A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally Administered RO7234292 (RG6042) in Patients With Manifest Huntington's Disease
Phase: PHASE3
Conditions: Huntingtons Disease
Sponsor: Hoffmann-La Roche

 
Official Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase 
III Clinical Study to Evaluate the Efficacy and Safety of Intrathecally 
Administered RO7234292 (RG6042) in Patients With Manifest 
Huntington's Disease 
NCT Number: NCT03761849 
Document Dates: Protocol Version 6: 02-April-2021 
Protocol Version 4: 16-April-2019 
 
 

RO7234292F. Hoffmann-La Roche Ltd
2/Protocol BN40423, Version 6
PROTOCOL HISTORY
Protocol
Associated Region-Specific Protocols
Version
Date Final
Region
Version
Date Final
6
See electronic date 
stamp on title page



5
5 November 2019



4
16 April 2019



1
18 September 2018
VHP
3
24 January 2019
European Union
2
13 December 2018

RO7234292F. Hoffmann-La Roche Ltd
3/Protocol BN40423, Version 6
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Protocol BN40423 has been amended in accordance with the Urgent Safety Measure 
Dear Investigator Letter issued on 22 March 2021.  A pre-planned review of safety and 
efficacy data from Study BN40423, as well as available open-label data, was conducted 
by the BN40423 independent Data Monitoring Committee (iDMC).  Following review of 
the data, the iDMC has recommended that all dosing (120 mg every 8 weeks [Q8W] and 
every 16 weeks [Q16W] and placebo) in Study BN40423 be stopped.  This iDMC 
recommendation was not based on any new emergent safety concerns, but on a totality 
of evidence indicating that the treatment arms demonstrated unfavorable safety and 
efficacy trends compared to the placebo arm over time.
The iDMC has also made a recommendation for the ongoing patients in the Study 
BN40423 to be followed for safety and efficacy outcomes as per protocol, without study 
drug administration.  Study BN40955 (open-label extension [OLE]) is exploring similar
regimens (i.e, tominersen [RO7234292] 120 mg Q8W and Q16W); therefore, the 
Sponsor has made a decision to pause dosing in the OLE until further data assessments 
can be conducted.
Changes to the protocol, along with a rationale for each change, are summarized below:

Language has been added to indicate that no further study treatment will be 
administered in this study as of 22 March 2021.  Patients on the study will continue 
to be followed for safety and efficacy outcomes until study completion (Sections 1.3, 
3.1.1, 4.5, and 4.6, and Figure 2, and Appendices 1a and 1b).

It has been clarified that neurologic examinations should be performed prior to 
lumbar puncture (LP), if there is no study treatment administration (Sections 3.1.1
and 4.5.3, and Appendices 1a, 1b, and 9).

Language has been added to clarify that patients will no longer be able to enter the 
OLE study (BN40955) after completion of this study (Section 3.1.1).

It has been clarified that all patients in the treatment period will discontinue study 
treatment and enter the early treatment termination (ETT) schedule. The previous 
version of the protocol already described the ETT schedule for following of 
individuals, for safety and efficacy outcomes, who have discontinued the study drug 
but not withdrawn consent for continued study participation (Sections 3.1.1, 4.2, and 
4.6, and Figure 1 and 2). Additional clarification on visits and assessments required 
on the ETT schedule has been provided (Section 3.1.1.1, and Figure 3, and 
Appendices 1a and 1b).

The ETT visit window has been extended from 28 ( 7 days) from last dose to 
within 56 days of the decision to discontinue study treatment (i.e., from 22 March 
2021).  This extension has been made to facilitate scheduling of the ETT visit using 
the existing planned visit schedule (Section 3.1.1.1, and Appendices 1a and 1b).

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
It has been clarified that following the iDMC recommendation to discontinue study 
treatment dosing in this study, the Sponsor will be unblinded to treatment 
assignment, to allow for data analyses to occur, in order to enhance the 
understanding of RO7234292 effects and to inform RO7234292 program next steps 
(Sections 3.1.2, 4.2, and 4.5.9.22).

End of study and length of study have been adjusted, as a result of all patients 
moving to the ETT schedule (Section 3.2).

It has been clarified that patients should not perform any activity that is associated 
with a change in the ambient air pressure for at least 24 hours post lumbar 
procedure, irrespective if study treatment is administered or not (Section 4.5.5, 
Appendices 1a and 1b).

As per protocol, individuals will have an LP at the ETT visit.  Additional safety 
assessments including lumbar puncture and laboratory tests have been added to 
the end of treatment (EoT) assessment for ETT to ensure complete and adequate 
collection of follow-up safety outcomes (Section 4.5.5, Appendices 1a and 1b).

Wording in Section 5.1.1 and Section 5.1.2 has been amended to be consistent with 
the latest available risk data as per the RO7234292 Investigator’s Brochure 
Version 7.

Adverse event reporting period has been clarified, as a result of all patients moving 
to ETT schedule and discontinuing study treatment (Sections 5.3.1 and 5.4.2.2).

RO7234292F. Hoffmann-La Roche Ltd
5/Protocol BN40423, Version 6
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Huntington's Disease.................................... 28
1.2
Background on RO7234292 .................................................. 29
1.3
Study Rationale and BenefitRisk Assessment..................... 31
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
2.1
Efficacy Objectives ................................................................ 32
2.1.1
Primary Efficacy Objective..................................................... 32
2.1.2
Secondary Efficacy Objective................................................ 32
2.1.3
Exploratory Efficacy Objective............................................... 33
2.2
Safety Objective .................................................................... 33
2.3
Pharmacokinetic Objectives .................................................. 34
2.4
Immunogenicity Objectives.................................................... 34
2.5
Biomarker Objectives............................................................. 34
2.5.1
Primary Biomarker Objective................................................. 34
2.5.2
Secondary Biomarker Objective ............................................ 35
2.5.3
Exploratory Biomarker Objective ........................................... 35
2.6
Health Status Utility Objective ............................................... 35
3.
STUDY DESIGN......................................................................................... 36
3.1
Description of the Study......................................................... 36
3.1.1
Overview of Study Design ..................................................... 36
3.1.1.1
Clarification of Existing Study Design for Early 
Treatment Termination (Applicable to all Patients 
from 22 March 2021) ............................................................. 40
3.1.1.2
Study Design Overview for Patients Enrolled 
prior to Implementation of Protocol Version 4........................ 41
3.1.2
Independent Data Monitoring Committee .............................. 45
3.2
End of Study and Length of Study......................................... 45
3.3
Rationale for Study Design.................................................... 45
3.3.1
Rationale for RO7234292 Dose and Schedule...................... 45

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3.3.2
Rationale for Patient Population ............................................ 48
3.3.3
Rationale for Control Group................................................... 48
3.3.4
Rationale for Biomarker Assessments................................... 48
3.3.4.1
Cerebrospinal Fluid Biomarkers ............................................ 48
3.3.4.2
Blood Biomarkers .................................................................. 49
3.3.4.3
Genetic Testing to Determine CAG Repeat 
Length.................................................................................... 49
3.3.4.4
Clinical Genotyping................................................................ 49
3.3.4.5
Magnetic Resonance Imaging ............................................... 49
4.
MATERIALS AND METHODS .................................................................... 50
4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 50
4.1.2
Exclusion Criteria................................................................... 52
4.2
Method of Treatment Assignment and Blinding..................... 54
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 56
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 56
4.3.1.1
RO7234292 ........................................................................... 56
4.3.1.2
Placebo.................................................................................. 56
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 56
4.3.2.1
RO7234292 and Placebo ...................................................... 57
4.3.3
Investigational Medicinal Product Accountability ................... 57
4.3.4
Continued Access to RO7234292 ......................................... 57
4.4
Concomitant Therapy ............................................................ 58
4.4.1
Permitted Therapy................................................................. 58
4.4.2
Prohibited Therapy ................................................................ 59
4.5
Study Assessments ............................................................... 59
4.5.1
Informed Consent Forms and Screening Log........................ 59
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 60
4.5.3
Physical and Neurologic Examinations.................................. 61
4.5.4
Vital Signs.............................................................................. 61

