Part 2 will be determined based on review of the Part 1 data (see Section 4.1.5.2). 
Ascending doses are planned in order to establish the safety and tolerability at low dose 
levels before proceeding to higher dose levels. Dose levels may be adjusted (increased, 
decreased, or repeated), or intermediate doses may be used depending on the 
emerging safety and PK data at each dose level. 
In Part 3 (to be run after the highest dose in MAD QD dosing is completed) the safety, 
tolerability, and effect of RO6953958 on the PK of the CYP3A substrate midazolam will 
be assessed by evaluating PK parameters of midazolam. In addition, concentrations of 


RO6953958—F. Hoffmann-La Roche Ltd
63/Protocol BP41695, Version 7
4-hydroxycholesterol (4HC) and total cholesterol will be measured, and the 
4HC/cholesterol ratio will be calculated as an endogenous marker of CYP3A activity.
4.1.1
Part 1 (SAD/FE)
Part 1 will be a randomized, Investigator-/ subject-blind, placebo-controlled SAD study 
with a parallel design and sentinel dosing, to explore the safety, tolerability, PK, and PD 
of single doses of orally administered RO6953958 in the fasted state and using one 
cohort to administer RO6953958 in the fed state.
Participants will be recruited in seven sequential cohorts. In each cohort, participants will 
receive either a single oral dose of RO6953958 or placebo while fasted. Participants in 
the FE cohort (90 mg) will return to receive the same dose repeated in the fed state. 
Each participant in the selected cohort will receive a single dose of RO6953958 30 
minutes after starting a standardized high fat, high calorie breakfast. If participants are 
not willing to complete the fed part, additional participants will be recruited to ensure that 
a minimum number of participants complete food effect investigations (6 on active 
treatment and 2 on placebo in each period).
The starting dose of 5 mg is anticipated to be safe and have minimal pharmacological 
effects. Subsequent doses will be selected during study conduct based on emerging 
safety and PK data. In all cohorts, sentinel dosing will be employed to allow for an 
evaluation of safety data by the Investigator up to 23 hours after the start of treatment 
before subsequent participants are dosed (see Section 4.1.6.3). There will be at least 
1 week between each dose level in order to permit adequate time for collation and 
review of emerging data before the next dose is administered. A tentative dose 
escalation scheduled is provided in Table 11. After review of the PK exposures (Cmax
and area under the concentration–time curve from Time 0 to infinity [AUCinf]) in Cohort 1 
and in the case that the observed exposure of the first dose in humans is significantly 
below the predicted concentrations, the dose of Cohort 2 may be adjusted by a greater 
than 3.3-fold increase in order to reach the expected exposure level for the original 
starting dose (with the same maximum increase of 3.3-fold multiples thereafter for 
further dose-escalation steps).


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Table 11 Confirmed and Tentative Dose Escalation in the SAD (Part 1)
Cohort 1
5 mg (2*2.5 mg)
Cohort 2
15 mg (1*10 mg and 2*2.5 mg)
Cohort 3
45 mg (4*10 mg and 2*2.5 mg)
Cohort 4
90 mg (1*80 mg and 1*10 mg) and FE*
Cohort 5
180 mg (2*80 mg and 2*10 mg)
Cohort 6
360 mg (4*80 mg and 4*10 mg)
Cohort 7**
to be determined
FE = food effect; SAD = single-ascending dose.
* Cohort 4 will return to receive the same dose in the fed state.
** Cohort 7 may run pending emerging data review from the MAD. Timing of dosing of 
RO6953958 may be in the evening and dosing may be done under different food condition (fed 
vs fasted).
The dose for FE part of Part 1 is confirmed to be performed at the dose tested in 
Cohort 4 (90 mg dose). The fed part will not proceed until adequate safety coverage 
from a higher dose (Cohort 5) is confirmed.
4.1.2
Part 2 (MAD)
Part 2 will be a randomized, Investigator-/ subject-blind, placebo-controlled MAD study 
with the purpose of evaluating the safety, tolerability, PK, and PD of multiple doses of 
orally administered RO6953958. Participants from Part 1 cannot participate in Part 2.
The criteria to move from Part 1 to Part 2 of the study are detailed in Section 4.1.5.2.
Part 2 will explore the safety, tolerability, PK, and PD of multiple doses of RO6953958. 
The starting dose for Part 2 is 45 mg RO6953958 QD, established on the basis of safety 
and PK data in Part 1. The first dosing in Part 2 will only commence once safety is 
confirmed on the basis of dosing in Part 1 that allows at least 4 times’ coverage (e.g., 
start 40 mg MAD once safety confirmed at a dose of 160 mg or higher in SAD). A 
maximum of five dose levels are anticipated. For each dose level, a minimum of 8 and a 
maximum of 16 participants will receive either a multiple oral dose of RO6953958 or 
placebo QD for 10 days (active to placebo ratio 3:1). The treatment period may be 
extended to 14 days in subsequent cohorts depending on emerging data. In addition, a 
lumbar puncture for CSF sampling will be performed in all participants in each cohort on
Day 7 or alternatively Day 6 or 8. In a cohort CSF sampling will be done predose in 
4 participants and approx. 5 to 7 h after dosing of RO6953958 (around Tmax of the M3 
metabolite) in the other 4 participants for determination of RO6953958, M3 
(RO7021594) and M1 (RO7045755) concentrations in CSF. A corresponding blood 
sample will be taken at the same time point. As an alternative to CSF sampling on 
Day 7, it may also be performed on Day 6 or Day 8. The time points of CSF sampling in 
a participant may be adjusted with emerging PK or CSF samples from preceding 


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cohorts. In addition, these results might also lead to the conclusion to stop CSF 
sampling in subsequent cohorts.
The data requirements for dose escalations and stopping rules for each dose group are 
outlined in Sections 4.1.5.1, 4.1.5.3, and 4.1.6.4. The dose may be adjusted during the 
treatment period depending on the safety and/or PK observations. In addition, a different 
dosing regimen (Section 6.1) may be explored if warranted based on the safety and/or 
PK profile of RO6953958 (e.g., BID or exploration of titration). A dose escalation 
schedule is provided in Table 12. The starting dose in Part 2 Cohort 1 selected based on 
the safety and PK from Part 1 is 45 mg RO6953958 QD. Based on the outcome of 
Part 1, RO6953958 will be administered under fed conditions (a standard breakfast).
Subsequent doses in Part 2 will be based on emerging safety and PK data. Additionally, 
the timing of dosing may be changed for additional participants in a cohort at a specific 
dose level, in order to explore the effect of time of dosing on the pharmacokinetics. A 
decision to include additional participants dosed in the evening at a specific dose level 
would only be made following review of the safety and PK following morning 
administration at the chosen dose level. CSF sampling would not be done in participants 
who are administered the dose in the evening.
Table 12 Confirmed and Tentative Dose Escalation in the MAD (Part 2)
Cohort 1 
45 mg (4*10 mg and 2*2.5 mg) QD
Cohort 2 
140 mg (1*80 mg and 6*10 mg) QD
Cohort 3
210 mg (2*80 mg and 5*10 mg) QD
Cohort 4
to be determined
Cohort 5
to be determined
MAD = multiple-ascending dose; QD = once daily.
4.1.3
Part 3 (DDI)
Part 3 will be a single-center, non-randomized, open-label, five-treatment, fixed
sequence crossover study with the purpose of evaluating the safety and tolerability of 
RO6953958 alone and in combination with midazolam and to assess the effect of 
RO6953958 on the PK of the CYP3A substrate midazolam. In addition, the effect of 
RO6953958 treatment on an endogenous marker of CYP3A activity will be assessed.
RO6953958 will be administered QD following a standardized breakfast on Day 3 to 
Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD). 
Midazolam will be administered as single IV bolus injection of 100 g on Day 1 and
Day 13, and as single oral dose of 300 g on Day 2 and Day 14.


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4.1.4
Length of the Study
Part 1 (SAD/FE)
The total duration of the study for each participant in each cohort will be up to 7 weeks
(14 weeks if the participant is part of the FE cohort) divided as follows: 

Screening: Up to 4 weeks

In-clinic period: Days -2 to 5

Treatment period: Day 1
Washout period between each treatment (FE cohort only): Approximately 21 days. 
This might be adjusted/extended based on PK data from Part 1 or to await safety 
information from the subsequent dose level to provide adequate safety coverage for 
the fed part.

Safety follow-up: 7 to 14 days after the last dose
Part 2 (MAD)
The total duration of the study for each participant will be up to 8 weeks approximately 
divided as follows:

Screening: Up to 4 weeks

In-clinic period: 16 days (Days -22 to 14; 2 baseline days, 10 dosing days, 
6 follow-up days)

Treatment period: Days 1 to 10 (possibly to Day 14)

Safety follow-up: 7 to 14 days after last dose
Part 3 (DDI)
The total duration of the study for each participant will be up to 8 weeks approximately 
divided as follows:

Screening: Up to 4 weeks.

In-clinic period: 19 days (Days -1 to 18; 1 baseline day, 14 dosing days, 
4 follow-up days).

Five treatment periods: Days 1 to 14 (Days 1 and 2 midazolam, Days 3 through 14 
RO6953958, Days 13 and 14 midazolam).

Safety follow-up: 7 to 14 days after the final dose of RO6953958.
4.1.5
Dose-Escalation Decision Criteria
The dose-escalation decision will be made by the Roche Clinical Pharmacologist, the 
Principal Investigator, and appropriate personnel as required. The dose will not be 
escalated further if the tolerability, safety, or PK at the preceding dose level is not 
                                           
2 Participants may be admitted on Day-3 to ensure severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) testing can be reported prior to dosing.


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acceptable as judged by the Principal Investigator and the Clinical Pharmacologist. After 
review of the safety and PK data and discussion between the Roche Clinical 
Pharmacologist and the Principal Investigator, the same dose or regimen or a lower 
dose within the tolerated dose range may be given again in subsequent treatments to 
increase data within the tolerated dose range (see Section 4.1.7).
Dose escalation in Part 1 and Part 2 for all participants will be stopped if any of the 
changes detailed in Section 4.1.6.3 (Part 1 only) and/or Section 4.1.6.4 occur in 
participants receiving RO6953958. However, the same or a lower dose may be 
administered after the discussion between the Sponsor’s Clinical Pharmacologist and 
the Investigator. Additionally, dosing will be stopped if any of the stopping rules in
Section 4.1.6.1 applies during the conduct of the study and Section 4.1.6.2 applies to an 
individual participant during the study.
Participants who prematurely discontinued from the study may be replaced (see
Section 7.2) to ensure adequate numbers (at least 6 participants; 4 on RO6953958) of 
evaluable participants (for the definition of evaluable participant, see Section 9.3) for 
each dose-escalation step.
Dose escalation is dependent on the safety and PK data at each dose level. Dose-level 
increments will be no more than 3.3-fold and may be adjusted downwards, or doses may 
be repeated if safety or PK concerns emerge from ongoing results. In the case that the 
observed exposure (Cmax and AUCinf) at the first SAD dose level (Cohort 1) is 
significantly below the predicted human exposure, a dose increment higher than 3.3-fold 
may be given subsequently at the second dose level (Cohort 2) to achieve the predicted 
exposure for the starting dose (with the same dose-escalation multiples thereafter).
Due to the exploratory nature of this clinical study, its conduct can be discontinued 
before the last foreseen dose level has been investigated. This will not constitute a 
premature termination of the study.
4.1.5.1
Data Requirements for Dose-Escalation Decision for Sentinel 
Group and Dose Groups in Part 1
In Part 1 for each sentinel group, if the safety and tolerability results of the first 23 hours 
following dosing for the initial 2 participants (sentinel group) are acceptable in the 
judgment of the Investigator and Sponsor (see Section 4.1.7), the remaining
6 participants within the cohort will be dosed at least 24 hours after the sentinel group. 
After a satisfactory review of the safety, tolerability (i.e., at minimum AEs, ECG, vital 
signs), and PK data, progression to the next dose level will occur if the last dose and 
regimen is well tolerated. There will be at least 7 days between dosing in each cohort in 
order to permit adequate time for collation and review of emerging data before the next 
dose is administered.