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4.5.5
Collection of Cerebrospinal Fluid (Lumbar 
Puncture Procedure) ............................................................. 61
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 63
4.5.7
Magnetic Resonance Imaging ............................................... 65
4.5.8
Electrocardiograms................................................................ 65
4.5.9
Patient-Reported, Clinician-Reported, Study 
Observer-Reported, and Performance Outcomes ................. 66
4.5.9.1
Composite Unified Huntington's Disease Rating 
Scale...................................................................................... 67
4.5.9.2
Total Functional Capacity Scale ............................................ 67
4.5.9.3
Total Motor Score.................................................................. 67
4.5.9.4
Symbol Digit Modalities Test ................................................. 68
4.5.9.5
Stroop Word Reading Test .................................................... 68
4.5.9.6
UHDRS Functional Assessment............................................ 68
4.5.9.7
Independence Scale.............................................................. 68
4.5.9.8
HD Daily Activities Scale ....................................................... 68
4.5.9.9
Clinical Global ImpressionSeverity and Change 
Scales.................................................................................... 69
4.5.9.10
Patient Global ImpressionSeverity and Change 
Scales.................................................................................... 69
4.5.9.11
Companion-Reported Global 
ImpressionSeverity and Change Scales .............................. 69
4.5.9.12
Montreal Cognitive Assessment ............................................ 70
4.5.9.13
Work Productivity and Activity Impairment............................. 70
4.5.9.14
Apathy Evaluation Scale........................................................ 70
4.5.9.15
Neuro-Qol Cognition Function Short Form, 
Version 2 ............................................................................... 70
4.5.9.16
HD Speaking Difficulty Item ................................................... 70
4.5.9.17
Symptoms of Major Depressive Disorder Scale .................... 71
4.5.9.18
HD Companion-Reported Irritability and Angry 
Outbursts Scale..................................................................... 71
4.5.9.19
EuroQol 5-Dimension, 5-Level Questionnaire ....................... 71
4.5.9.20
Health Utilities Index Mark 2 and Mark 3 ............................... 71
4.5.9.21
Columbia-Suicide Severity Rating Scale ............................... 72
4.5.9.22
Optional Exit Interviews ......................................................... 72

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4.5.9.23
Roche HD Mobile Application:  Remote Testing 
(Smartphone and Wrist-Worn Wearable)............................... 72
4.5.9.24
Roche HD Mobile Application:  In-Clinic 
Assessments ......................................................................... 73
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 74
4.5.10.1
Overview of the Research Biosample Repository.................. 74
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74
4.5.10.3
Sample Collection.................................................................. 74
4.5.10.4
Confidentiality........................................................................ 75
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 76
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 76
4.5.10.7
Monitoring and Oversight....................................................... 76
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 77
4.6.1
Study Treatment Discontinuation........................................... 77
4.6.2
Patient Discontinuation from Study........................................ 78
4.6.3
Study Discontinuation............................................................ 78
4.6.4
Site Discontinuation............................................................... 78
5.
ASSESSMENT OF SAFETY....................................................................... 79
5.1
Safety Plan ............................................................................ 79
5.1.1
Known Risks Associated with Lumbar Puncture.................... 79
5.1.1.1
PostLumbar Puncture Syndrome......................................... 80
5.1.1.2
Spinal Hematoma.................................................................. 81
5.1.1.3
Meningitis .............................................................................. 81
5.1.2
Potential Risks Associated with RO7234292......................... 81
5.1.2.1
Neurologic Changes .............................................................. 81
5.1.2.2
Elevations in CSF WBCs and Protein.................................... 83
5.1.2.3
Thrombocytopenia................................................................. 83
5.1.2.4
Kidney Effects........................................................................ 83
5.1.2.5
Liver Effects........................................................................... 84
5.1.2.6
Hydrocephalus....................................................................... 84

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5.1.2.7
Neuropsychiatric Changes..................................................... 84
5.1.2.8
Potential Risk due to Reduction of Target Protein 
HTT........................................................................................ 85
5.1.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 86
5.1.3.1
Dose Modifications ................................................................ 86
5.1.3.2
Treatment Interruption ........................................................... 86
5.1.3.3
Management Guidelines........................................................ 86
5.2
Safety Parameters and Definitions ........................................ 89
5.2.1
Adverse Events ..................................................................... 89
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 89
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 90
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 91
5.3.1
Adverse Event Reporting Period ........................................... 91
5.3.2
Eliciting Adverse Event Information....................................... 91
5.3.3
Assessment of Severity of Adverse Events ........................... 92
5.3.4
Assessment of Causality of Adverse Events ......................... 92
5.3.5
Procedures for Recording Adverse Events............................ 93
5.3.5.1
Injection Reactions ................................................................ 93
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 93
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 93
5.3.5.4
Persistent or Recurrent Adverse Events................................ 94
5.3.5.5
Abnormal Laboratory Values ................................................. 95
5.3.5.6
Abnormal Vital Sign Values ................................................... 95
5.3.5.7
Abnormal Liver Function Tests.............................................. 96
5.3.5.8
Deaths ................................................................................... 96
5.3.5.9
Preexisting Medical Conditions.............................................. 97
5.3.5.10
Lack of Efficacy or Worsening of Huntington's 
Disease.................................................................................. 97
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 97

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5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 98
5.3.5.13
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 99
5.3.5.14
Safety Biomarker Data........................................................... 99
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 99
5.4.1
Emergency Medical Contacts.............................................. 100
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 100
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 100
5.4.2.2
Events That Occur after Study Drug Initiation...................... 100
5.4.3
Reporting Requirements for Pregnancies............................ 101
5.4.3.1
Pregnancies in Female Patients.......................................... 101
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 101
5.4.3.3
Abortions ............................................................................. 101
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 102
5.5
Follow-Up of Patients after Adverse Events ........................ 102
5.5.1
Investigator Follow-Up......................................................... 102
5.5.2
Sponsor Follow-Up .............................................................. 102
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 102
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 103
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 103
6.1
Analysis Populations ........................................................... 103
6.2
Determination of Sample Size ............................................. 104
6.3
Testing Strategy and Multiplicity Adjustment ....................... 106
6.4
Summaries of Conduct of Study.......................................... 106
6.5
Summaries of Demographic and Baseline 
Characteristics..................................................................... 106
6.6
Efficacy Analyses ................................................................ 106
6.6.1
Estimands............................................................................ 107
6.6.2
Primary Efficacy Analysis .................................................... 108

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6.6.3
Secondary Efficacy Analyses .............................................. 108
6.6.4
Subgroup Analyses ............................................................. 109
6.6.5
Exploratory Efficacy Analysis............................................... 109
6.6.6
Historical Controls ............................................................... 109
6.7
Safety Analyses................................................................... 110
6.8
Pharmacokinetic Analyses................................................... 111
6.9
Immunogenicity Analyses.................................................... 111
6.10
Biomarker Analyses............................................................. 112
6.11
HEALTH STATUS UTILITY Analysis................................... 112
6.12
OPTIONAL Interim AnalysEs............................................... 112
7.
DATA COLLECTION AND MANAGEMENT ............................................. 112
7.1
Data Quality Assurance....................................................... 112
7.2
Electronic Case Report Forms............................................. 113
7.3
Electronic Patient-, Clinician-, and 
Observer-Reported Outcome Data...................................... 113
7.4
Electronic Data Obtained by the Roche HD 
Digital Monitoring Platform................................................... 114
7.5
Source Data Documentation................................................ 114
7.6
Use of Computerized Systems ............................................ 115
7.7
Retention of Records........................................................... 115
8.
ETHICAL CONSIDERATIONS.................................................................. 115
8.1
Compliance with Laws and Regulations .............................. 115
8.2
Informed Consent................................................................ 116
8.3
Institutional Review Board or Ethics Committee.................. 117
8.4
Confidentiality...................................................................... 117
8.5
Financial Disclosure ............................................................ 118
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ................................................................................... 118
9.1
Study Documentation .......................................................... 118
9.2
Protocol Deviations.............................................................. 119
9.3
Management of Study Quality ............................................. 119
9.4
Site Inspections ................................................................... 119
9.5
Administrative Structure....................................................... 119

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Appendix 2
Clinician-Reported Outcomes for Patients Enrolled after 
Implementation of Protocol Version 4 ....................................... 140
Appendix 3
Patient-Reported, Observer-Reported, and Performance 
Outcomes and Roche HD Mobile Application for Patients 
Enrolled after Implementation of Protocol Version 4................. 141
Appendix 4
Clinical Assessments Order and Duration for Patients 
Enrolled after Implementation of Protocol Version.................... 144
Appendix 5
Guidelines for Order of Assessments ....................................... 148
Appendix 6
Grading Scale for Adverse Events Relating to Laboratory 
Abnormalities for All Patients .................................................... 149
Appendix 7
Roche HD Mobile Application for Patients Enrolled after 
Implementation of Protocol Version 4:  Active Test................... 152
Appendix 8
Diagnostic Confidence Level for All Patients............................. 156
Appendix 9
Guidance for Neurological Examination for All Patients............ 157
Appendix 10
Schedule of Activities for Patients Enrolled before 
Implementation of Protocol Version 4 ....................................... 158
Appendix 11 Clinician-Reported Outcomes for Patients Enrolled before 
Implementation of Protocol Version 4 ....................................... 165
Appendix 12
Patient-Reported, Observer-Reported, and Performance 
Outcomes and Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4.............. 166
Appendix 13
Clinical Assessments Order and Duration for Patients 
Enrolled before Implementation of Protocol Version 4.............. 169
Appendix 14 Roche HD Mobile Application for Patients Enrolled before 
Implementation of Protocol Version 4:  Active Test................... 173

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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III CLINICAL 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF INTRATHECALLY ADMINISTERED 
RO7234292 (RG6042) IN PATIENTS WITH 
MANIFEST HUNTINGTON'S DISEASE
PROTOCOL NUMBER:
BN40423
VERSION NUMBER:
6
EUDRACT NUMBER:
2018-002987-14
IND NUMBER:
137873
NCT NUMBER
NCT03761849
TEST PRODUCT:
RO7234292 
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.