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As a minimum, the following data will be required from at least 6 participants (4 on 
RO6953958) of the previous dose level for dose escalation in Part 1 (SAD/FE):

PK data over 24 hours postdose (plasma only)

Safety data from dosing to 48 hours postdose
4.1.5.2
Decision Criteria to Progress from Part 1 to Part 2
Progression to Part 2 will be based on satisfactory review of the safety and PK data by 
the Investigator and Sponsor from Part 1 (SAD) data. The starting dose for Part 2 (MAD)
will be determined by analysis of safety and tolerability data and using PK data from the 
SAD part of the study. The starting dose in Part 2 will be chosen so as to produce 
exposures at steady-state close to those predicted to target an average V1a receptor 
occupancy of approximately 90% over 24 hours.
The first dosing in Part 2 will commence once safety is confirmed on the basis of dosing 
in Part 1 that allows at least 4 times’ coverage (i.e., start 40 mg MAD once safety has 
been confirmed in 160 mg SAD).
4.1.5.3
Data Requirements for Dose-Escalation Decision Criteria for 
Part 2
Doses in Part 2 (MAD) will be selected based on satisfactory review of the safety and PK
data by the Investigator and Sponsor from Part 1 (SAD) data and emerging data from 
subsequent cohorts in Part 2. Dose escalation for each cohort in Part 2 will be based on 
data collected in at least 6 participants (4 on RO6953958) and from previous dose 
levels. If a dose de-escalation is planned at later cohorts (e.g., cohort 4), dosing would 
proceed based on initial safety of ongoing cohorts up to Day 10 (at least 3 on 
RO6953958) and safety and PK data from a preceding cohort that ensured at least 
3-fold coverage.
As a minimum, the following data will be required from at least 6 participants of the 
previous dose level for dose escalation in Part 2 (MAD):

PK data over 24 hours post-last dose (plasma only)

Safety data from first dosing to 24 hours post-last dose
4.1.5.4
Decision to Expand Cohorts in Part 2 Based on Review of 
Sleep Biomarkers
Following review of Part 2 and establishing a recommended dose range that supports 
characterization of the PK/PD relationship of the sleep biomarkers, additional 
participants may be enrolled in order to increase the number of participants within Part 2
or explore alternative doses (on doses that do not exceed the maximum exposures 
observed in Part 1 [SAD]). Up to a maximum of 8 additional participants will be included 
per cohort to bring the maximum per cohort to 16 participants (active to placebo ratio 
3:1) in order to better characterize the relationship (as described above). The selected 


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doses will be chosen in a dose range that optimally informs PK/PD modelling of sleep 
biomarkers in the Part 2.
4.1.6
Stopping Rules
4.1.6.1
Stopping Rules for the Study
The trial will be stopped if the following criteria are met:

A serious adverse reaction (i.e., a serious adverse event considered as, at least,
possibly related to the investigational medicinal product (IMP) administration) in one 
participant or

Severe adverse reactions (i.e., severe non-serious adverse events considered as, at 
least, possibly related to the IMP administration) in two participants in the same 
cohort.
Following an internal safety review, if it is appropriate to restart the trial, a substantial 
amendment will be submitted to the Medicines and Healthcare products Regulatory 
Agency (MHRA) and Research Ethics Committee (REC). The trial will not restart until 
the amendment has been approved by the MHRA and REC.
4.1.6.2
Stopping Rules for Individuals
Dosing will be stopped at any time during the study in a given participant receiving
RO6953958 if one of the following circumstances occurs:

SAE considered related to study treatment.

Alanine aminotransferase (ALT)5upper limit of normal (ULN).

ALT3ULN and total bilirubin2ULN or international normalized ratio (INR)1.5 
(if a participant meets this withdrawal criterion, serum bilirubin fractionation should 
be performed).

ALT3ULN if associated with the appearance or worsening of rash or hepatitis 
symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness,
fever, rash or eosinophilia). Participants who have ALT3ULN and5ULN, total 
bilirubin2ULN or INR1.5, and who do not exhibit hepatitis symptoms or rash 
can continue in the study (and continue receiving trial medication) as long as they 
can be monitored at least weekly until abnormal results are within the reference 
range or close to pretreatment values.
If any of the above stopping rules are met, see Section 8.3.3 for the follow-up of AEs and 
SAEs.
If a dose administration is suspended to allow for additional safety assessments, but no 
safety concerns are raised to prevent continued dosing in the judgment of the 
Investigator, dosing may resume at the next planned dosing date. A missed dose will not 
be made up (applicable to Part 2 [MAD] only).


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4.1.6.3
Stopping Rules after Dosing of the Sentinel Group in Part 1 (all 
Dose Levels)
At all dose levels in Part 1, in order to avoid simultaneous exposure of all the 
participants, only 2 participants (sentinel group; composed of 1 participant on active
treatment and 1 on placebo) will be dosed first prior to dosing further participants at the 
same dose level. If the safety and tolerability data (AEs, ECG, vital signs, and clinical 
laboratory test results) of the first 23 hours following dosing for the initial 2 participants 
are acceptable in the judgment of the Investigator, 6 additional participants (5 on active 
treatment and 1 on placebo) will be dosed at the same dose level at least 24 hours after 
the sentinel group. Dosing will be stopped after the sentinel group if one of the following 
circumstances occurs in the participant receiving RO6953958, unless it is determined by 
the Investigator that the occurrence is not related to the administration of the study drug:

One SAE

Any other findings that, at the joint discretion of the Sponsor’s Clinical 
Pharmacologist, the Medical and Safety monitor and the Investigator, indicate that 
the dosing should be stopped
4.1.6.4
Dose-Escalation and Study Cohort Stopping Rules in Part 1 
and Part 2
Dose-escalation will be stopped and treatment within an ongoing cohort will be stopped 
in Part 1 and/or Part 2, if one of the following circumstances occurs in participants 
receiving RO6953958 within the same dose level, unless it is determined by the 
Investigator that the occurrence is not related to the administration of the study drug:

SAE considered to be related to study drug in 1 participant receiving RO6953958

Severe non-serious AEs considered to be related to study drug in 2 or more 
participants receiving RO6953958 in the same cohort

Clinical significant RO6953958-related laboratory abnormalities of the same type in 
2 or more participants

Clinical significant RO6953958-related changes in vital signs or ECGs of the same 
type in 2 or more participants

If maximum individual exposure is anticipated to exceed the predicted Cmax
(approximately 3500 ng/mL) and AUC (35,000 ng·h/mL) at the next planned dose 
level based on PK from previous dose cohorts or MFD level of 800 mg QD is 
achieved

Any other findings that, at the joint discretion of the Sponsor’s study team and the 
Investigator, indicate that the dosing should be stopped
4.1.7
Communication Strategy for Preceding from the Sentinel
Group and each Dose Groups in Parts 1 and 2
In Parts 1 and 2, there will be ongoing reviews of available data (based on datum
requirements outlined in Section 4.1.5) prior to initiation of the next dose. For the 


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sentinel cohort, the Sponsor must confirm via email to Investigator that the Sponsor 
agrees to proceed with dosing the subsequent 6 participants based on Investigator’s 
safety review and interpretation and ensuring none of the stopping rules as outlined in 
Sections 4.1.6.1, 4.1.6.2, or 4.1.6.3 have been met.
For each cohort (at least 6 participants; 4 on RO6953958), a dose-escalation meeting 
will be conducted between the Sponsor study team and the Investigator prior to dosing 
of the next cohort. In addition to review of the safety and PK data, in order to proceed,
none of the stopping rules as outlined in Sections 4.1.6.1, 4.1.6.2, and 4.1.6.4 are 
allowed to have been met.
In Parts 1 and 2, after each participant receives RO6953958 or placebo and following 
completion of dosing (Day 1 [Part 1 only] and Day 10), the Investigator must confirm to 
the Sponsor that all participants have been dosed and provide a brief summary of the 
status of the participant in terms of safety and tolerability to RO6953958. Additional 
details for communication strategy and dose-escalation procedure are found in the 
separate Medical Data Review Plan.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
In order to ensure maximum safety, the effects of each dose level will be reviewed 
carefully before escalating to the next dose level. Dose escalation will take place after 
the review of safety, tolerability, and PK as described in Section 4.1.5. Dose-escalation 
stopping rules are detailed in Sections 4.1.6.2, 4.1.6.3, and 4.1.6.4.
4.2.1
Rationale for Number of Dosing Days and Regimen in Part 2
The treatment period in Part 2 (MAD) will be 10 days in duration, anticipated to be 
sufficient to reach steady-state PK conditions and support the first planned patient trials. 
A once-daily (QD) dosing regimen has been chosen for Part 2 on the basis of the
predicted PK properties of RO6953958 to provide exposures for the efficacious dose 
anticipated to target an average V1a receptor occupancy of90% over a 24-hour period. 
The treatment period may be extended to 14 days to better characterize the safety 
profile of RO6953958 over a longer period after achievement of the steady-state, if 
warranted. The timing of dosing may be changed for additional participants in a cohort at 
a specific dose level, in order to explore the effect of time of dosing on the 
pharmacokinetics (evening vs morning).
4.2.2
Rationale for Study Population
Prior to initiating studies in individuals diagnosed with NDDs and sleep disorders, it is 
considered important to assess RO6953958 in this entry-into-human study in healthy, 
adult, neurotypical participants. Females have been excluded as nonclinical 
teratogenicity studies have not been conducted to date. Since individuals with NDDs are 
a particularly vulnerable population, it is prudent to assess safety and tolerability, PK and 
PD effects, and food effect of this novel compound first in neurotypical adult participants 


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prior to any dosing in the NDD population. This population are further unlikely to require 
concomitant medication, which could interfere with the study drug or its PD effects. The 
absence of confounding disease factors will lead to a clearer and more consistent 
assessment of drug disposition and biological activity.
4.2.3
Rationale for Control Group
This study is designed to be adequate and well controlled. Participants will be 
randomized to RO6953958- or placebo-treatment groups. 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-/subject-blind to eliminate potential bias.
4.2.4
Rationale for Orthostatic Challenge
Whilst there is no indication for relevant blood pressure changes from nonclinical 
profiling because normal vasopressin levels are too low to activate V1a receptors in the 
periphery, orthostatic challenge testing is included to document absence of orthostatic 
dysregulation when participants are dosed with RO6953958.
4.2.5
Rationale for PD/Biomarker Assessments
The PD/biomarker assessments will be timed to coincide with the anticipated time of 
maximum pharmacological effect of RO6953958 at single dose and steady-state. The 
timing of PD assessments is based on experience from the nonclinical pharmacology 
studies, model-based predictions of RO6953958 plasma concentrations, and anticipated 
effects of RO6953958. The number and timing of the samples are considered adequate 
to allow characterization of key elements of the response versus time profile.
Exploratory PD assessments will include cortisol, melatonin, Patient-Reported Outcomes 
Measurement Information System (PROMIS) Sleep Disturbance and Sleep-Related 
Impairment questionnaires, KSS, polysomnography (PSG), sleep mat, Facial Emotion 
Recognition Task (FERT), core body temperature, wake EEGs and platelet aggregation 
assay (PAA). These exploratory assessments are included on the basis of the 
theoretical relationship of the vasopressin system to circadian rhythmicity and 
corresponding effects on sleep and sleepiness or related functions.
4.2.6
Rationale for CSF sampling
Cerebrospinal fluid sampling is planned to be performed in each cohort of Part 2. In 
order to confirm that RO6953958 and its metabolite M3 (RO7021594), which is a potent 
antagonist on the V1a receptor, enter the CSF/brain, CSF sampling and determination of
RO6953958, M3 (RO7021594) and M1 (RO7045755) concentrations in CSF is included 
in the study.


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4.2.7
Rationale for Drug-Drug Interaction Study Design and the 
Use of Midazolam
An important aspect of drug development is to predict clinically relevant DDI. In vitro 
data have demonstrated that RO6953958 is metabolized by CYP3A and may be an 
inhibitor (time-dependent and direct) and/or an inducer of CYP3A. The DDI part 
(Part 3) of this study will assess the effect of RO6953958 on the PK of a sensitive 
CYP3A substrate (midazolam) as measured by midazolam systemic exposure. The 
potential induction/inhibitory potential of multiple oral doses of RO6953958 on 
CYP3A will be assessed, using both oral and IV microdose of midazolam. The extent of 
change in exposure (if any) of the CYP3A substrate midazolam will be assessed when 
dosed both in absence and in the presence of steady-state exposures of RO6953958. 
Dosing with food significantly increases RO6953958 bioavailability and, therefore,
RO6953958 dosing will be with food to maximize drug exposure. Administration of 
RO6953958 and midazolam will be staggered for midazolam dosing to coincide with 
anticipated peak concentrations of RO6953958 in gut wall enterocytes and liver 
hepatocytes. On Day 13, RO6953958 dosing will be 2 hours prior to midazolam dosing,
and on Day 14, 1.5 hours prior to midazolam dosing. In addition, plasma 
concentrations of 4HC and total cholesterol will be measured according to the SoA 
(Section 1.3). 4HC is a metabolite formed by CYP3A4 and CYP3A5-catalyzed 
metabolism of cholesterol and rises with increasing CYP3A activity. Recent studies 
have shown that 4HC and the 4HC/total cholesterol ratio is a convenient biomarker 
for preliminary assessment of CYP3A induction of drugs in the liver
(Björkhem-Bergman et al 2013; Kasichayanula et al 2015). 
The DDI part (Part 3) of the study will allow for an initial assessment of the effect of 
RO6953958 as a perpetrator on midazolam. Furthermore, this assessment may help 
design future clinical trials with treatment combinations that may have potential 
CYP3A interaction and inform concomitant drug inclusion and exclusion criteria with 
respect to CYP3A substrates. Midazolam is a short-acting benzodiazepine. It is selected 
because it is exclusively metabolized by CYP3A, is not a substrate of P-glycoprotein,
and has been validated in a number of studies. It is recommended as a sensitive model 
substrate for CYP3A by regulatory agencies (e.g., the FDA and EMA) and is the most 
widely used CYP3A probe substrate in the literature (Hohmann et al 2014). Midazolam 
hydrochloride, given orally, is subject to extensive first-pass metabolism by CYP3A 
located in the intestine and the liver (Thummel et al 1996; Gorski et al 1998). 
Therefore, the induction or inhibition of CYP3A in the small intestine and/or liver will 
affect the oral bioavailability of midazolam. The 100 g IV dose and 300 g oral dose 
have been selected to adequately characterize the pharmacokinetics of midazolam and 
distinguish between CYP3A4 inhibition in the small intestine vs. the liver. 
Midazolam was selected as a probe for CYP3A activity in this study also on the basis of 
its safety profile, rapid elimination half-life, simple metabolic scheme, and availability 
of a validated bioanalytical assay. Midazolam may transiently cause sedation 


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(including respiratory depression) and short-term memory loss, however with the use of 
a microdose, concentrations within the body will be far below the pharmacologically 
active levels of midazolam; thus no adverse events are anticipated (Hohmann et al 2014;
midazolam Summary of product Characteristics [SmPC]). Nevertheless, participants 
will be monitored for safety and tolerability in the clinic after receiving midazolam.
4.2.8
Rationale for Measuring 4-Hydroxycholesterol/Cholesterol 
Ratio
In Part 3 of the study, the 4HC/cholesterol ratio in plasma will be measured as an 
endogenous marker for hepatic CYP3A4 inhibition. 4HC is a metabolite formed by 
CYP3A4 and CYP3A5-catalyzed metabolism of cholesterol (Björkhem-Bergman et al 
2013). The ratio of metabolite to parent will be calculated to adjust for between-subject 
differences in cholesterol levels. This ratio has been used to assess CYP3A4 activity in 
humans and has been shown to have concordance with the midazolam method. Unlike 
midazolam, which is extensively metabolized by the intestinal and liver CYP3A4, the 
metabolism of cholesterol in the intestine is not expected to be significant. Hence, the 
magnitude of the induction determined by oral midazolam can be greater than by 
4HC/cholesterol as it mostly reflects liver CYP3A4 only. Correlation between 
midazolam clearance and endogenous substances ratios will be explored in this study. If 
CYP3A4 activity needs be monitored for future RO6953958 clinical studies, the 
4HC/cholesterol ratio, instead of midazolam, can be conveniently employed in such 
studies.
4.3
JUSTIFICATION FOR DOSE
4.3.1
Starting Dose
In Part 1, the starting dose will be a single dose of 5 mg. Further dose levels will be 
dependent on the safety and PK data of the preceding dose levels.
A starting dose of 5 mg RO6953958 has been selected for this first study in humans. 
The starting dose is predicted to be below the anticipated therapeutic dose of 80 mg QD 
in humans, whilst maintaining relevant safety margins of approximately 128-fold the 
average exposure at the NOAEL in cynomolgus monkeys (900-fold based on unbound 
exposure). The NOAEL in cynomolgus monkeys was the highest feasible dose tested 
with no safety findings identified (Table 13). Furthermore, based on the NOAEL in rats, 
the 5-mg starting dose represents a margin of approximately 650-fold (1,400 unbound 
in males) to2,500-fold (6,000-fold based on unbound in females; Table 13).
Two approaches were taken into consideration for the selection of starting dose of 5 mg 
single dose administration of RO6953958. One approach uses the U.S. Food and Drug 
Administration’s Guidance estimating the maximum recommended starting-dose (U.S. 
FDA 2005). The NOAEL of cynomolgus monkey is converted to the human equivalent 
dose (HED) by using an appropriate scaling factor, followed by an application of a safety 
factor of 10. The NOAEL in the 13-week study in rats is 250 mg/kg in females. This 


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equates to an HED of 40 mg/kg, which corresponds to a flat dose of 2,400 mg/day in a 
60-kg participant. After applying a safety factor of 10, a dose of 240 mg/day is derived. A 
dose of 240 mg would be within the anticipated therapeutic dose range (10 mg to 
160 mg BID) but is considered too high for a starting dose.
Therefore, an alternative approach is a starting dose offering the possibility to assess 
safety of dose levels that are below the anticipated therapeutic PAD range in humans 
based on PK/PD (EMA 2017). The current hypothesis is that V1a receptor occupancy 
of 90% over the dosing interval (at Ctrough) may provide therapeutic benefit in the human 
ASD population. Therefore, a dose providing 20% of this range (i.e., V1a receptor 
occupancy at Ctrough) is considered to have no pharmacological effect. Considering the 
range of projected human clearance (1 to 8 ml/hr/kg) of RO6953958, a single dose of 
5 mg was selected. This dose is expected to translate into an average receptor 
occupancy of 20% at Ctrough and 89% at Cmax. This dose is not expected to lead to a PD
effect after a single dose based on the clinical data with balovaptan, a similar V1a 
antagonist currently in development (see Section 2.2.2.1), receptor occupancy of 88% at 
Cmax (77% at Ctrough) showed no or minimal signs of efficacy under repeated dosing 
conditions but required receptor occupancies90% over 24 hours.
Table 13 Estimated Margins of Safety for Entry-Into-Human Starting and 
Therapeutic Dose
Species
NOAEL (mg/kg/day)
Cmax / AUC0–24*
(ng/mL / ngh/mL)
Exposure Margins to 
Cynomolgus Monkey 
(total [free])
Rat 13-week NOAEL: 
500 mg/kg/day (M) and 
250 mg/kg/day (F)
18,900 / 217,000 (M)
52,100 / 930,000 (F)
Cynomolgus monkey 13-week
NOAEL: 600 mg/kg/day
4,140 / 42,600
Human 5 mg anticipated starting 
dose
56 / 334
74 (565) / 128 (975)
80 mg therapeutic dose
583 / 5,286
7 (54) / 8 (62)
Abbreviations: AUC0–24=area under the concentration-time curve from 0 to 24 hours;
Cmax=maximum plasma concentration; F=female, M=male; NOAEL=no-observed-adverse-
effect level.
* Refers to AUCtau and AUCinf for animals and human, respectively.
** Free fraction in humans 1.7%, rat 3.8%, and cynomolgus monkey 13%.
4.3.2
Part 3 Dose Justification 
In Part 3 (DDI), the maximum dose QD that was tested in the ongoing Part 2 (MAD) 
which allows exploration of the highest exposures of RO6953958 will be given QD from
Day 3 through Day 14 to maximize potential effect on CYP3A. The treatment duration 
of RO6953958 alone (12 days) has been selected based on data from Part 2, which 
indicate that steady-state plasma concentrations are achieved within 10 days in all 


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individuals (see Section 2.2.2.2). Exposure to RO6953958 is not expected to be 
impacted by co-administration with midazolam. The dose level will not exceed the 
exposure limits described in Section 4.3.3. 
Part 3 will not begin before review of sufficient safety and PK data of the highest safe 
dose QD dose escalation data at a minimum (see Section 4.1.5.3).The available data on 
the kinetics of enzyme inhibition/induction by RO6953958 (Report 1098857) and the 
turnover by CYP3A enzymes suggest that maximal inhibition/induction of CYP3A 
activity should be achieved soon after achievement of steady state (Xu et al 2011).
The midazolam microdoses (i.e., single IV dose of 100 g and single oral dose of 
300 g) have been selected based on published information from previous clinical 
studies and from scientific literature involving microdoses of midazolam administered 
to healthy participants. The recommended oral dose of midazolam for preoperative 
sedation, anxiolysis, and amnesia in pediatric patients is 0.25 to 0.5 mg/kg with a 
maximum dose of 20 mg. The single doses of midazolam selected in Part 3 of this study 
are far below the pharmacological active concentrations of midazolam but are still high 
enough to allow characterization of midazolam pharmacokinetics (Hohmann et al 2014). 
Local inflammation and pain at the injection site is considered unlikely because 
intravenous injection of midazolam is usually well tolerated and a very low dose is used 
in this study.
4.3.3
Maximum Exposure/Dose
An estimated efficacious dose of RO6953958 has been projected assuming that target 
inhibition profiles need to match those estimated for balovaptan, a similar V1a antagonist 
currently in development. Based on in vitro binding data and stimulated plasma-free 
concentration at steady-state, there is confidence that the desired target inhibition profile 
can be achieved. A likely scenario projects a daily dose of 80 mg to match the inhibition 
profile for 10 mg balovaptan. Assuming a high clearance, a dose of 160 mg BID would 
be needed, with the low clearance scenario the dose would be only 10 mg/day. Given 
that RO6953958 is mainly metabolized by CYP3A, current predictions using a static 
model and assuming both gut and liver inhibition estimate a 7- to 10-fold increase in 
exposure could not be excluded with a strong CYP3A inhibitor. Therefore, maximum
individual exposure parameters have been selected to allow exploration of exposures in 
Part 1 to cover a drug–drug-interaction scenario in combination with a strong CYP3A 
inhibitor. In Part 1, maximum individual exposures would not exceed a Cmax of 
approximately 3500 ng/mL and/or AUC0-24 35,000 ngh/mL or a MFD of 10 dose units of 
80 mg (800 mg) QD. The maximum dose in Part 2 (MAD) will not exceed total exposures 
observed in Part 1 (SAD) or maximum dose tested in Part 1 (SAD). 


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4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if the participant has completed 
all phases of the study including the last scheduled procedure shown in the Schedule of 
Activities (see Section 1.3).
The end of the study is defined as the date when the last participant, last observation 
(LPLO) occurs. LPLO is expected to occur approximately 2 weeks after the last 
participant last dose in Part 3.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.2.
The participants in this study will be healthy male volunteers between 18 to 55 years of 
age, inclusive, who fulfill all of the given inclusion criteria.
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to International Council on Harmonisation (ICH) and local 
regulations.
Age
2.
Participants must be 18 to 55 years of age, inclusive, at the time of signing the 
informed consent form (ICF).
Type of Participants and Disease Characteristics
3.
Healthy, as judged by the Investigator. Healthy status will be defined as the absence 
of evidence of any active or chronic disease following a detailed medical and 
surgical history, a complete physical examination, vital signs, 12-lead ECG, 
hematology, blood chemistry, serology, and urinalysis.
Weight
4.
Body mass index (BMI) within the range 18 to 31 kg/m2 (inclusive).


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Sleep (Part 2 MAD only)
Habitual sleep pattern
5.
Participants must be prepared to collect a sleep log and wear an actigraphy device 
the week before participation in the study. Participants must also have scored 5 or 
less on the Pittsburgh Sleep Quality Index (PSQI), less than 13 on the Epworth 
sleepiness scale (ESS), and not be considered an extreme morning or evening type 
according to the morningness–eveningness questionnaire (MEQ) at screening to be 
eligible.
Sex
6.
Male participants
The contraception and abstinence requirements are intended to prevent exposure of 
an embryo to the study treatment. The reliability of sexual abstinence for male 
enrollment eligibility needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the participant. Periodic abstinence 
and withdrawal are not acceptable methods of contraception.
During the treatment period and for at least 14 days after the last dose of study drug, 
agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use a condom with a 
female partner of childbearing potential (WOCBP, as defined in Section 1 of 
Appendix 5), or pregnant female partner, to avoid exposing the embryo.

Refrain from donating sperm for at least 14 days after last dose. 
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Any condition or disease detected during the medical interview/physical examination 
that would render the participant unsuitable for the study, place the participant at 
undue risk, or interfere with the ability of the participant to complete the study, as 
determined by the Investigator.
2.
History or evidence of any medical condition potentially altering the absorption, 
metabolism, or elimination of drugs. This includes a surgical history of the 
gastrointestinal tract affecting gastric motility or altering the gastrointestinal tract.
3.
History of any clinically significant gastrointestinal, renal, hepatic, 
bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological, 
hematological, or allergic disease, sleep disorders (Part 2 [MAD] only), unexplained 
syncope (within 12 months prior to screening), metabolic disorder, cancer, or 
cirrhosis.