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PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PHASE III CLINICAL STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF INTRATHECALLY ADMINISTERED 
RO7234292 (RG6042) IN PATIENTS WITH MANIFEST 
HUNTINGTON'S DISEASE
PROTOCOL NUMBER:
BN40423
VERSION NUMBER:
6
EUDRACT NUMBER:
2018-002987-14
IND NUMBER:
137873
NCT NUMBER
NCT03761849
TEST PRODUCT:
RO7234292
PHASE:
Phase III
INDICATION:
Huntington's disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, pharmacokinetic (PK), and biomarker effects of 
RO7234292 compared with placebo in patients with manifest Huntington's disease (HD).  
Specific objectives and corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of RO7234292 compared 
with placebo on the basis of the following endpoint:

Change from baseline in the composite Unified Huntington's Disease Rating Scale
(cUHDRS) score at Week 101 
Note:  The primary efficacy endpoint for the U.S. Food and Drug Administration (FDA) 
will be change from baseline in the Total Functional Capacity (TFC) score at Week 101 
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of RO7234292 
compared with placebo on the basis of the following endpoints:  

Change from baseline in scores for the following individual scales at Week 101: 
-
TFC 
-
Total Motor Score (TMS)
-
Symbol Digit Modalities Test (SDMT)
-
Stroop Word Reading Test (SWR)
Note:  For the U.S. FDA, the first secondary endpoint will be change from baseline in 
the cUHDRS score at Week 101 instead of TFC, as TFC will be the primary endpoint.

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
Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S) score at 
Week 101

Proportion of patients with a decrease from baseline of 1 point on the TFC at Week 101

Proportion of patients with a decline from baseline of 1.2 points on the cUHDRS at Week 
101

Proportion of patients with an unchanged or improved score on the Clinical Global 
Impression, Change Scale (CGI-C) score from baseline at Week 101
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoints:  

Change from baseline in the Apathy Evaluation Scale (AES) score at Week 101

Change from baseline in the Symptoms of Major Depressive Disorder Scale (SMDDS) 
score at Week 101

Change from baseline in the Huntington's Disease Daily Activities Scale (HD-DAS) score at 
Week 93

Change from baseline in the Patient Global Impression, Severity Scale (PGI-S) score at 
Week 101

Change from baseline in the Quality of Life in Neurological Disorders (Neuro-Qol) Cognition 
Function Short Form at Week 101

Change from baseline in the Huntington's Disease Speaking Difficulty Item Scale (HD-SDI) 
score at Week 101

Change from baseline in the Huntington's Disease Companion-Reported Irritability and 
Angry Outbursts Scale (HD-CIAOS) score at Week 101

Change from baseline in the in-clinic patient-reported EuroQol 5-Dimension Questionnaire 
(5-level version; EQ-5D-5L) index-score and visual analogue scale (VAS) at Week 101

Change from baseline in the sensor-based measures collected by the Roche HD mobile 
application (app; smartphone and wrist-worn wearable) at Week 101
Safety Objective
The safety objective for this study is to evaluate the safety and tolerability of RO7234292 
compared with placebo on the basis of the following endpoints: 

Incidence and severity of adverse events, with severity determined according to the 
Adverse Event Severity Grading Scale

Change from baseline in Montreal Cognitive Assessment (MoCA)

Change from baseline in vital signs 

Change from baseline in ECG parameters

Change from baseline in clinical laboratory results

Proportion of patients with suicidal ideation or behavior, as assessed by Columbia-Suicide 
Severity Rating Scale (C-SSRS) score at each visit, including detailed focus on any 
individual cases identified as having severe ideation or behavior during the study conduct
Pharmacokinetic Objectives
The PK objective for this study is to characterize the RO7234292 PK profile in plasma and 
trough CSF on the basis of the following endpoints:

Concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints

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The exploratory pharmacokinetic/pharmacodynamic (PK/PD) objective for this study is to 
evaluate potential relationships between drug exposure and the efficacy and safety of 
RO7234292 on the basis of the following endpoints:

Relationship between plasma profiles and/or trough CSF concentrations of PK parameters 
for RO7234292 and efficacy endpoints 

Relationship between plasma profiles and/or trough CSF concentrations of PK parameters 
for RO7234292 and safety endpoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to RO7234292
on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence 
of ADAs at baseline

Titer and antibody subtype, determined if ADAs are identified
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objectives
Primary Biomarker Objective
The primary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoint:

Change from baseline in CSF mHTT protein level at Week 101
Secondary Biomarker Objective
The secondary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoints:

Change from baseline in whole and regional brain volumes (caudate, whole brain, and 
ventricular), as determined by structural magnetic resonance imaging (MRI), at Week 101

Change from baseline in CSF neurofilament light chain (NfL) protein level at Week 101
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to RO7234292 (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), are 
associated with acquired resistance to RO7234292, are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring or investigation 
(i.e., safety biomarkers), can provide evidence of RO7234292 activity (i.e., PD biomarkers), or 
can increase the knowledge and understanding of disease biology and drug safety, on the basis 
of the following endpoints:

Relationship between biomarkers in blood, plasma, and CSF and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers (e.g., putamen, cortical grey matter, cortical 
white matter volumes, resting state functional MRI signal) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with RO7234292 on the basis of the following endpoint:

Change from baseline in patient- and companion-reported EQ-5D-5L Index and VAS scores 
at specified timepoints 

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
Change from baseline in companion self-reported and proxy-reported Health Utilities Index 
Mark 2 (HUI2) and Mark 3 (HUI3) scores at specified timepoints

Change from baseline in patient- and companion-reported Work Productivity and Activity 
Impairment (WPAI) scores at specified timepoints 
Study Design
Description of Study
Study BN40423 is a Phase III, randomized, placebo-controlled, double-blind, multicenter clinical 
study to evaluate the efficacy, safety, PK, and biomarker effects of intrathecally administered 
RO7234292 in patients with manifest HD. 
Effective 22 March 2021, no further study treatment will be administered in this study.
Patients on the study will continue to be followed for safety and efficacy outcomes until study 
completion.
Prospective patients will undergo screening assessments during a 4-week screening period.  A 
maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for 
patients who fail the initial screening.  If re-screening is required, the CAG repeat length testing 
from the initial screening does not need to be repeated (historical values prior to screening will 
not be accepted).  The screening MRI and viral serology from the initial screening, including 
from other Roche RO7234292 studies, may be acceptable as part of the re-screening 
assessments if performed within 12 weeks of the baseline visit.
Upon completion of the screening period, eligible patients will be randomly allocated in a 
1:1:1 ratio to receive RO7234292 every 8 weeks (Q8W; RO7234292 Q8W arm), RO7234292 
every 16 weeks (Q16W; RO7234292 Q16W arm), or placebo Q8W (placebo arm) by IT 
injection.  To maintain the study blind and integrity, patients in the RO7234292 Q16W arm will 
also receive placebo (i.e., alternating doses of active drug and placebo).
During scheduled clinic visits, patients will undergo safety and tolerability evaluations that 
include neurologic examinations, vital signs, ECGs, clinical laboratory tests, MoCA, C-SSRS, 
neuroimaging assessments (neurologic safety sequences), and a review of any adverse events 
including related concomitant medications, as detailed in the schedule of activities.  Patients in 
Japan must be monitored in the hospital setting for at least 24 hours after Day 1 study drug 
administration.  Discharge will be determined at the discretion of the principal investigator.
In the case of a failed IT bolus dosing procedure or a failed CSF collection procedure (e.g., due 
to an inadequate establishment of access to the IT space), a second attempt may occur up to 7 
days after the originally scheduled attempt.  For this additional visit, safety and tolerability 
evaluations on the day of LP administration will be performed as detailed in the protocol, 
including neurological examination (predose and postdose, or pre-procedure if no study 
treatment is being administered), vital signs, and a review of adverse events and concomitant 
medication.  If the second attempt occurs more than 3 days after the first attempt, local 
laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets need to be 
conducted again and results reviewed prior to the LP attempt.
During the treatment period, a telephone safety follow-up call will be conducted for the months 
in which no clinic visits are scheduled to check for any change in patient status (i.e., adverse 
events, concomitant medications) since the patient’s last visit.  Where deemed appropriate, an 
unscheduled clinic visit should be arranged for safety follow-up; no dosing will occur at these 
unscheduled visits. A safety follow-up telephone call will also be conducted approximately 2 
months after the last in-clinic visit at Week 101.
Effective 22 March 2021, all patients will discontinue study treatment and will no longer be 
able to enter the OLE study (BN40955) after completing this study.
For patients enrolled in Study BN40423 who discontinue study treatment prematurely, but do 
not withdraw consent for continued participation in the study, an ETT schedule will apply.  
An independent Data Monitoring Committee (iDMC) and independent Data Coordinating Center 
(iDCC) will be employed to monitor and evaluate patient safety throughout the study as well as 
to evaluate evidence of early efficacy.  
Clarification of Existing Study Design for Early Treatment Termination (Applicable to all 
Patients from 22 March 2021)

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Following the iDMC recommendation and Sponsor’s decision to discontinue study treatment 
in this study, as of 22 March 2021, all patients will transition to the existing ETT schedule.
All patients who discontinue study treatment prematurely but do not withdraw consent for 
continued participation in the study, will return to the clinic for the following visits as part 
of the ETT schedule:

ETT visit to be performed within a maximum of 56 days of the decision to discontinue 
study treatment.

Follow-up study visits at Weeks 53 and 69 (if not already completed) for collection of 
clinical outcome data for the primary and secondary endpoints.  If the ETT visit falls 
within 30 days of either scheduled visits at Week 53 or Week 69, then only the ETT 
visit should be performed.

End-of-treatment (EoT) visit at Week 101 (EoT for ETT).
Therefore, after discontinuation of study treatment, patients will attend a minimum of two 
and up to four in-clinic visits depending on which visits have already been completed at the 
time of study drug discontinuation.
After discontinuation of study treatment, telephone safety follow-up calls will be conducted 
every 8 weeks between the clinic visits to check for any change in patient status (i.e., adverse 
events, concomitant medications) since the patient’s last visit.  Where deemed appropriate, an 
unscheduled clinic visit should be arranged for safety follow-up.
For patients consented to version 6 of the protocol, who received their last dose of study 
treatment less than 5 months before the scheduled Week 101 EoT for ETT visit, an additional 
safety telephone call should be performed 5 months after the last dose.
Study Design Overview for Patients Enrolled prior to Implementation of Protocol Version 4
All patients enrolled in Study BN40423 prior to implementation of the Version 4 protocol 
amendment will be prematurely discontinued by the Sponsor from this study and will be offered 
treatment in the OLE Study BN40955, once approval has been granted by the relevant 
competent authority and ECs/IRBs.  
Patients who choose to enroll in the OLE will complete an end-of-treatment visit in 
Study BN40423, which can also serve as the inclusion visit for Study BN40955.  All patients 
who are prematurely discontinued by the Sponsor who choose not to consent to Study 
BN40955 will additionally undergo safety follow-up telephone call approximately 2 months after 
the last dose and a 5-month postdose safety follow-up visit. 
Number of Patients
Approximately 801 patients with HD will be enrolled in this global study from the implementation 
of Protocol Version 4 and onwards.  This is in addition to patients who enrolled prior to Version 
4, who will be discontinued from this study and offered participation in OLE Study BN40955.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at baseline prior to randomization and study drug dosing):

Signed Informed Consent Form

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form and at the time 
of first dose administration

Manifest HD diagnosis, defined as a diagnostic confidence level (DCL) score of 4 

Independence Scale (IS) score 70 

Genetically confirmed disease by direct DNA testing with a CAP score 400 (Zhang et al. 
2011), calculated as follows:
CAP Age (CAG repeat length 33.66)

Ability to read the words "red," "blue," and "green" in native language

Ability to walk unassisted without a cane or walker and move about without a wheelchair on 
a daily basis as determined at screening and baseline visit

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-
Long-distance (e.g., 50 meters) use of wheelchairs for convenience or transfer is
permitted.

Body mass index 1632 kg/m2; total body weight 40 kg

Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no severe chorea or 
other condition that precludes MRI scans or renders scanning intolerable for the patient, no 
MRI-incompatible intrauterine devices, metallic dental braces, or other metal implants)

Ability to tolerate blood draws and lumbar punctures

Creatinine clearance (CrCl) 60 mL/min (Cockcroft-Gault formula)

Ability and willingness, in the investigator's judgment, to comply with all aspects of the 
protocol including completion of interviews and questionnaires for the duration of the study 

Ability and willingness, in the investigator's judgment, to carry a smartphone, wear a digital 
monitoring device, and complete smartphone-based tasks

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to screening 
and at the time of enrollment

Signed study companion consent for participation who fulfills all of the following criteria:
-
Age 18 years
-
Reliable and competent, in the investigator's judgment
-
Sufficiently knowledgeable of the patient's condition to complete study companion 
assessments of the patient, and likely to remain sufficiently knowledgeable throughout 
the study, in the investigator's judgment
-
Able to comment on study participant's symptoms and functioning experience
-
Able and willing to attend in person all clinical visits for completion of companion 
assessments and for input into the clinician-rated TFC scale
Note:  Companions must have no cognitive, behavioral or motor change, in the opinion 
of the investigator, that would question the validity of the acquired observer-reported 
data.
All effort should be made to retain the study companion; however, should this not be 
possible, a study companion should be replaced and new consent obtained. 
A study companion is required for all patients who enroll after implementation of 
Version 5 of the protocol. The companion is optional but highly recommended for 
patients who enrolled under Protocol Versions 14.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, as defined below:
Women must remain abstinent or use two methods of contraception, including at least 
one method with a failure rate of 1% per year, during the treatment period and for 5 
months after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.  A vasectomized man must undergo a medical 
assessment that confirms the success of the surgery before he can be considered 
surgically sterile.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

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For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 5 months after 
the final dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that 
required hospital visit and/or change in level of care within 12 months prior to screening
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
investigator.  If suicidal ideation is present, a risk assessment should be done by an 
appropriately qualified mental health professional to assess whether it is safe for the 
patient to participate in the study.  Mild passive suicidal ideation (i.e., occasional 
thoughts that life is not worth living or is hard) without history of attempts or 
hospitalization over the past 12 months is generally acceptable for study participation, 
but final decision on participation should be made carefully and in consultation with an 
appropriately qualified mental health professional. 

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, or vital sign abnormality or 
claustrophobia at screening that, in the investigator's judgment, precludes the patient's safe 
participation in and completion of the study

History known to the investigator or presence of an abnormal ECG that is clinically 
significant in the investigator's opinion, including complete left bundle branch block, second-
or third-degree atrioventricular heart block, or evidence of prior myocardial infarction

Lifetime clinical diagnosis of chronic migraines

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
5 months after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test result at 
screening and a confirmatory urine pregnancy test prior to initiation of study drug.  

Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter

Positive for hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) at screening

Known HIV infection

Current or previous use of an antisense oligonucleotide (including small interfering RNA)

Current or previous use of anti-psychotics prescribed for a primary independent psychotic 
disorder (i.e., schizophrenia, schizoaffective disorder, bipolar disorder type I, severe with 
psychotic features), cholinesterase inhibitors, memantine, amantadine, or riluzole within 
12 weeks from initiation of study treatment

Current use of antipsychotics for motor symptoms or mood stabilization (i.e., irritability or 
aggressive behavior) and/or tetrabenazine, valbenazine, or deutetrabenazine at a dose that 
has not been stable for at least 12 weeks prior to screening or is anticipated to change 
between screening and treatment initiation

Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose that has not 
been stable for at least 6 weeks prior to screening or is anticipated to change during the 
study

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
Current use of an antidepressant or benzodiazepine at a dose that has not been stable for 
at least 12 weeks prior to screening or is anticipated to change between screening and 
treatment initiation

Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives prior to 
screening, whichever is longer

Antiplatelet or anticoagulant therapy within 14 days prior to screening or anticipated use 
during the study, including, but not limited to, aspirin (unless 81 mg/day), clopidogrel, 
dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban

History of bleeding diathesis or coagulopathy

Platelet count less than the lower limit of normal  
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as the 
investigator confirms there is no evidence of current bleeding diathesis or 
coagulopathy.  

History of gene therapy, cell transplantation, or any experimental brain surgery

Concurrent or planned concurrent participation in any interventional clinical study, including 
explicit pharmacological and non-pharmacological interventions (e.g., lumbar puncture)
Observational studies (e.g., ENROLL-HD prospective study) are acceptable. 

Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse or 
psychological or physiological dependency within 12 months prior to screening, as per the 
investigator's judgment
Abuse is defined as a maladaptive pattern of use that leads to failure to fulfill major 
work or social obligations or use in situations where it leads to physical danger or legal 
problems, and may be the focus of clinical attention.  