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4.
Use of any psychoactive medication, or medications known to have effects on CNS,
or blood flow taken within 4 weeks prior to the first dosing (or within 5 times the 
elimination half-life of the medication) prior to the first dosing (whichever is longer).
5.
History of convulsions (other than benign febrile convulsions of childhood), including 
epilepsy, or personal history of significant cerebral trauma or CNS infections (e.g., 
meningitis).
6.
History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic 
reactions.
7.
Any major illness within 1 month before the screening examination or any febrile 
illness within 1 week prior to screening and up to the first study drug administration.
8.
Abnormal BP, defined as confirmed (based on the average of 3 consecutive 
measurements) systolic BP (SBP) greater than 140 or less than 90 mmHg, and 
diastolic BP (DBP) greater than 90 or less than 50 mmHg.
9.
Presence of orthostatic hypotension at screening. Orthostatic hypotension is defined 
as decrease by 20 mmHg in SBP and/or 10 mmHg in DBP after erection from a 
supine position and/or clinical presyncopal/syncopal AE during test.
10. Abnormal pulse rate, defined as confirmed (based on the average 
of 3 consecutive measurements) resting pulse rate greater than 100 or less than 
40 bpm.
11. History or presence of clinically significant ECG abnormalities before study 
treatment administration (e.g., PQ/PR interval 220 ms, QT interval corrected using 
Fridericia’s formula [QTcF] 450 ms) or cardiovascular disease (e.g., cardiac 
insufficiency, coronary artery disease, cardiomyopathy, congestive heart failure, 
family history of congenital long QT syndrome, family history of sudden death).
12. Clinically significant abnormalities in laboratory test results (including hepatic and 
renal panels, complete blood count, chemistry panel, and urinalysis). In the case of 
uncertain or questionable results, tests performed during screening may be 
repeated before randomization to confirm eligibility.
13. ALT and/or bilirubin 1.5 ULN (isolated bilirubin 1.5 ULN is acceptable if 
bilirubin is fractionated and direct bilirubin 35%).
14. Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
15. Participants who, in the Investigator's judgment, pose a suicidal or homicidal risk, or 
any participant with a history of suicidal or homicidal attempts.
16. Known active or any major episode of infection within 4 weeks prior to the start of 
drug administration.
17. Participants who test positive for acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) on admission to the study site should not be enrolled. 


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Prior/Concomitant Therapy
18. Have used or intend to use over-the-counter (OTC) or prescription medication 
including herbal medications within 30 days prior to dosing.
19. Participants likely to need concomitant medication during the study period (including 
for dental conditions).
20. Part 3 (DDI) only – History of hypersensitivity to benzodiazepines (including 
midazolam) or its formulation ingredients.
Prior/Concurrent Clinical Study Experience
21. Participation in an investigational drug or device study within 3 months before 
admission to this study or more than 4 times a year.
Diagnostic Assessments
22. Positive test for drugs of abuse or alcohol.
23. Positive test for human immunodeficiency virus (HIV) antibody at screening.
24. Positive result on hepatitis B or hepatitis C virus (HCV), presence of hepatitis B 
surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or 
within 3 months prior to starting study treatment.
Other Exclusions
25. Dietary restrictions that would prohibit the consumption of standardized meals.
26. Inability or unwillingness to fully consume standardized breakfast at Day 1 (for 
Part 1, FE cohort).
27. Consumption of any prohibited medications and food/beverages before study start 
and during the study.
28. Any suspicion or history of alcohol abuse and/or suspicion of regular consumption of 
drug of abuse or previous history of or treatment for a dependence disorder.
29. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates the participation in the 
study.
30. Participants who are smokers for at least 90 days prior to screening.
31. Part 2 (MAD) only – Participants who have issues sleeping or who have travelled 
across 2 or more time zones in the month prior to screening.
32. Part 2 (MAD) only – Participants who cannot produce sufficient saliva for study 
assessments.
33. Participants who have donated more than 500 mL of blood or blood products or had 
significant blood loss within 3 months prior to screening.
34. Participants under judicial supervision, guardianship, or curatorship.


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For participants with planned lumbar punctures, the following additional 
exclusion criteria apply:
35. Have a history of clinically significant back pain, back pathology, and/or back injury 
(e.g. degenerative disease, spinal deformity, or spinal surgery) that may predispose 
to complications from, or technical difficulty with, lumbar puncture
36. Have criteria that would preclude a lumbar puncture, such as local infection at the 
site of the lumbar puncture, clinically significant coagulation parameter 
abnormalities, or treatment with an anticoagulant or with antiplatelet agents within 
6 weeks prior to the day of lumbar puncture
37. Have a clinically significant hypersensitivity to local anesthetics that may be used for 
lumbar puncture (e.g., lidocaine).
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
In all parts of the study, participants will have to be fasted for at least 4 hours prior to 
laboratory safety tests at screening.
On Day 1 of each dose in Part 1, study treatment administration will be performed after 
an overnight fast of at least 10 hours. Water will be allowed ad libitum until 1 hour prior 
to dosing and from 1 hour postdosing. A standard lunch will be provided 4 hours after 
dosing. 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.
In Part 1, for study drug administration under fed conditions, participants will be given 
the RO6953958 dose 30 minutes after starting a standardized high fat, high calorie 
breakfast. This breakfast should be consumed within 30 minutes or less. In Part 2,
based on review of Part 1 data, study drug administration will be under fed conditions,
i.e., participants will be given the RO6953958 dose 30 minutes after starting a 
standardized breakfast. The same food conditions (in term of meal constitution and time 
of administration) will apply on Day -1, Day 1, and Day 10 (as appropriate). In each part 
of the study, participants will be served standardized meals.
Meals will be similar in composition and time of administration across all cohorts. 
Consumption of nutrients known to modulate CYP3A activity (e.g., grapefruit or 
grapefruit juice, Seville orange) will not be permitted within 2 weeks prior to first dosing 
until discharge from the clinical unit.
Participants should not consume any foods containing poppy seeds within 48 hours 
(2 days) prior to each admission to the clinical research center as this could cause a 
false positive drug screen result.


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5.3.2
Caffeine, Alcohol, and Tobacco
The consumption of caffeine-containing food and beverages or other 
methylxanthine-containing products (e.g., tea, coffee, caffeinated soft drinks, cola, 
chocolate) will not be permitted from 48 hours before dosing until the end of the 
residential period. During the period from Screening to the follow-up visit when 
participants are not resident in the unit, they will be asked to limit coffee or tea 
consumption to no more than 3 cups per day and to limit methylxanthine-containing 
products (e.g., cola and chocolate) to a maximum of 1 L per day (cola) and 60 g per day 
(chocolate).
Consumption of alcohol will not be allowed from 48 hours before dosing until the end of 
the residential period, and participants will be asked to limit alcohol to a maximum of 
2 units per day (1 unit equates to approximately 330 mL beer, 125 mL of wine, or 25 mL 
of spirits) during the out-clinic phase until follow-up.
Smokers will be excluded as nicotine withdrawal can affect circadian rhythm and impact 
the sleep wakefulness cycle.
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. After the participants leave the unit, they 
will be asked to refrain from strenuous physical activity until the end of their participation 
in the study.
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. 
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 rescreened unless there is an agreement with the Sponsor. A repeat of a 
screening laboratory test because of a borderline result is not considered a rescreening.
5.5
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment using prescreening enrollment 
logs, clinical database, and Independent Ethics Committee (IEC)/ Institutional Review
Board (IRB)-approved newspaper/radio/social-media advertisements prior to consenting 
to take part in this study 


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6.
TREATMENTS
Study intervention is defined as any investigational product (including placebo) or 
marketed product intended to be administered to a study participant according to the 
study protocol.
The IMPs for this study are RO6953958 capsules of 2.5 mg, 10 mg, and 80 mg; and 
matching placebo.
All IMPs required for completion of this study (RO6953958 and matching placebo) will be 
provided by the Sponsor. All study drug administration will be at the study center under 
supervision of site staff.
The non-investigational product (NIMP) for this study is midazolam. Midazolam will 
be supplied by the clinical site. For information on the formulation, packaging, and 
handling of midazolam, see the clinical site drug-dispensing form and the local 
prescribing information for midazolam. Further information on dosing of midazolam 
may be provided in a separate pharmacy manual.
Cases of RO6953958 accidental overdose or medication error, along with any 
associated AEs, should be reported as described in Appendix 2, Section 5.2.
6.1
TREATMENTS ADMINISTERED
Table 14 summarizes the treatments administered. Guidelines for dosage modification 
and discontinuation are provided in Section 6.6 and Section 7, respectively.


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Table 14 Summary of Treatments Administered
Study Treatment Name:
RO6953958
Placebo (Part 1 and Part 2 only)
Midazolam (Part 3 only)
IMP and NIMP
IMP
NIMP
Dose Formulation:
Capsule
Solution
Unit Dose 
Strength(s)/Dosage 
Level(s):
2.5 mg, 10 mg, and 80 mg
NA
1 mg/mL solution (oral)
1 mg/mL or 2 mg/mL (IV)
Dose:
Part 1 Cohort 1 = 5 mg. 
Parts 1 and 2: See Section 4.1.5 for 
dose-escalation information.
Part 3 = Maximum dose QD tested in 
Part 2.
NA
100 g (IV) and 300 g (oral)
Route of Administration:
Oral
Oral solution/IV bolus injection


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Table 14 Summary of Treatments Administered (cont.)
Study Treatment Name:
RO6953958
Placebo (Part 1 and Part 2 only)
Midazolam (Part 3 only)
Dosing Instructions:
Part 1 (SAD/FE) – Fasted Condition: RO6953958 or matching placebo capsules will 
be administered orally and swallowed whole with approximately 240 mL water at room 
temperature in the morning of Day 1 after an overnight fast of at least 10 hours. Water 
will be allowed ad libitum until 1 hour prior to dosing and from 1 hour postdosing. A 
standard lunch will be provided 4 hours after dosing. If solubility is limited at higher 
doses, the dose may be given BID. For BID dosing, details on timing of dosing will be 
provided separately following review of PK data. Cohort 7 may have a different timing 
of study drug administration (evening vs morning) and food condition (fed vs fasted).
FE cohort – Fed Condition: RO6953958 will be administered 30 minutes after 
starting a standardized high fat, high calorie breakfast. Breakfast should be consumed 
within 30 minutes or less.
Part 2 (MAD): RO6953958 or matching placebo capsules will be administered orally 
and swallowed whole with approximately 240 mL water at room temperature from 
Day 1 to Day 10 once daily (in the morning) or twice daily (BID) depending on study 
data. If BID dosing, dosing on Day 10 will only be in the morning. Fasted conditions 
for administration were determined from Part 1 data. A dose level may have a 
different timing of daily drug administration (evening vs morning) in additional 
participants.
Part 3 (DDI): RO6953958 will be administered orally 30 minutes after starting a 
standardized breakfast. Breakfast should be consumed within 30 minutes or less. 
Capsule should be swallowed whole with approximately 240 mL of water at room 
temperature from Day 3 to Day 14 once daily. On Day 13 dosing will be 2 hours 
prior to midazolam dosing, and on Day 14, 1.5 hours prior to midazolam dosing.
Part 3 (DDI): Midazolam at a 100 g 
dose will be administered via a single 
bolus injection on Day 1 and Day 13. 
Midazolam at a 300 g dose will be 
administered via a single oral dose 
(solution) on Day 2 and Day 14. On 
Day 13 dosing of midazolam will be 
2 hours after RO6953958 dosing and 
on Day 14 dosing of midazolam will be 
1.5 hours after RO6953958 dosing.
Packaging and Labeling:
Study treatment will be provided in bottles. Each bottle will be labeled as required per 
country requirement.
Information as per local drug 
suppliers.
Storage Conditions
Store at 2C8C. Protect from light.
Manufacturer
F. Hoffmann-La Roche Ltd Basel, Switzerland
Please see RO6953958 Investigator’s Brochure for more details.