Poor peripheral venous access

Scoliosis or spinal deformity or surgery making IT injection not feasible in an outpatient 
setting and potentially interfering with distribution of RO7234292 up the neuraxis

An infection requiring oral or IV antibiotics within 14 days prior to screening and prior to 
randomization

Antiretroviral medications, including antiretroviral medication taken as prophylaxis within 
12 months of study enrollment

Malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been successfully treated

Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous malformation, 
meningiomas) as assessed by a centrally read MRI scan during the screening period
End of Study
The end of this study is defined as the date when the last patient, last visit occurs.  The end of 
the study is expected to occur approximately 101 weeks (25 months) after the last patient is 
enrolled.  
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years, however following the decision to stop study 
treatment, the total length of the study, from screening of the first patient to the end of the 
study, is now expected to be approximately 4 years.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are RO7234292 and RO7234292 
placebo. 
Test Product (Investigational Drug)
RO7234292 will be supplied by the Sponsor as sterile, preservative-free liquid in a 20-mL 
single-use vial containing 10 mL of 6.0 mg/mL RO7234292 drug product for IT injection. For a 

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120-mg dose (20-mL dosing volume), two vials containing 10 mL of 6.0 mg/mL RO7234292 will 
be pooled by drawing them up into the same injection syringe containing 20 mL of study drug.
For information on the formulation, preparation, and handling of RO7234292, refer to the 
pharmacy manual.
Placebo
RO7234292 placebo will be supplied by the Sponsor as a sterile, preservative-free liquid in a 
20-mL single-use vial containing 10 mL RO7234292 placebo drug product for IT injection.  The 
liquid is no different in color than the active drug.
For a 20 mL dosing volume, two vials containing 10 mL of RO7234292 placebo will have to be 
pooled by drawing them up into the same injection syringe containing 20 mL of placebo drug 
product.
For information on the formulation, preparation, and handling of RO7234292 placebo, refer to 
the pharmacy manual.
Statistical Methods
Primary Analysis
The primary efficacy endpoint is the change from baseline in cUHDRS score at Week 101.  This 
is defined as the attribute "variable" of the primary estimand.
Note: The primary efficacy endpoint for the U.S. FDA will be change from baseline in the TFC 
score at Week 101.  TFC will be analyzed the same way as the cUHDRS.
The primary efficacy analysis for this study will compare each active treatment arm, RO7234292 
Q8W and RO7234292 Q16W, against the placebo arm. To account for the multiple 
comparison, an appropriate procedure will be used to maintain the overall two-sided type I error 
at 5% (details will be given in the SAP). 
The analysis of the primary endpoint will be performed by means of analysis of covariance
(ANCOVA).  The model will include the corresponding endpoint baseline score, CAG repeat 
length, baseline CAP score, and treatment as covariates; the final list of covariates will be 
defined in the SAP.  On the basis of this analysis, least squares mean for the treatment 
differences at Week 101 and corresponding 95% CIs will be derived.  
The robustness of the primary method of estimation described above may be explored by 
alternative sensitivity estimators based on varying assumptions underlying the multiple 
imputation strategy. These sensitivity analyses will be described in the SAP.
Determination of Sample Size  
The planned sample size is adequate to capture meaningful clinical decline on both the TFC 
and cUHDRS and was estimated on the basis of data available from non-interventional studies 
(TRACK-HD, COHORT, ENROLL-HD) and a randomized placebo-controlled study (2CARE).  
Based on these data, using the anticipated trial population, a meta-analysis for the change from 
baseline at 24 months in TFC score suggested a natural decline of 1.36 points and a 
corresponding pooled standard deviation of 1.78.  A conservative treatment discontinuation rate 
at Week 101 for patients receiving placebo or active is assumed to be 20% and 15%, 
respectively.  Using these assumptions, the simulation described in the protocol was performed 
to estimate the sample size.  
It was estimated that 267 patients per arm will provide approximately 80% power, at a two-sided 
0.025 level, to detect a 40% slowing of clinical decline for RO7234292 as compared with 
placebo at 101 weeks.  This treatment effect translates into an expected average decline of 
~0.82 points at 101 weeks for the RO7234292 arms.  The minimal detectable difference with 
these assumptions is ~0.38 points.  
Optional Interim Analyses
The Sponsor may choose to conduct one or more interim analyses for efficacy.  Below are the 
specifications in place to ensure the study continues to meet the highest standards of integrity 
when an optional interim analysis is executed.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis will be 
conducted by an iDCC and reviewed by the iDMC.  Interactions between the iDMC and Sponsor 
will be carried out as specified in the iDMC Charter.

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The decision to conduct an interim analysis, along with the rationale, specification of the 
endpoint (e.g., clinical and/or biomarker endpoint), number of patients, and statistical details for 
each analysis, will be introduced via a future protocol amendment, which will be submitted to 
relevant health authorities at least 2 months prior to the conduct of the interim analysis.  The 
iDMC Charter will document potential recommendations the iDMC can make to the Sponsor as
a result of an interim analysis, and the iDMC Charter will be made available to relevant health 
authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of an interim 
analysis of efficacy data, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Additional criteria for recommending that the study be stopped for positive efficacy 
will be added to a future protocol amendment.  

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ANCOVA
analysis of covariance
AES
Apathy Evaluation Scale
app
application
ASO
antisense oligonucleotide
CAP
CAGAge Product
CGI-C
Clinical Global ImpressionChange
CGI-S
Clinical Global ImpressionSeverity
ClinRO
clinician-reported outcome
CrCl
creatinine clearance
CrGI-C
Companion-Reported Global ImpressionChange
CrGI-S
Companion-Reported Global ImpressionSeverity
CSF
cerebrospinal fluid 
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
cUHDRS
composite Unified Huntington's Disease Rating 
Scale
DCL
diagnostic confidence level
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
EMA
European Medicines Agency
FDA
Food and Drug Administration
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HD
Huntington's disease
HD-CIAOS
Huntington's Disease Companion-Reported 
Irritability and Angry Outbursts Scale
HD-DAS
Huntington's Disease Daily Activities Scale
HDID
Huntington's Disease Identification Number
HD-SDI
Huntington's Disease Speaking Difficulty Item
HIPAA
Health Insurance Portability and Accountability Act

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Abbreviation
Definition
HRQoL
health-related quality of life
HTT
huntingtin (gene)
HTT
huntingtin (protein)
HUI
Health Utilities Index
HUI2
HUI Mark 2
HUI3
HUI Mark 3
ICE
intercurrent event
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IS
Independence Scale
IT
intrathecal
ITT
intent-to-treat (population)
IxRS 
interactive voice or web-based response system 
LP
lumbar puncture
mHTT
mutant huntingtin (protein)
MoCA
Montreal Cognitive Assessment
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
Neuro-Qol
Quality of Life in Neurological Disorders
NfL
neurofilament light chain (protein)
NRS
numeric rating scale
NSDR
nonstudy drugrelated (reasons)
ObsRO
observer-reported outcome
OLE
open-label extension
PD
pharmacodynamic
PerfO
performance outcome
PGI-C
Patient Global ImpressionChange
PGI-S
Patient Global ImpressionSeverity
PK
pharmacokinetic
PRO
patient-reported outcome
Q4W
every 4 weeks

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Abbreviation
Definition
Q8W
every 8 weeks
Q16W
every 16 weeks
QTc
corrected QT interval
RBR
Research Biosample Repository
SAP
Statistical Analysis Plan
SDMT
Symbol Digit Modalities Test
SDR
study drugrelated (reasons)
SMDDS
Symptoms of Major Depressive Disorder Scale
SWR
Stroop Word Reading
TFC
Total Functional Capacity Scale
TMS
Total Motor Score
UHDRS
Unified Huntington's Disease Rating Scale
VAS
visual analogue scale
WES
whole exome sequencing
WGS
whole genome sequencing
WPAI
Work Productivity and Activity Impairment
wtHTT
wild-type huntingtin (protein)

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1.
BACKGROUND
1.1
BACKGROUND ON HUNTINGTON'S DISEASE
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused 
by expansion of CAG repeats in exon 1 of the Huntingtin HTT gene on chromosome 4, 
which encodes for a mutant huntingtin (mHTT) protein.  Based upon nonclinical and 
clinical evidence, mHTT is considered the primary driver of HD pathophysiology 
(Wild and Tabrizi 2017).  Individuals who carry at least 40 CAG repeats inevitably 
experience progressive motor, cognitive, and functional decline usually in adult life, with 
a mean age of motor onset of 45 years.  The average illness course postmotor onset is 
approximately 1020 years, with pneumonia, heart failure, or other complications
frequently cited as the cause of death (Sorensen and Fenger 1992).  Individuals with 
end-stage disease have complete physical disability and profound body wasting.  
The estimated prevalence of HD in North America, northwestern Europe, and Australia 
ranges from 5.96 to 13.17 cases per 100,000 (Baig et al. 2016).  Although genetic 
testing can be used to identify individuals who will develop the disease, the diagnosis of 
HD is clinical through neurologic examination of the motor system.  The clinical 
diagnosis of HD is made when the patient exhibits "unequivocal presence of an 
otherwise unexplained extrapyramidal movement disorder" (e.g., chorea, dystonia, 
bradykinesia, rigidity) or "motor onset" (Huntington Study Group 1996;
Hogarth et al. 2005).  Motor onset is typically confirmed through use of the 15-item motor 
examination of the Unified Huntington's Disease Rating Scale (UHDRS).  After 
completion of the examination, a certified motor rater assigns a diagnostic confidence 
level (DCL) score.  Scores range from 0 to 4, with 0 representing no impairment and 
4 representing unequivocal motor signs of HD (99% confidence).  Among the 
considerable clinical phenotypic heterogeneity of the disease, motor onset is one of the 
more robust and consistently-agreed-upon disease features.  Behavioral features, 
including emotional disorders and personality changes, do not have a uniform 
presentation, are episodic in nature, and do not usually progress steadily over time 
(Ross et al. 2014).  
Individuals with HD can be categorized as having either premanifest disease (diagnosed 
prior to motor onset) or manifest disease (diagnosed on the basis of motor onset).  The 
premanifest disease period can be subdivided into presymptomatic and prodromal
periods.  During the presymptomatic period, from birth to young adulthood, individuals 
are not clinically distinguishable from controls.  During the prodromal period, which can 
last many years before threshold clinical motor diagnosis, subtle motor changes and 
variable cognitive and behavioral changes appear but are not sufficient to make the 
clinical diagnosis of HD. 
The manifest disease period can be subdivided into five stages based on functional 
capacity (Ross et al. 2014).  Stage 1 represents the highest level of capacity and is 
characterized by mild or no incapacity in terms of independence in daily activities.  

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Stage 5 represents severe disability and dependence on full-time care (Shoulson and 
Fahn 1979).  The five clinical stages are defined by the score on the UHDRS Total 
Functional Capacity (TFC) Scale, with Stage 1 corresponding to TFC scores of 1113, 
Stage 2 to scores of 710, Stage 3 to scores of 36, Stage 4 to scores of 12, and 
Stage 5 to a score of 0 (Shoulson et al. 1979).  
Currently approved treatments aim to reduce the burden of symptoms, maximize 
function, and improve the patient's quality of life (Nance et al. 2011).  Tetrabenazine and 
deutetrabenazine target abnormal involuntary movements (i.e., chorea) associated with 
HD, and these symptomatic therapies have a challenging benefitrisk profile.  These 
drugs have been linked to many significant adverse events, including parkinsonism, 
akathisia, sedation, and depression and suicidal thoughts.  They are contraindicated in 
patients who are actively suicidal and in patients with untreated or inadequately treated 
depression.  Additionally, they may prolong the corrected QT interval (QTc), and caution 
is advised when used in combination with other drugs or medical conditions that 
potentially prolong the QTc.
Other medications are utilized in HD to address particular symptoms, such as 
antidepressants (for depression, agitation, irritability), anticonvulsants (for irritability, 
impulsive behavior), anxiolytics (for anxiety), cognitive-enhancing agents (for cognitive 
disturbances), and neuroleptics (for chorea) (Paulson and Albin 2011).  
To date, there are no approved treatments able to slow or stop the clinical progression
of HD.  
1.2
BACKGROUND ON RO7234292
Neuropathological abnormalities in HD appear to be the consequence of a toxic 
gain of function of the mHTT protein (Wexler et al. 1987; Walker 2007; 
Moumné et al. 2013).  Therefore, a therapy that reduces synthesis of the toxic mHTT
protein should directly target the primary disease mechanism.  As the genetic origin of 
HD is localized to just one gene, inhibiting the expression of this HTT gene is a 
promising therapeutic option (Stanek et al. 2013).
RO7234292 (RG6042) was originally developed by Ionis Pharmaceuticals, Inc. and was 
formerly known as ISIS443139 and IONIS-HTTRx.  This antisense 
oligonucleotide (ASO) is being developed to reduce the synthesis of all forms of the HTT
protein by targeting the HTT mRNA from both the wild-type and the mutant alleles and 
directing its catalytic degradation through the action of ribonuclease H1, an endogenous 
enzyme present in most mammalian cells (Crooke and Bennett 1996; Cerritelli and 
Crouch 2009), including cells of interest in the CNS (e.g., neurons and neuroglia).  
Reduction of the HTT gene mRNA, which in turn limits translation of the wild-type and 
mutant huntingtin protein, could potentially inhibit all downstream toxic effects and lead 
to a sustained reversal in HD symptoms.

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Pharmacology data support selective targeting of HTT mRNA transcripts from both 
alleles as a potentially safe and effective mechanism for the treatment of HD.  Using 
ASOs targeting human HTT mRNA in rodents and non-human primates, significant 
reduction of mutant HTT mRNA transcripts, wild-type HTT mRNA transcripts, and mHTT
protein has been achieved throughout most brain regions (Kordasiewicz et al. 2012).  
Furthermore, transient delivery of these ASOs in transgenic mouse models of HD
delayed disease progression and mediated a sustained reversal of disease phenotype 
that persisted longer than HTT mRNA knockdown (Kordasiewicz et al. 2012; Stanek et 
al. 2013).  
Nonclinical proof-of-concept studies with ASOs targeting mutant HTT have been 
conducted in three models of HD, including YAC128 mice expressing the full-length 
mutant human HTT transgene with a 128 CAG repeat expansion, bacterial artificial 
chromosome (BAC)HD mice expressing the full-length mutant human HTT genomic 
sequence with 97 CAG/CAA repeats, and R6/2 mice expressing exon 1 of the mutant 
human HTT gene with 110135 CAG repeats.  These studies demonstrate that ASOs 
targeting human HTT mRNA improve motor function and protect against human HTT
transgene expression in YAC128 mice; improve motor function, hypoactivity, and stress 
response in BACHD mice; and preserve striatal volume and increase survival in R6/2 
mice.
The pharmacokinetics and toxicity of intrathecal (IT) administration of RO7234292, an 
ASO that targets human HTT mRNA, were assessed in cynomolgus monkeys for 
13 weeks (biweekly for the first month and then monthly thereafter) at dose levels up to 
50 mg/dose (5 bolus administrations, for a total dose of 250 mg) and chronically for 
9 months, up to 35 mg/dose (10 bolus monthly administrations for a total dose of 
350 mg).  The drug was safe and well tolerated in these studies.
In a first-in-human, Phase I/IIa double-blind, placebo-controlled, dose-escalation study 
(Clinicaltrials.gov Identifier NCT02519036) (ISIS 443139-CS1) four doses of RO7234292 
(ranging from 10 mg to 120 mg) were well tolerated and achieved significant 
dose-dependent lowering of cerebrospinal fluid (CSF) mHTT protein when administered 
intrathecally every 4 weeks (Q4W; monthly) to 46 patients with early manifest HD.  
Exploratory analyses identified a relationship between lowering of mHTT protein and 
improvement in some clinical measures.  Taken together, these data support further 
clinical testing to demonstrate definitive clinical benefit of mHTT protein reduction in the 
CNS. The data from this study also supported the initiation of Study ISIS 443139-CS2 
(Study BN40697; Clinicaltrials.gov Identifier NCT03342053), a 15-month, Phase II,
open-label extension (OLE) study for patients who participated in Study ISIS 443139-
CS1.  
Preliminary data from an analysis conducted when all individuals in Study BN40697 had 
reached 9 months of treatment showed that a 120 mg every-8-week (Q8W; every 
2 months) dosing regimen of RO7234292 achieved a 47% median CSF mHTT lowering 

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at trough (i.e., sample taken immediately before the next dose) and the 120 mg Q4W 
dosing regimen achieved a 66% median lowering at trough.  Both results exceed the 
20%40% target for CSF mHTT lowering at trough and steady state based upon efficacy 
data from nonclinical models, and exceed the result of approximately 40% median 
lowering observed in the completed Phase I/IIa study. Details on the most recent 
information from nonclinical and clinical studies can be found in the RO7234292
Investigator's Brochure.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Presently, there are no therapies available to stop or slow the clinical progression of HD, 
which is relentless until patients experience premature death.  The ASO RO7234292 is 
designed to target the cause of HD and offers the potential to meet this unmet medical 
need.  
To date, nonclinical and clinical data support further investigation of RO7234292 in 
patients with manifest HD.  Building on the completed Phase I/IIa study and the ongoing 
Phase II OLE study, this Phase III, double-blind, placebo-controlled study (BN40423) will 
collect longer-term clinical efficacy and safety data to definitively evaluate the benefit 
and potential risks of RO7234292 when administered by IT bolus injection Q8W or every 
16 weeks (Q16W; every 4 months) over a 25-month (2-year) period to patients with 
manifest HD.  
Review of safety and tolerability 9-month data for RO7234292 from the Phase II OLE 
suggests that, relative to the Q4W treatment regimen, the Q8W treatment regimen may 
be more suitable for chronic IT dosing, as evidenced by improved adherence to the less 
frequent regimen.  This is supported by observations of fewer overall adverse events, 
decreased proportion of patients with moderate adverse events, and fewer adverse 
events considered possibly related to study drug in the Q8W regimen compared to the 
Q4W regimen (for details see the RO7234292 Investigator’s Brochure).
There have been no acute safety concerns meriting a change to the ongoing Phase II 
OLE study protocol (BN40697).  However, given the 9-month CSF mHTT results, which 
suggest a longer than anticipated duration of effect of RO7234292 on CSF mHTT 
lowering, it is not necessary to use a Q4W paradigm to test the dose rationale.   As a 
result, the results from OLE Study BN40697 justify a change in Study BN40423 to 
explore less frequent dosing regimens by continuing the Q8W RO7234292 and placebo 
arms, and replacing the Q4W arm with a Q16W arm.
The existing dose rationale tests a more frequent dosing regimen (i.e., 120 mg Q8W), 
which from present data is anticipated to maintain trough CSF mHTT reduction of at 
least ~40%, and a less frequent regimen (i.e., 120 mg Q16W), which is still anticipated to 
lower mHTT acutely, but will allow greater recovery of HTT levels between doses.  From 
present data, trough CSF mHTT reduction of ~25% are predicted to be maintained in a 
120-mg Q16W paradigm.  