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6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Sponsor’s clinical study 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 the 
Sponsor’s standard and local regulations.
The study site should follow all instructions included with each shipment of IMP. The 
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The Investigator or designee 
must confirm that appropriate temperature conditions have been maintained during 
transit for all IMPs received and that any discrepancies have been reported and resolved 
before use of the IMPs. All IMPs must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area in accordance with the labeled storage 
conditions, with access limited to the investigator and authorized staff.
Only participants enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
The study site (i.e., Investigator or other authorized personnel [e.g., pharmacist]) is 
responsible for maintaining records of IMP delivery to the site, IMP inventory at the site, 
IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that participants are provided with 
doses specified by the protocol.
Upon arrival of the IMPs at the site, site personnel will complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Study Monitor upon discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the randomization schedule.
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.


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The Investigator 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 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.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the drug accountability log.
Refer to the pharmacy manual and/or the RO6953958 Investigator’s Brochure for 
information on IMP formulation, IMP handling, including preparation and storage, and 
accountability.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
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 dosing groups/cohorts in 
the appropriate place on each participant’s electronic case report form (eCRF).
Participants can be replaced (for details see Section 7.2).
Part 1 (SAD)
Fifty-six participants will be randomized, 8 per cohort. For all dose levels, a sentinel 
group of 2 participants will be randomized as 1 on active treatment and 1 on placebo 
and the remaining participants will be randomized as 5 on active treatment and 1 on 
placebo at the same dose level at least 24 hours later. If participants in the FE cohort do 
not agree to perform the fed part, additional participants will be recruited.
Part 2 (MAD)
Up to 80 participants will be randomized with a minimum of 6 active treatment and 
2 placebo participants in each dose level with the option to expand up to a maximum of 
12 active treatment and 4 placebo participants per dose level. All dose levels will be 
assigned to active treatment or placebo using a 3:1 ratio. Criteria for expansion of 
cohorts are outlined in Section 4.1.5.4.


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Part 3 (DDI)
Sixteen participants will be enrolled to have at least 12 evaluable participants complete 
study Part 3. All participants will receive active treatment.
6.3.2
Blinding and Emergency Unblinding
The study is Investigator-/subject-blind. This means that the participant, the Investigator,
and all individuals in direct contact with the participant at the site will be blinded to the 
individual treatment assignment except the pharmacist handling the study drug. To allow 
informed recommendations or decisions regarding dosing in this study, an integrated 
assessment of the safety, tolerability, and available PK data will be made prior to each 
dose-escalation decision. Members of the project and study team who are not in direct 
contact with the participants are blinded with the following exceptions: The Clinical 
Pharmacologist and the Clinical Pharmacology Scientist who perform this assessment 
— together with the Statistician, Data Acquisition Specialist, and Clinical/Statistical 
Programmer — will be unblinded with regard to the treatment allocation of participants. 
PK/PD data can be received and cleaned on an ongoing basis. The data will be handled 
and cleaned in a secure area that is not accessible by any blinded Study Management 
Team member. Likewise, the Bioanalytical Manager, Bioanalyst, and the 
Pharmacometrician will be unblinded. Other 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. 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 they should not disclose 
individual treatment assignment. In order to maintain the blind, the unblinded pharmacist 
at the site will be responsible for the dispensation of all study treatment. The 
randomization list will be made available to the pharmacist preparing the study 
treatment. A sealed envelope that contains the treatment assignment for each 
participant will be provided to the Investigator. The sealed envelope will be retained by 
the Investigator (or representative) in a secured area.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAEs (see Appendix 2) that are considered by the Investigator 
to be related to study treatment. If possible, 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, where 
possible. The date and reason for breaking the blind must be recorded, and the name of 
all the person(s) who had to be unblinded in the source documentation and eCRF, as 
applicable. Once the study is complete, all envelopes (sealed and opened) must be 
inventoried and returned to the Sponsor.


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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 bottle, 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 (except COVID-19 vaccines) (including OTC or prescription 
medicines, approved dietary and herbal supplements, nutritional supplements) used by a 
participant from 4 weeks prior to screening until the follow-up visit must be recorded 
along with reason for use, dates of administration (including start and end dates), and 
dosage information (including dose and frequency).
Participants are allowed to receive a dose of COVID-19 vaccine at least 21 days prior to
the first dose of study treatment or a dose of COVID-19 vaccine at least 10 days after 
the last dose of study treatment.
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 eCRF and any non-pharmacological interventions (e.g., 
individual psychotherapy, cognitive behavioral therapy, smoking cessation therapy, and 
rehabilitative therapy) as appropriate on the eCRF.
All medication administered to manage adverse events should be recorded on the AE
eCRF.
6.5.1
Permitted Therapy
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 30 days or 5 half-lives (whichever is 
longer) before the start of study intervention until completion of the follow-up visit, 
unless, in the opinion of the Investigator and Sponsor, the medication will not interfere 
with the study.
Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor if required.
Acetaminophen/paracetamol is allowed up to a maximum dose of 2 g/day up to 48 hours 
prior to dosing and after the in-house treatment, but dosage should not exceed 4 g total 
during the week prior to dosing.


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6.5.2
Prohibited Therapy
All medications (prescription and OTC) taken within 30 days of study screening will be 
recorded on the appropriate eCRF.
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor.
Use of the following therapies is prohibited during the study and for at least 30 days, or 
at least 5 half-lives of the medication, prior to initiation of study treatment (whichever is 
longer), unless otherwise specified below:

Any prescribed or OTC medication (including herbal products, vitamin, mineral, 
dietary supplements, melatonin, and melatonin agonists).

Any known inhibitor of cytochrome P450 (CYP) 3A4 or CYP2C19 taken within 
4 weeks prior to start of administration of study drug (Day 1) or within 5 times the 
elimination half-life of the medication prior to start of study drug intake (whichever is 
longer), including but not limited to the following drugs: ritonavir, troleandomycin, 
telaprevir, danoprevir, elvitegravir, saquinavir, lopinavir, indinavir, nelfinavir, 
boceprevir, voriconazole, mifepristone, posaconazole, telithromycin, ketoconazole, 
itraconazole, fluconazole, erythromycin, clarithromycin, mibefradil, ceritinib, 
ribociclib, idelalisib, conivaptan, nefazodone, diltiazem, verapamil, cimetidine, 
fluvoxamine, fluoxetine, ASP8477, and ticlopidine.

Any known inducer of CYP3A4 or CYP2C19 taken within 4 weeks prior to start of 
administration of study treatment (Day 1), including but not limited to the following 
drugs: rifampicin, rifabutin, glucocorticoids, carbamazepine, oxcarbazepine, 
phenytoin, phenobarbital, St. John’s Wort extract, mitotane, avasimibe, rifapentine, 
ivosidenib, carbamazepine, lumacaftor, apalutamide, enzalutamide, and ritonavir.

Use of drugs acting on platelets such as aspirin, clopidogrel, dipyridamole, 
ticlopidine, or with anticoagulant effect like heparin or warfarin.
6.6
DOSE MODIFICATION
In Part 1 it is anticipated that solubility may limit absorption at higher doses (> 400 mg);
therefore, in order to explore higher exposures in the Part 1, doses may be split over the 
day (i.e., given BID).
Depending on the safety and/or PK characteristics of RO6953958, a BID regimen may 
be used instead of QD dosing regimen in Part 2. A detailed SoA in Part 2 if BID dosing 
will be provided in this case.
In Part 2 or Cohort 7 (Part 1), the timing of dosing may be changed for participants
(Cohort 7 only) or additional participants in a cohort at a specific dose level, in order to 
explore the effect of time of dosing on the pharmacokinetics.


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6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO6953958 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 (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided, and efforts should be taken 
to motivate participants to comply with all the study-specific procedures as outlined in 
this protocol.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed, see the SoA (Section 1.3).
Reasons for discontinuation of study treatment (or withdrawal from the study) may 
include, but are not limited to, the following:

Participant withdrawal of consent at any time.

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues in the study.

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant.

Any event that meets stopping rules defined in Section 4.1.6.2.
Every effort should be made to obtain information on participants who withdraw from the 
study but have not withdrawn consent. Participants who discontinue study treatment 
prematurely will be asked to return to the clinic for a study completion/early termination 
visit (see Section 8.11.3) and may undergo follow‑up assessments (see Section 8.11.4), 
unless the participant withdrew consent. The primary reason for premature study 
treatment discontinuation should be documented on the appropriate eCRF. Participants 
who discontinue study treatment prematurely may be replaced (Section 7.2).
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined (Appendix 3, 
Section 5) or if the Investigator believes that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF) after enrollment, the Investigator or qualified designee will determine if 


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the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. 
Any new clinically relevant finding should be reported as an AE.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY AND PARTICIPANT REPLACEMENT
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 the participant 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 to ensure 
adequate numbers of evaluable participants for dose escalation. Replacement of 
participants for other reasons will be discussed between the Investigator and the 
Sponsor, based on existing data. Replacement participants will start the study at the 
dose level due to be received by the participant they are replacing.
For data to be collected at the time of study discontinuation and at safety and follow-up 
visits, and for any further evaluations that need to be completed, see the SoA 
(Section 1.3).
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.


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
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, the participant will be considered 
to have withdrawn from the study.
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 timepoints 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 ICF may be used for screening or 
baseline purposes if the procedure met the protocol-specified criteria and was performed 
within the time-frame defined in the SoA (see Section 1.3).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
EFFICACY ASSESSMENTS
Not applicable.
8.2
SAFETY ASSESSMENTS
Planned timepoints for all safety assessments are provided in the SoA (see Section 1.3).
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest (NSAESI); measurement of protocol-specified safety 
laboratory assessments; measurement of protocol-specified vital signs, ECGs; 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 be performed at screening and at the follow-up 
visit. The examination should include an evaluation of the head, eyes, ears, nose, and 
throat; and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, neurological, and genitourinary (at the Investigator discretion) systems.
In addition, neck and lymph nodes will be examined in Part 2 (MAD). Body weight will be 
measured at screening and follow-up visit; height will be measured at screening and 
used to calculate the BMI. Further examination of other body systems may be performed 
in case of evocative symptoms at the Investigator’s discretion.


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A brief physical examination will be performed at other timepoints in the SoA (see 
Section 1.3) and include, at a minimum, assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen), as well as symptom-driven checks. Any 
abnormality identified at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF. Changes from baseline abnormalities should be 
recorded in subject notes. New or worsened clinically significant abnormalities should be 
recorded as AEs on the Adverse Event eCRF.
8.2.2
Vital Signs
Vital signs will include body temperature (tympanic), pulse rate, respiratory rate, and BP.
Core body temperature will be collected as an exploratory measure during PSG 
assessment nights; see Section 8.7.12 for further details. Vital signs will be taken before 
blood collection and will be measured in a supine position after a resting period of at 
least 5 minutes at the timepoints specified in the SoA (Section 1.3). 
BP and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. When 
possible, the same arm should be used for all BP measurements.
When measuring BP, the participant's arm should be unconstrained by clothing or other 
material, and the participant should be comfortably supine, with the legs uncrossed, and 
the back and arm supported, such that the middle of the cuff on the upper arm is at the 
level of the right atrium (the mid-point of the sternum). The “ideal” cuff should have a 
bladder length that is 80% and a width that is at least 40% of arm circumference (a 
length-to-width ratio of 2:1).
8.2.2.1
Orthostatic Challenge Testing
This test will be performed in Part 1 and Part 2 only. During a 10-minute period during 
which the participant will remain in a supine position, BP and pulse rate will be measured 
after approximately 8, 9, and 10 minutes. If the last BP measurement deviates from the 
previous measurement by more than 5 mmHg, a 5-minute extension period will be 
added. If an extension period is needed. BP and pulse rate will be obtained after 
approximately 13, 14, and 15 minutes in the supine position.
The participant will then be asked to move into a standing position, and BP and pulse 
rate will be assessed again after 3 minutes of standing.
Standing BP and pulse rates will be compared against the latest blood pressure and 
pulse rate values obtained in the supine position. Orthostatic hypotension is defined as a 
decrease in SBP by at least 20 mmHg and/or a decrease in DBP by at least 10 mmHg.
8.2.3
Electrocardiograms
At each timepoint (see Section 1.3) at which triplicate ECGs are required, 3 individual 
ECG tracings should be obtained as closely as possible in succession, but no more than 


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2 minutes apart. The full set of triplicates should be completed in less than 5 minutes. 
The average of the 3 readings will be used to determine ECG intervals (e.g., PR, QRS, 
QT).
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 meals and
any scheduled vital sign measurements and blood draws. In case of an absolute QT 
corrected for heart rate (QTc) of > 500 ms and an increase from baseline QTc > 60 ms, 
another ECG triplicate must be recorded within the next 5 minutes. It may be 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 the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory and may be electronically captured.
ECG characteristics, including heart rate, QRS duration, and PR and QT intervals, will 
be recorded on the eCRF or loaded electronically. QTcF 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 2 categories: absent/normal or 
abnormal.
8.2.3.1
Holter ECG Monitoring
Digital continuous recordings (Holter) for the extraction of 12-lead ECG traces at 
predefined timepoints will be performed in Part 1 and Part 2 of the study, excluding the 
fed part in the FE cohort in Part 1, as specified in the SoA (see Section 1.3). Holter
recordings will be sent to a central ECG analysis laboratory for ECG extraction and 
potential retrospective expert review with estimation of ECG intervals. Replicate ECG 
tracings will be extracted from the continuous recording during a 5-minute time window 
immediately preceding the scheduled timepoint. 
Replicate ECG tracing will be extracted at the timepoints specified in the SoA (see 
Section 1.3). At these specific timepoints, the participants should be at rest and in a 
supine position for10 minutes before and remain in a supine position for5 more 
minutes after the specified ECG extraction timepoints.
While the participants are on Holter ECG monitoring, the absence of any environmental 
distractions (e.g., television, radio, conversation, or phone calls) during the pre- and 


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post-ECG rest period, and at every ECG timepoints specified in SoA (see Section 1.3),
must be emphasized. In particular, activities known to cause changes in heart rate 
should be avoided.
The timings of assessments may be amended or the number of assessments increased 
during study conduct on the basis of emerging data to allow for optimal characterization 
of the effect profile.
The 12-lead Holter and ECG equipment will be supplied and supported by ERT. All ECG 
data will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG 
continuous 12-lead digital recorder. The continuous 12-lead digital ECG data will be 
stored onto SD memory cards.
The following principals will be followed in ERT’s core laboratory:

ECG readers are blinded to the participant, visit and treatment allocation.

A limited number of readers will be employed for the study.

Baseline and on-treatment ECGs for a particular subject will be over-read on the 
same lead and will be analyzed by the same reader.

The primary analysis lead is lead II. If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire participant data set.
The following is a brief description of ECG analysis methods used by ERT’s core 
laboratory.
8.2.3.1.1
TQT Plus ECG Extraction Technique
Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘TQT Plus method’, a computer assisted and statistical process 
used by ERT. The method enables extraction of ECGs with the lowest heart rate (HR)
variability and noise within the protocol-specified extraction time window (e.g., the HR 
and QT changes from beat-to-beat in the range of10%). At each protocol-specified 
timepoint, 10 ECG replicates will be extracted from a 5-minute “ECG window” (typically, 
the last 5 minutes of the 15-minute period when the participant is maintained in a supine 
or semi-recumbent quiet position).
8.2.3.1.2
Expert-Precision QT Analysis
Expert-precision QT analysis will be performed on all analyzable (non-artifact) beats in 
the 10 ECG replicates. Statistical quality control procedures are used to review and 
assess all beats and identify “high” and “low” confidence beats using several criteria, 
including:

QT or QTc values exceeding or below certain thresholds (biologically unlikely)

RR values exceeding or below certain thresholds (biologically unlikely)

Rapid changes in QT, QTc or RR from beat to beat


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Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” will be performed using COMPAS 
software. All low confidence beats will be reviewed manually and adjudicated using 
pass-fail criteria. The final quality-control assessment will be performed by a cardiologist. 
The beats found acceptable by manual review will be included in the analysis. The 
median QT, QTc, and RR value from each extracted replicate will be calculated, and 
then the mean of all available medians from a nominal timepoint will be used as the 
participant’s reportable value at that timepoint.
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals 
will be performed manually in 3 of the 10 ECG replicates at each timepoint. Each fiducial 
point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) will be 
electronically marked.
For T-wave morphology and U-wave presence, treatment-emergent changes will be 
assessed (i.e., changes not present at baseline). For each category of T-wave 
morphology and of U-waves, the category will be deemed as present if observed in any 
replicate at the time point. For baseline, the category will be deemed as present if 
observed in any replicate from all time points that constitute baseline. The T-wave 
morphology categories are described in Table 15.
Table 15 T-Wave Morphology and U-Wave Presence Categories (Assessed 
Manually)
Category
Description
Normal T-wave
Any positive T-wave not meeting any criterion below
Flat T-wave
T amplitude1 mm (either positive or negative) including flat isoelectric 
line
Notched T-wave (+)
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave
Biphasic
T-wave that contains a second component with an opposite phase that 
is at least 0.1 mV deep (both positive/negative and negative/positive 
and polyphasic T-waves included)
Normal T-wave (-)
T amplitude that is negative, without biphasic T-wave or notches
Notched T-wave (-)
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave
U-waves
Presence of abnormal U-waves
8.2.4
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 (see Section 1.3).


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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 eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.

In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated as soon as possible 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 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 are considered clinically significant by the Investigator (e.g., 
SAE or AE or dose-modification) then, the results must be recorded in the eCRF.
Results of clinical laboratory testing will 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 laboratory results at screening is considered 
uncertain, screening laboratory 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 should be repeated to confirm washout.
8.2.5
Suicidal Risk Monitoring
RO6953958 is considered to be a CNS-active study treatment. There has been some 
concern that some CNS-active study treatments may be associated with an increased 
risk of suicidal ideation or behavior when given to some participants. Although this study 
treatment or other similar drugs in this class have not been shown to be associated with 
an increased risk of suicidal thinking or behavior when given to healthy participants, the 
Sponsor considers it important to monitor for such events before or during this clinical 
study.
Participants being treated with multiple doses of RO6953958 or placebo should be 
monitored appropriately and observed closely for suicidal ideation and behavior or any 
other unusual changes in behavior. Consideration should be given to discontinuing 


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RO6953958 or placebo in participants who experience signs of suicidal ideation or 
behavior.
Baseline assessment of suicidal ideation and behavior and/or treatment-emergent 
suicidal ideation and behavior will be monitored during the study using the
Columbia-Suicide Severity Rating Scale (C-SSRS) “Baseline-Screening” version at 
screening and “Since Last Visit” version at subsequent visits. C-SSRS assessments will 
be completed by suitably trained staff.
8.2.6
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse 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 SAE can be found in Appendix 2. The NSAESI and 
disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs 
are discussed in Sections 8.3.6.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity, and causality; see Appendix 2) are 
recorded on the AE eCRF and reported to the Sponsor in accordance with instructions 
provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3.
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.
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the AE eCRF as follows:
After informed consent has been obtained but prior to initiation of study 
treatment, only SAEs caused by a protocol-mandated intervention should be reported 
(e.g., SAEs related to invasive procedures such as biopsies). Any other AE should not 
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After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until the last follow-up visit for each part.
Post-Study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period (i.e., the last follow-up visit 
for each part).
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to previous 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 nonleading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of nondirective questioning should be adopted for eliciting AE
information at all participant evaluation timepoints.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the AE eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event details 
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) to perform an independent medical assessment of the reported event.


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8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate, according to local requirements.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, Investigators, IRB, and Ethics Committee (EC), see 
Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day 7 days a week. Details will be available separately.
8.3.5
Pregnancy
Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 28 days after 
the final dose of study drug.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest
NSAESI 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).


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NSAESI for this study include the following:

Cases of an elevated ALT or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product. This term applies only
when a contamination of the study treatment is suspected.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental administration of a drug in a quantity that is 
higher than the assigned dose. An overdose or incorrect administration of study 
treatment is not an AE unless it results in untoward medical effects (see Sections 5 and 
5.2 of Appendix 2 for further details).
Decisions regarding dose modifications, if applicable, will be made by the 
Investigator/treating physician in consultation with the Medical Monitor based on the 
clinical evaluation of the participant.
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. In case of AE/SAE, standard of care is to be used.
3. Obtain a blood sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose, as well as the duration of the 
overdose, in the eCRF.
8.5
PHARMACOKINETICS
Concentrations of RO6953958 and its metabolites, RO7021594 and RO7045755, will be 
measured in plasma, urine and CSF using separate specific and validated LC-MS/MS 
assays. The blood, urine and CSF samples will be taken as outlined in the SoA (see 
Section 1.3). The date and time of each sample collection will be recorded in the eCRF. 
During the course of the study, PK sampling timepoints may be modified on the basis of 
emerging data to ensure the PK of RO6953958 can be adequately characterized. 
In a cohort, CSF sampling will be done predose in 4 participants and in the other 4 
participants at approx. 5 to 7 h after dosing of RO6953958 (around Tmax of the M3 


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metabolite) for determination of RO6953958, M3 (RO7021594) and M1 (RO7045755) 
concentrations in CSF (i.e., one CSF sample per participant per cohort). A 
corresponding blood sample will be taken at the same timepoint. As an alternative to 
CSF sampling on Day 7, it may also be performed on Day 6 or Day 8. The time points of 
CSF sampling in a participant may be adjusted with emerging PK or CSF samples from 
preceding cohorts. In addition, these results might also lead to the conclusion to stop 
CSF sampling in subsequent cohorts.
Lumbar punctures will be performed by an experienced anesthesiologist using sterile 
techniques and local anesthesia, such as lidocaine. Subjects will be required to remain 
supine for up to 2 hours after the procedure. The Investigator may prescribe analgesics 
as needed for headache or pain in the lumbar puncture area.
Blood samples for the determination of plasma concentrations of midazolam will be 
collected as detailed in the SoA (Section 1.3). Plasma concentrations of midazolam will 
be measured by a specific and validated LC-MS/MS method. 
A decision to stop PK sampling earlier or to collect more samples than the currently 
proposed scheduled times will be based on the PK profile of RO6953958 from preceding 
dose groups. Up to 3 additional PK samples may be taken per participant, and the timing 
of PK sampling may be changed based on emerging PK results after agreement with the 
Sponsor Clinical Pharmacologist and the Investigator without exceeding the total number 
of scheduled (+3 additional) PK samples.
Any changes in the timing or addition of timepoints 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.
Remaining PK plasma, urine and CSF samples may be used for exploratory biomarker 
profiling, identification, assay development purposes, and assay validation during the 
development of study or compound related assays after the mentioned intended uses. 
The PK plasma, urine and CSF samples may be destroyed 6 months after the date of 
finalization of the bioanalytical report only after Sponsor’s approval or shipped to Roche. 
In the latter case, the PK plasma, urine and CSF samples may be stored up to 5 years 
after the final CSR has been completed unless the participant gives specific consent for 
his or her leftover samples to be stored in the RBR for optional exploratory research.
Details on sampling procedures, sample storage and shipment are given in the sample 
documentation. Drug concentration information that may unblind the study will not be 
reported to investigative sites or blinded personnel until the study has been unblinded.

Other metabolites may be measured using a specific validated or qualified 
LC-MS/MS assay, as appropriate.


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
PK samples from participants treated with placebo may not be analyzed but retained 
for subsequent analysis if appropriate. At a minimum, the Tmax sample will be 
analyzed for placebo participants.
8.6
IMMUNOGENICITY ASSESSMENTS 
Not applicable.
8.7
PHARMACODYNAMICS AND BIOMARKER ANALYSES
8.7.1
Genetic and Genomic Analyses
8.7.1.1
Clinical Genotyping
A mandatory whole blood sample will be collected for DNA extraction according to the 
SoA (see Section 1.3). If, however, the genetic blood sample is not collected during the 
scheduled visit, it may be collected at any time during the conduct of the clinical study.
The DNA may be used to determine if genetic variants (e.g., at drug metabolizing
enzymes, transporters, receptors) affect the PK, PD, efficacy, and/or safety of 
RO6953958. This may include genome sequencing to detect these variants as well as, 
genotyping the AVPR1A gene including promoters. DNA may also be used to detect 
whether genetic variants in genes controlling circadian rhythms and sleep are 
associated with the sleep-related measurements.
Data arising from all biosamples, including samples for analyses of inherited DNA, will 
be subject to the confidentiality standards described in as described in Section 1.4 of
Appendix 1. For participants who consent to research biosample repository (RBR), 
leftover samples will be transferred to RBR (see Section 8.9).
8.7.2
Pittsburgh Sleep Quality Index
The PSQI questionnaire will be recorded according to the SoA (see Section 1.3). The 
PSQI assesses sleep quality during the previous month (Buysse et al 1989). It consists 
of 19 self-rated questions. A wide variety of factors relating to sleep quality are 
assessed, including estimates of sleep duration and latency and the frequency and 
severity of specific sleep-related problems. These 19 items are grouped into seven 
component scores, each weighted equally on a 0–3 scale. The global PSQI score has a 
range of 0–21 and higher scores indicate worse sleep quality.
8.7.3
Patient-Reported Outcomes Measurement Information System 
Sleep Questionnaires
The PROMIS sleep questionnaire will be recorded according to the SoA (see 
Section 1.3).
The PROMIS Sleep Disturbance Short Form (Yu et al 2011; Buysse et al 2010) 
assesses self-reported perceptions of sleep quality, sleep depth, and restoration 
associated with sleep. This includes perceived difficulties and concerns with getting to 