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A pre-planned review of safety and efficacy data from Study BN40423, as well as 
available open-label data, was conducted by the BN40423 independent Data Monitoring 
Committee (iDMC). Following review of the data, the iDMC recommended that all 
dosing (120 mg Q8W and Q16W and placebo) in Study BN40423 be stopped. This 
iDMC recommendation was not based on any new emergent safety concerns, but on a 
totality of evidence indicating that the treatment arms demonstrated unfavorable safety 
and efficacy trends compared to the placebo arm over time. The iDMC also made a 
recommendation for the ongoing patients in the Study BN40423 to be followed for 
safety and efficacy outcomes as per protocol, without study drug administration.
As a result of iDMC’s recommendation and Sponsor’s decision, effective 22 March 
2021, no further study treatment will be administered in this study. Patients on the 
study will continue to be followed for safety and efficacy outcomes until study 
completion (see Section 3.1.1.1, Appendix 1a, and Appendix 1b).
The known potential risks related to lumbar punctures are elaborated, along with 
mitigation measures, in Section 5.1.  
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, pharmacokinetic (PK), and biomarker effects
of RO7234292 compared with placebo in patients with manifest HD.  Specific objectives 
and corresponding endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoint:

Change from baseline in the composite Unified Huntington's Disease Rating Scale
(cUHDRS) score at Week 101 
Note:  The primary efficacy endpoint for the U.S. Food and Drug Administration 
(FDA) will be change from baseline in the TFC score at Week 101.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of RO7234292 
compared with placebo on the basis of the following endpoints:  

Change from baseline in scores for the following individual scales at Week 101: 
-
TFC
-
Total Motor Score (TMS)
-
Symbol Digit Modalities Test (SDMT)
-
Stroop Word Reading (SWR) Test

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Note:  For the U.S. FDA, the first secondary endpoint will be change from 
baseline in the cUHDRS score at Week 101 instead of TFC, as TFC will be the 
primary endpoint.

Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S) 
score at Week 101

Proportion of patients with a decrease from baseline of 1 point on the TFC at 
Week 101

Proportion of patients with a decline from baseline of 1.2 points on the cUHDRS at 
Week 101

Proportion of patients with an unchanged or improved score on the Clinical Global 
Impression, Change Scale (CGI-C) score from baseline at Week 101
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoints:  

Change from baseline in the Apathy Evaluation Scale (AES) score at Week 101

Change from baseline in the Symptoms of Major Depressive Disorder Scale 
(SMDDS) score at Week 101

Change from baseline in the Huntington's Disease Daily Activities Scale (HD-DAS) 
score at Week 93

Change from baseline in the Patient Global Impression, Severity Scale (PGI-S) 
score at Week 101

Change from baseline in the Quality of Life in Neurological Disorders (Neuro-Qol) 
Cognition Function Short Form at Week 101

Change from baseline in the Huntington's Disease Speaking Difficulty Item Scale 
(HD-SDI) score at Week 101

Change from baseline in the Huntington's Disease Companion-Reported Irritability 
and Angry Outbursts Scale (HD-CIAOS) score at Week 101

Change from baseline in the in-clinic patient-reported EuroQol 5-Dimension 
Questionnaire (5-level version; EQ-5D-5L) index-score and visual analogue scale 
(VAS) at Week 101

Change from baseline in the sensor-based measures collected by the Roche HD 
mobile application (app; smartphone and wrist-worn wearable) at Week 101
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of RO7234292 
compared with placebo on the basis of the following endpoints: 

Incidence and severity of adverse events, with severity determined according to the 
Adverse Event Severity Grading Scale (see Table 4)

Change from baseline in Montreal Cognitive Assessment (MoCA)

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
Change from baseline in vital signs 

Change from baseline in ECG parameters

Change from baseline in clinical laboratory results

Proportion of patients with suicidal ideation or behavior, as assessed by 
Columbia-Suicide Severity Rating Scale (C-SSRS) score at each visit, including 
detailed focus on any individual cases identified as having severe ideation or 
behavior during the study conduct
2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the RO7234292 PK profile in plasma 
and trough CSF on the basis of the following endpoints:

Concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints
The exploratory pharmacokinetic/pharmacodynamic (PK/PD) objective for this study is to 
evaluate potential relationships between drug exposure and the efficacy and safety of 
RO7234292 on the basis of the following endpoints:

Relationship between plasma profiles and/or trough CSF concentrations of
PK parameters for RO7234292 and efficacy endpoints 

Relationship between plasma profiles and/or trough CSF concentrations of PK 
parameters for RO7234292 and safety endpoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
RO7234292 on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the 
prevalence of ADAs at baseline

Titer and antibody subtype, determined if ADAs are identified
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
2.5
BIOMARKER OBJECTIVES
2.5.1
Primary Biomarker Objective
The primary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoint:

Change from baseline in CSF mHTT protein level at Week 101

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2.5.2
Secondary Biomarker Objective
The secondary biomarker objective for this study is to evaluate the effects of 
RO7234292 compared with placebo on the basis of the following endpoints:

Change from baseline in whole and regional brain volumes (caudate, whole brain, 
and ventricular), as determined by structural magnetic resonance imaging (MRI), at 
Week 101

Change from baseline in CSF neurofilament light chain (NfL) protein level at 
Week 101
2.5.3
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to RO7234292 (i.e., predictive biomarkers), are early surrogates 
of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to RO7234292, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of RO7234292 activity (i.e., PD biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following 
endpoints:

Relationship between biomarkers in blood, plasma, and CSF (listed in Section 4.5.6)
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers (e.g., putamen, cortical grey matter, 
cortical white matter volumes, resting state functional MRI signal) (see 
Section 4.5.7) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints
2.6
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with RO7234292 on the basis of the following endpoint:

Change from baseline in patient- and companion-reported EQ-5D-5L Index and 
VAS scores at specified timepoints 

Change from baseline in companion self-reported and proxy-reported Health Utilities 
Index Mark 2 (HUI2) and Mark 3 (HUI3) scores at specified timepoints

Change from baseline in patient- and companion-reported Work Productivity and 
Activity Impairment (WPAI) scores at specified timepoints 

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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
Study BN40423 is a Phase III, randomized, placebo-controlled, double-blind, multicenter
clinical study to evaluate the efficacy, safety, PK, and biomarker effects of intrathecally 
administered RO7234292 in patients with manifest HD. 
Effective 22 March 2021, no further study treatment will be administered in this study.
Patients on the study will continue to be followed for safety and efficacy outcomes until 
study completion (see Section 3.1.1.1, Appendix 1a, and Appendix 1b).
Prospective patients will undergo screening assessments during a 4-week screening 
period.  A maximum of one re-screening will be allowed within 8 weeks of the initial 
screening failure for patients who fail the initial screening (see Section 4.5.1). If 
re-screening is required, the CAG repeat length testing from the initial screening does 
not need to be repeated (historical values prior to screening will not be accepted). The 
screening MRI and viral serology from the initial screening, including from other Roche
RO7234292 studies, may be acceptable as part of the re-screening assessments if 
performed within 12 weeks of the baseline visit.
Upon completion of the screening period, eligible patients will be randomly allocated in a 
1:1:1 ratio to receive RO7234292 Q8W (RO7234292 Q8W arm), RO7234292 Q16W
(RO7234292 Q16W arm), or placebo Q8W (placebo arm) by IT injection, as described in 
Table 1.  To maintain the study blind and integrity, patients in the RO7234292 Q16W
arm will also receive placebo (i.e., alternating doses of active drug and placebo).
Table 1
Treatment Regimens after Implementation of Protocol Version 4
Arm
Treatment Regimen
RO7234292 Q8W arm
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
RO7234292:  120 mg Q8W from Week 13 to Week 93 (11 doses)
RO7234292 Q16W arm
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
RO7234292:  120 mg Q16W from Week 21 to Week 85 (5 doses)
Placebo:  Q16W from Week 13 to Week 93 (6 doses)
Placebo arm
Placebo:  at Days 1 and 29 (2 doses) and Q8W from Week 13 to 
Week 93 (11 doses)
Q8W every 8 weeks; Q16W every 16 weeks.
Note: Effective 22 March 2021, no further study treatment will be administered in this 
study.
During scheduled clinic visits, patients will undergo safety and tolerability evaluations
that include neurologic examinations, vital signs, ECGs, clinical laboratory tests, MoCA, 