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sleep or staying asleep, as well as perceptions of the adequacy of and satisfaction with 
sleep. This questionnaire assesses sleep disturbance over the past 7 days.
The PROMIS Sleep-Related Impairment Short Form (Buysse et al 2010) focuses on 
self-reported perceptions of waking alertness, sleepiness, and function within the context 
of overall sleep-wake function. This questionnaire assesses sleep-related impairment 
over the past 7 days.
8.7.4
Karolinska Sleepiness Scale (KSS)
The KSS will be recorded according to the SoA (see Section 1.3). The KSS measures 
the subjective level of sleepiness at a particular time during the day. On this scale,
participants indicate which level best reflects the psycho-physical state experienced in 
the last 5 minutes.
The KSS (version b) is a 9-point scale (with descriptions from 1 = extremely alert to
9 = extremely sleepy – fighting sleep).
8.7.5
Epworth Sleepiness Scale (ESS)
The Epworth Sleepiness Scale (ESS; Johns 1991, Johns 1992) will be completed 
according to the SoA (see Section 1.3). The ESS is a brief, self-administered eight-item 
questionnaire that measures daytime sleepiness in adults. The participant will be asked 
to rate on a scale of 0 to 3 the chances that, “over recent times the past month” he/she 
would have dozed in eight specific situations that are commonly met in daily life 
(0 = would never doze; 3 = high chance of dozing). Thus, the participant is asked to 
characterize, retrospectively, part of his usual behavior in a variety of situations that are 
more or less soporific. The ESS score is the sum of eight item-scores and can range 
from 0 to 24. 
This assessment takes approximately 5 minutes to perform.
8.7.6
Morningness-Eveningness Questionnaire (MEQ)
The morningness–eveningness questionnaire (MEQ; Horne et al 1976) is a 
self-assessment questionnaire that will be completed according to the SoA (see 
Section 1.3). The MEQ consists of 19 items, and was developed to assess individual 
differences in morningness and eveningness – the degree to which respondents are 
active and alert at certain times of day. Its main purpose is to measure whether a 
person's circadian rhythm (biological clock) produces peak alertness in the morning, in 
the evening, or in between.
8.7.7
Sleep Mat
A sleep mat that will be placed under the participant’s mattress and contains a vibration 
sensor to detect breathing and heart rate signals will be used to collect data on the 
participant’s sleep behavior according to the SoA (see Section 1.3).


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Test data for the sleep mat will be collected from four participants during Part 1 (SAD) to 
ensure functioning of equipment for Part 2 (MAD).
8.7.8
Polysomnography
Polysomnography will be recorded according to the SoA (see Section 1.3) and used to 
assess the effect of RO6953958 on sleep. Specific endpoints will include but are not 
limited to total sleep time, sleep latency, wake after sleep onset, distribution of sleep 
stages (in minutes and/or %), amount of slow waves, density, amplitude and frequency 
of sleep spindles and sleep efficiency. A detailed description of PSG procedures will be 
provided separately.
8.7.9
Platelet Aggregation Assay
Inhibition of vasopressin-induced platelet aggregation will be tested on blood samples 
drawn at the indicated timepoints (see Section 1.3). This assay assesses the response 
to AVP EC80, which is the necessary concentration of vasopressin to be added to blood 
samples to provoke 80% platelet aggregation in absence of RO6953958. It is expected 
that the response to AVP EC80 will be increasingly inhibited by increasing concentration 
of RO6953958 in the blood of participants dosed with the drug. Participants must have a 
positive PAA at baseline for further sampling.
8.7.10
Facial Expression Recognition Task
The FERT will be recorded according to the SoA (see Section 1.3). The FERT is an
emotion-related behavioral test designed to measure biases in emotional processing that 
are thought to be core components of affective disorders (Harmer et al 2008; Harmer et 
al 2009a; Harmer 2009b; Harmer et al 2010). The FERT assesses the interpretation of 
facial expressions. Faces with 6 different basic emotions (happiness, fear, anger, 
disgust, sadness, surprise) are displayed on a screen and participants are required to 
indicate the expression of the face. Different intensity levels of each emotion are 
presented, which increases the ambiguity of the facial expression and the sensitivity of 
the task.
8.7.11
Circadian Sleep Biomarkers
Serum cortisol and melatonin in both saliva and serum will be measured according to the 
SoA (see Section 1.3). Timings and number of samples (to a maximum of 12 samples 
per matrix) may be adjusted based on DLMO protocol. Full details on the timing of 
assessments will be detailed in a separate document.
8.7.12
Core Body Temperature Assessment
Core Body Temperature will be measured according to the SoA (see Section 1.3).
For measurements of core body temperature the Equivital EQ-02+ LifeMonitor in 
combination with the Philips VitalSense core body temperature pill will be used. Once 
the activated Core Body Temperature Pill is swallowed, the body worn sensor 


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(LifeMonitor) acts as antenna for picking up the core pill readings. The transit time 
through the body of the core pill varies between individuals, and normally ranges
between 24 and 48 h. Additional details will be provided in a separate document.
8.7.13
Wake EEG
Wake EEG will be measured according to the SoA with the same EEG equipment used 
in PSG nights with a full 10-20 electrode montage (see Section 1.3).
8.7.14
4-Hydroxycholesterol and Total Cholesterol
Blood samples for the determination of plasma concentrations of 4HC and total 
cholesterol will be collected from participants in Part 3 of the study as detailed in the 
SoA (Section 1.3). 
8.8
PHARMACODYNAMICS AND BIOMARKER SAMPLES
The samples may also be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to RO6953958, identifying biomarkers useful for 
predicting, and monitoring RO6953958 safety and assessing PD effects of RO6953958. 
Additional markers may be measured in the case that a strong scientific rationale 
develops.
Samples should be collected as specified in the SoA (see Section 1.3).
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered to be critical for safety may be stopped at any time if 
the data from the samples collected do not produce useful information. 
The residual PD samples (including blood, serum, plasma, saliva, and derivatives such 
as DNA samples) will be destroyed within 5 years after the date of final clinical study 
report (CSR), unless the participant gives specific consent for the remainder of the PD 
samples to be stored for potential exploratory research within the RBR. If the participant 
provides consent for RBR, the samples will be stored and used not longer than 15 years 
after the date of final CSR. Any remaining PD samples (including blood, serum, plasma, 
and saliva) after the specified analyses may also be used for additional (assay) 
validation experiments, for research to develop methods, assays, prognostics, and/or 
companion diagnostics related to vasopressin, sleep disorders, ASD, or other related 
pathways and conditions.
Details on processes for collection and shipment of these samples will be described in a 
separate sample documentation.
8.9
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY
8.9.1
Overview of the Research Biosample Repository
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 


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(e.g., DNA, RNA, proteins, peptides). The collection, storage and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Residual samples for RBR (from participants who give specific consent to participate in 
this optional RBR) will be used to achieve the following objectives:

To study the association of biomarkers with efficacy or progressive disease

To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study treatment response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
8.9.2
Sample Collection
The following samples will be stored in the RBR and used for research purposes,
including, but not limited to, research on biomarkers related to study treatment or
diseases:

Residual plasma samples

Residual CSF samples

Residual saliva samples

Residual urine samples

Residual whole blood samples

Residual samples prepared from whole blood (e.g., DNA, RNA)

Residual samples from additional safety monitoring, if applicable
The sample collected for DNA extraction includes, but is not limited to, genomic analysis,
and may be sent to one or more laboratories for analysis of germline or somatic
mutations via whole genome sequencing, whole exome sequencing, next-generation
sequencing, or other genomic analysis methods.
Genomics is increasingly informing researcher's understanding of disease pathobiology.
Whole genome sequencing provides a comprehensive characterization of the genome
and, along with clinical data collected in this study, may increase the opportunity for
developing new therapeutic approaches. Data will be analyzed in the context of this
study but will also be explored in aggregate with data from other studies. The availability
of a larger dataset will assist in identification of important pathways, guiding the
development of new targeted agents.


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For all samples, dates of consent and specimen collection should be recorded on the
associated RBR page of the eCRF. For sampling procedures, storage conditions, and
shipment instructions, see the separate laboratory manual.
RBR samples will be stored and used not longer than 15 years after the date of final 
CSR. The RBR storage period will be in accordance with the IRB/EC‑approved ICF and 
applicable laws (e.g., Health Authority requirements).
The repository samples will be subject to the confidentiality standards (as described 
under Section 1.4 Confidentiality in Appendix 1).
8.10
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS
Medical resource utilization and health economics parameters are not evaluated in this 
study.
8.11
TIMING OF STUDY ASSESSMENTS
8.11.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. ICFs for enrolled 
participant and for participants who are not subsequently enrolled will be maintained at 
the study site.
All screening, and all pretreatment 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.
8.11.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and
re-enroll in the study.
All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study treatment administration should be performed prior to 
administration of study treatment, unless otherwise noted in the SoA. 
8.11.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study (as defined in Section 4.4) or discontinue from the 
study early (as described in Section 7) will be asked to return to the clinic after the final 
dose of study drug for a follow-up visit (see SoA in Section 1.3 and Section 8.11.4).


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8.11.4
Follow-Up Assessments
Assessments at the follow-up/early termination visit will be performed as indicated in the
SoA (Section 1.3).After the study completion/early termination visit, AEs should be 
followed as outlined in Sections 8.3.1 and 8.3.3.
8.11.5
Assessments at Unscheduled Visits
Activities that are required to be performed in the case of an unscheduled visit triggered 
by an AE are guided by the nature of the AE and refer to further diagnostics and 
optimization of any therapy as needed.
9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
See Section 9.4.3.2.
9.2
SAMPLE SIZE DETERMINATION
9.2.1
Part 1 (Single Ascending Doses) and Part 2 (Multiple 
Ascending Doses)
For the SAD and MAD parts, the number of participants to be randomized was chosen 
based on practical clinical judgment. The current planned study design and sample size 
complies with standard safety review rules applied in SAD and MAD studies.
9.2.2
Part 3 (Drug-Drug Interaction)
A formal sample size calculation was performed to determine the number of participants 
required for midazolam drug-drug interaction part.
With a 20% drop out rate, 16 participants will be enrolled to obtain at least 
12 participants who complete Part 3. With information from previous midazolam DDI
studies (WP29393, BP41361, and BP40387), the intra-subject coefficient of variation 
(CV) for AUCinf and Cmax following administration of RO6953958 are assumed to be 
21%. 
Assuming a CV of 21%, a sample size of 12 evaluable participants will ensure the 
2-sided 90% CI to not extend more than 1.33-fold above and not less than 
0.75-fold below the true geometric mean ratio with 80% probability.


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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 16.
Table 16 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 (RO6953958)
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.
Pharmacodynamic
Analyses of PD parameters will include all participants who 
received at least one dose of study drug treatment, are 
evaluable and have no major protocol violations. A participant 
is considered evaluable if at least one analysis parameter can 
be derived and subject did not vomit within 4 hours of drug 
administration. 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.
9.4
STATISTICAL ANALYSES
9.4.1
Demographics and Baseline Characteristics
Demographic and other baseline characteristics of the safety analysis population will be 
listed and summarized with descriptive statistics.
9.4.2
Safety Analyses
All safety analyses will be based on the safety analysis population (see Table 17).


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Table 17 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.
AEs 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.
Vital signs
Vital sign (supine and orthostatic) 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.
The relationship between QTcF prolongation and the plasma concentration
of RO6953958 may be investigated in an exploratory manner.
Concomitant 
medications
The original terms recorded on the participants’ eCRFs 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.
Suicidal risk 
monitoring
Individual data on C-SSRS will be presented by listings.
9.4.3
Pharmacokinetic Analyses
Analyses will be carried out on the PK analysis population. All PK parameters will be 
presented by listings and descriptive summary statistics (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum) separately by group or 
cohorts.
9.4.3.1
Pharmacokinetic Parameters
Individual and mean plasma and urine concentrations of RO6953958 and its metabolites 
RO7021594 and RO7045755 (all parts) and midazolam (Part 3) versus time data will 
be tabulated and plotted by dose level. Graphical displays of PK data may also be 
provided. The plasma, urine, and CSF PK of RO6953958 and its metabolites 
RO7021594 and RO7045755 (all parts) and midazolam (Part 3) will be tabulated and 
summarized as appropriate. Inter-participant variability and drug accumulation will be 
evaluated. Calculation of urine PK parameters (fractional excretion, renal clearance) will 
also be performed. PK parameters will be read directly from the plasma concentration-
time profiles or calculated using standard non-compartmental methods. Parameters 
calculated will include but not be limited to the following:


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Part 1 (SAD/FE)

Cmax, tmax, Clast, tlast, z, t1/2, AUC0–12h, AUC0–last, AUCinf, CL/F

V/F, Ae, Fe, and CLR
Part 2 (MAD)
Day 1 and Day 10:

Cmax, Cavg, tmax, AUC0-τ, λz, t½, CL/F, V/F, Ae, Fe, and CLR

Steady-state achievement: Ctrough

Accumulation: RAUC, RCmax, RCtrough

Molecular weight adjusted metabolite-to-parent ratio for Cmax and AUC parameters 
as appropriate.
Part 3 (DDI)
RO6953958 and its metabolites RO7021594 and RO7045755(as appropriate):

Cmax, Cavg, tmax, AUC0-τ, λz, t½, CL/F, V/F

Steady-state achievement: Ctrough (Days 12-14)

Accumulation: RAUC, RCmax, RCtrough

Molecular weight adjusted metabolite-to-parent ratio for Cmax and AUC parameters 
as appropriate.
Midazolam:

Tmax, Cmax, t1/2, AUClast, AUCinf, AUC%extra, z, CL/F, V/F

Accumulation: RAUC, RCmax, on days 1 and 2 vs. days 13 and 14

CL: Total plasma clearance (IV midazolam only)

F

VSS
Using data from all study parts, additional PK analyses maybe be conducted as 
appropriate for RO6953958 and its metabolites RO7021594 and RO7045755.
CSF/plasma concentration ratios will be calculated for RO6953958, M3, and M1, as 
applicable.
9.4.3.2
Statistical Analysis Methods
Part 1 (SAD/FE)
The following statistical analysis on the PK parameters (AUC0-∞[or if cannot properly be 
determined AUC0-t or AUC0-last] and Cmax) will be performed after completion of the study 


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to explore dose proportionality. The following linear model will be applied to the 
log-transformed, dose-normalized PK study variables:
yij ~ µ + si + λj + εij        (i= 1,2,...,N; j=1,2,...,M)
where M is the number of different doses, N is the total number of participants, µ 
denotes the general mean of the transformed variables, si is the random subject effect, λj
is the effect of the jth dose and εij is the residual error for subject i in the dose level j. The 
random effects are assumed to be independent and normally distributed with zero 
means and variances σ2s and σ2ε respectively.
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 PK
parameters:
H0: There is no deviation from dose proportionality (i.e., λ1 = λ2 = ⋯= λM)
versus
H1: There is a deviation from dose proportionality (λ1≠λj for some i, j).
All p-values will be interpreted in an exploratory sense only.
A similar linear model will be applied to the log-transformed PK study variables to 
analyze FE:
yij ~ µ + λj + si + εij       (i= 1,2,…,N; j=1,2) 
where µ denotes the general mean of the transformed variables, λj is the effect of the 
feeding condition j (1=fed; 2=fasted), si is the random subject effect and εij is the residual 
error for subject i in feeding condition j. The random effects are assumed to be 
independent and normally distributed with zero means and variances σ2s and σ2ε
respectively.
Least square means with corresponding 90% CI will be derived to compare the relative 
bioavailability of the different feeding conditions.
Again, results of the statistical model will be interpreted in an exploratory sense.
Part 2 (MAD)
A similar model as for Part 1 will be applied to AUC0-t and Cmax in order to investigate 
possible deviations from dose proportionality. 


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The estimation of the time to attainment of steady-state in Part 2 will be based on the 
available trough concentrations (Ctrough) from Day 1 to Day 10. It is postulated that a 
participant has reached steady-state as soon as C24h is at least 90% of its plateau value, 
i.e., 90% of the true C24h that this participant would reach after “infinitely” many doses. In 
order to estimate the time to steady-state of a participant with regression analysis, it is 
assumed that the true C24h versus time curve approaches its asymptotic value C24h (∞)
(plateau) exponentially in time, i.e.,
C24h (t) = C24h (∞) x (1-e-kt)
Based on a statistical fit of this model to the measured concentrations one can estimate 
the earliest point in time where C24h reaches 90% of the curves maximum (C24h [∞]), the 
so called t90%. The analysis will be supported by appropriate graphical displays. If BID 
dosing is used in Part 2 (MAD) then C12h will be considered instead of C24h.
The dose dependency of the accumulation ratio, defined as:
PK −Param
PK −Param
will be estimated for the log–transformed primary PK parameters based on an analysis 
of variance model with “log accumulation ratio” as dependent variable and “dose group”
as factor.
Part 3 (DDI)
The effect of RO6953958 on the PK of midazolam will be assessed. The effect of 
RO6953958 on the natural log-transformed Cmax, AUCinf (AUClast if AUCinf cannot be 
derived) will be assessed with a linear mixed-effects model. Treatment will be used as 
fixed effect and participant will be used as a random effect. Point estimates for the 
means and corresponding 90% CI for the differences in means between the two 
treatments (RO6953958 plus midazolam as the test treatment, versus midazolam alone 
as the reference) will be obtained from the linear mixed effects model and exponentiated 
to obtain geometric means, geometric mean ratios, and respective 90% CI on the 
original scale. The model result will be derived separately for oral and IV midazolam.
9.4.4
Cardiodynamic Electrocardiogram (ECG) Assessment
Cardiodynamic ECG evaluation (optional) will be performed for Part 1 (SAD) under 
fasted conditions and Part 2 (MAD) if necessary (based on observed PK and other 
project considerations). If this evaluation is performed, the primary analysis will be based 
on concentration-QTc modeling of the relationship between the plasma concentrations of 
RO6953958 and its metabolites RO7021594 and RO7045755 and change-from-baseline 
QTcF (∆QTcF) with the intent to exclude an effect of placebo-corrected ΔQTcF 
(ΔΔQTcF) > 10 msec at clinically relevant plasma concentrations. The effect of 


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RO6953958 on the placebo-corrected ∆QTcF, ΔHR (heart rate), ΔPR, and ΔQRS 
(∆∆QTcF, ΔΔHR, ΔΔPR, and ΔΔQRS) will also be evaluated at each post-dosing time 
point ('by-time point' analysis) using the Intersection Union Test. In addition, an analysis 
of categorical outliers will be performed for changes in HR, PR, QRS, QTcF, T-wave 
morphology, and U-wave presence. 
Cardiodynamic ECG evaluation will be described in a separate statistical analysis plan.
9.4.5
Pharmacodynamic Analyses
All PD parameters will be presented by listings and descriptive summary statistics 
separately by dose.
Listings for the change from baseline (absolute and relative) and difference to placebo 
and the corresponding summary statistics may also be presented. Graphical displays 
may be used, as appropriate.
PD analysis may assess the correlation of PD baseline levels, peak concentrations after 
treatment or change from baseline with PD effects.
PKPD analysis may be performed for PD parameters if the data allow.
Further analysis may be described in a separate technical document if appropriate.
9.5
SUMMARIES OF CONDUCT OF STUDY
All protocol deviations will be listed. Data for study treatment 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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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (For regulatory, 
ethical and study oversight considerations), Appendix 2 (For Adverse Events: Definitions 
and Procedures for Evaluating, Follow-up and Reporting) and Appendix 3 (Procedures 
for Recording Adverse Events), Appendix 4 (Clinical Laboratory Tests), Appendix 5
(Contraceptive Guidance and Collection of Pregnancy Information).


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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 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, and the IRB/IEC or study center. The Sponsor 


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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.
Consent to Participate in the Research Biosample Repository
The ICF will contain a separate section that addresses participation in the RBR. The 
Investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of participation in the RBR. Participants will be told that 
they are free to refuse to participate and may withdraw their samples at any time and for 
any reason during the storage period. A separate, specific signature will be required to 
document a participant’s agreement to provide optional RBR samples. Participants who 
decline to participate will not provide a separate signature.
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a participant who is participating in the 
research, the participant's samples and data will continue to be used as part of the RBR.
Approval by the Institutional Review Board or Ethics Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site's 
IRB/EC and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site
Withdrawal from the Research Biosample Repository
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
BP41695 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP41695. Data already generated before time of withdrawal of consent to RBR will still 
be used.


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1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Confidentiality for Research Biosample Repository
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and the Sponsor’s monitors, 
representatives, and collaborators, as appropriate.
Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant, unless 
permitted or required by law.
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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Monitoring and Oversight Research Biosample Repository
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the 
Informed Consent Form (ICF). Roche monitors and auditors will have direct access to 
appropriate parts of records relating to participant participation in RBR for the purposes 
of verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the samples.
1.5.
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., last participant, 
last visit).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.


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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, 
participant files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical study.
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.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local health authorities.


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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 participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2.
Publication Policy and Protection of Trade Secrets
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific 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.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
2.3.3.
Dissemination of Clinical Study Data
The results of the study may be communicated in scientific meetings and/or peer-
reviewed literature. In addition, results of the study will also be included in submissions 
to regulatory agencies and other health authorities.
2.3.4.
Management of Study Quality
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks. Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation. Detection of deviations from 
quality tolerance limits will trigger an evaluation to determine if action is needed. Details 
on the establishment and monitoring of quality tolerance limits will be provided in a 
Quality Tolerance Limit Management Plan.
2.3.5.
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.
ADMINISTRATIVE STRUCTURE
The Sponsor of the study is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for 
the study management, data management, statistical analysis and medical writing for 
the clinical study report.
4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to, the 
following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants.

Participant enrollment is unsatisfactory.


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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 participant 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 serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any 
dose:

Results in death.

Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a 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.


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Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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 mild, moderate, or severe, or according to a predefined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event.


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Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see above).
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.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment, or reintroduction of study treatment.

Known association of the event with the study treatment or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.
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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.
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, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).


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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.
5.2
REPORTING REQUIREMENTS FOR CASES OF 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 RO6953958 and placebo, 


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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 RO6953958 and placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF and should be recorded as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the RO6953958 Investigator’s Brochure.


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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 appropriate medical terminology and consider medical 
concepts and adverse event may fall into 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.
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.

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.
2.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints. 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 timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.


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3.
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 or treatment 
discontinuation).

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN] 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
4.
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 or treatment 
discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.


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It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
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.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 8.3.6).
6.
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").


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7.
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”).
8.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study treatment 
administration or insertion of access device for study treatment administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the central laboratory.
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study treatment decision or response evaluation, the results must be 
captured in source documentation and entered as a comment into the eCRF.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
All study-required laboratory assessments may be performed by a central laboratory.
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate (CO2), 
glucose (fasting*), urea, creatinine, protein, 
albumin, phosphate, calcium, total and direct 
bilirubin, alkaline phosphatase, ALT, AST, uric 
acid, LDH gamma-glutamyl-transferase (GGT), 
creatine phosphokinase (CPK).
* In Part 2 and Part 3 where participants are 
dosed in fed state, on Day 2, Day 5, Day 9; safety 
blood samples and PK samples will be taken at 
the same time (to avoid additional venepunctures) 
and blood glucose will not be fasted.
Coagulation**

INR, aPTT.
**Coagulation samples taken for lumbar puncture 
are captured only for exclusion purposes and will 
not be recorded electronically.
Viral Serology

HIV (specific tests HIV-1 antibody, HIV-1/2 
antibody, HIV-2 antibody), hepatitis B surface 
antigen (HBsAg), hepatitis C virus (HCV) antibody.


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Laboratory Assessments
Parameters
Urinalysis

Specific gravity.

Dipstick: pH, glucose, protein, blood, nitrite, 
leukocyte.

If there is a positive result (confirmed by a positive 
repeated sample), urine will be sent to the 
laboratory for microscopy and if necessary a urine
culture. If there is an explanation for the positive 
dipstick results (e.g., menses), it should be 
recorded and there is no need to perform 
microscopy and culture.

Microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.
Other Screening Tests

Urine drug screen (to include at minimum: cotinine, 
amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).

Urine alcohol test.
The results of each test maybe entered into the eCRF or transferred electronically.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Potential analysis considerations for analyzing Laboratory data includes the use of 
Standard Reference Ranges and potential transformation of data for specific lab tests. 
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these parameters, the 
measured laboratory test result will be assessed directly using the Roche standard 
reference range. Certain laboratory parameters will be transformed to Roche’s standard 
reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.

Definition of Laboratory Abnormalities
For all laboratory parameters included in the analysis described above, 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.


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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.
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 
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.
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female partner of a male 
participant 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).