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C-SSRS, neuroimaging assessments (neurologic safety sequences), and a review of 
any adverse events including related concomitant medications, as detailed 
in Appendix 1a.  Patients in Japan must be monitored in the hospital setting for at least 
24 hours after Day 1 study drug administration.  Discharge will be determined at the 
discretion of the principal investigator.
In the case of a failed IT bolus dosing procedure or a failed CSF collection procedure 
(e.g., due to an inadequate establishment of access to the IT space), a second attempt 
may occur up to 7 days after the originally scheduled attempt.  For this additional visit,
safety and tolerability evaluations on the day of LP administration will be performed as 
detailed in Appendix 1a and Appendix 1b, including neurological examination (predose 
and postdose, or pre-procedure if no study treatment is being administered), vital signs, 
and a review of adverse events and concomitant medication. If the second attempt 
occurs more than 3 days after the first attempt, local laboratory analysis of coagulation 
factors (INR and/or PT, aPTT) and platelets need to be conducted again and results 
reviewed prior to the LP attempt (see Appendix 1a).
During the treatment period, a telephone safety follow-up call will be conducted for the 
months in which no clinic visits are scheduled to check for any change in patient status 
(i.e., adverse events, concomitant medications) since the patient’s last visit
(see Appendix 1a).  Where deemed appropriate, an unscheduled clinic visit should be 
arranged for safety follow-up; no dosing will occur at these unscheduled visits. A safety 
follow-up telephone call will also be conducted approximately 2 months after the last 
in-clinic visit at Week 101. 
Effective 22 March 2021, all patients will discontinue study treatment and will no 
longer be able to enter the OLE study (BN40955) after completing this study.
For patients enrolled in Study BN40423 who discontinue study treatment prematurely,
but do not withdraw consent for continued participation in the study, an ETT schedule 
will apply (Section 3.1.1.1).
An iDMC and independent Data Coordinating Center (iDCC) will be employed to monitor 
and evaluate patient safety throughout the study as well as to evaluate evidence of early 
efficacy (see Section 3.1.2).  
The Sponsor may choose to conduct one or more interim analyses during the study 
(further details are given in Section 6.12).
Figure 1 and Figure 2 present the study schema and overview of the dosing schedule
respectively, for patients enrolled in Study BN40423 after implementation of Protocol 
Version 4.  A schedule of activities is provided in Appendix 1a.

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Figure 1
Study Schema for Patients Enrolled after Implementation of Protocol Version 4
EoT end of treatment; ETT early treatment termination; HD Huntington disease; Q8W every 8 weeks; Q16W every 16 weeks.
a Patients in the RO7234292 Q16W arm will receive placebo at alternating visits to keep the double blind, as shown in Figure 2 and Appendix 1a
NOTE:  Effective 22 March 2021, all patients will be discontinued from study treatment and follow the ETT schedule (see Section 3.1.1.1).  

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Figure 2
Dosing Schema for Patients Enrolled after Implementation of Protocol Version 4
EoT end of treatment; Q8W every 8 weeks; Q16W every 16 weeks.
Notes:
Red, solid arrows indicate study drug administration, while black, dotted arrows indicate placebo administration.  Patients in the 
RO7234292 Q8W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by active study drug Q8W. 
Patients in the RO7234292 Q16W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by alternating 
Q8W doses of placebo and active study drug.
NOTE: Effective March 22, 2021, no further study treatment will be administered in this study.  Effective 22 March 2021, all patients will be 
discontinued from study treatment and follow the ETT schedule (see Section 3.1.1.1).  

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3.1.1.1
Clarification of Existing Study Design for Early Treatment 
Termination (Applicable to all Patients from 22 March 2021)
Following the iDMC recommendation and Sponsor’s decision to discontinue study 
treatment in this study, as of 22 March 2021, all patients will transition to the existing 
ETT schedule, outlined below and in Appendix 1b.
All patients who discontinue study treatment prematurely but do not withdraw consent 
for continued participation in the study, will return to the clinic for the following visits 
as part of the ETT schedule:

ETT visit to be performed within a maximum of 56 days of the decision to
discontinue study treatment.

Follow-up study visits at Weeks 53 and 69 (if not already completed) for collection
of clinical outcome data for the primary and secondary endpoints (see Sections
2.1.1, 2.1.2, 2.2, and Appendix 1b).  If the ETT visit falls within 30 days of
either scheduled visits at Week 53 or Week 69, then only the ETT visit should be
performed.

End-of-treatment (EoT) visit at Week 101 (EoT for ETT).
Therefore, after discontinuation of study treatment, patients will attend a minimum of 
two and up to four in-clinic visits depending on which visits have already been 
completed at the time of study drug discontinuation as shown in Figure 3.
After discontinuation of study treatment, telephone safety follow-up calls will be 
conducted every 8 weeks between the clinic visits to check for any change in patient 
status (i.e., adverse events, concomitant medications) since the patient’s last visit (see 
Appendix 1b).  Where deemed appropriate, an unscheduled clinic visit should be 
arranged for safety follow-up.
For patients consented to version 6 of the protocol, who received their last dose of study 
treatment less than 5 months before the scheduled Week 101 EoT for ETT visit, an 
additional safety telephone call should be performed 5 months after the last dose.

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Table 2
Treatment Regimens prior to Implementation of Protocol 
Version 4
Arm
Treatment Regimen
RO7234292 Q4W arm
–
RO7234292:  120 mg Q4W from Week 1 to Week 97 (25 doses)
RO7234292 Q8W arm
–
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
–
Placebo:  Q8W from Week 9 to Week 97 (12 doses)
–
RO7234292:  120 mg Q8W from Week 13 to Week 93 
(11 doses)
Placebo arm
–
Placebo:  Q4W from Week 1 to Week 97 (25 doses)
Q4W every 4 weeks; Q8W every 8 weeks.
Figure 4 and Figure 5 present study schema and overviews of the dosing schedule, 
respectively.  A schedule of activities is provided in Appendix 10, with additional 
assessments described in Appendix 11, Appendix 12, Appendix 13, and Appendix 14.

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Figure 4
Study Schema for Patients Enrolled prior to Implementation of Protocol Version 4
EoT end of treatment; HD Huntington disease; Q4W every 4 weeks; Q8W every 8 weeks.
Notes:  All patients who enroll prior to implementation of Protocol Version 4 will be prematurely discontinued from treatment by the Sponsor and 
offered treatment in the open-label extension study (BN40955).  These patients will complete an EoT visit in Study BN40423, which can also serve 
as the screening visit for Study BN40955.  All patients who are prematurely discontinued by the Sponsor who choose not to consent to 
Study BN40955 will additionally undergo a safety follow-up telephone call approximately 2 months after the last dose and a 5-month postdose
safety follow-up visit.  Patients in the Q8W arm will remain in the Q8W arm of the OLE study (BN40955).  Patients in the placebo arm or Q4W arms 
will be randomly allocated to the Q8W or Q16W arms in Study BN40955.

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Figure 5
Dosing Schema for Patients Enrolled prior to Implementation of Protocol Version 4
EoT end of treatment; Q4W every 4 weeks; Q8W every 8 weeks.
Notes:  Red, solid arrows indicate study drug administration, while black, dotted arrows indicate placebo administration.  Patients in the 
RO7234292 Q8W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by alternating doses of placebo and 
active study drug. 

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3.1.2
Independent Data Monitoring Committee 
The incidence and nature of adverse events, serious adverse events, adverse events of 
special interest, and abnormalities from neuroimaging assessments; vital signs; ECG
assessments; laboratory parameters; and any other relevant safety information will be 
reviewed on a regular basis by an iDMC in an unblinded fashion.  This information may 
also include MRI data and exploratory CSF biomarkers, for example NfL and Tau.
These reviews will occur approximately every 6 months or at the discretion of the iDMC. 
The iDMC will also undertake evaluation of any interim analysis. Specific operational 
details, such as the committee's composition, frequency and timing of meetings, and 
members' roles and responsibilities, will be detailed in an iDMC Charter.
As a result of the iDMC's recommendation and the Sponsor’s decision to permanently 
stop study treatment, the Sponsor will be unblinded to treatment assignment.  
Following the unblinding, the Sponsor will also monitor and evaluate patient safety 
outcomes.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs.  The 
end of the study is expected to occur approximately 101 weeks (25 months) after the last 
patient is enrolled.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years, however following the decision to stop study 
treatment, the total length of the study, from screening of the first patient to the end of 
the study, is now expected to be approximately 4 years. 
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for RO7234292 Dose and Schedule
The magnitude and duration of mHTT protein lowering that is required for clinical 
efficacy is unknown.  Specifically, it is unknown whether acute mHTT protein lowering 
alone with full recovery of protein levels between dosing will be sufficient for clinical 
efficacy, or whether more sustained suppression of protein levels will be required for 
clinical efficacy.  Data from transgenic animal models suggest that brain tissue lowering 
of mHTT protein in the range of 30%60% is associated with beneficial effects on the 
disease phenotype, which corresponds to a trough CSF lowering range of 20%40%
based on a non-human primate PK/PD model.  
Because of this uncertainty, two active dosing regimens and a placebo arm will be used 
in this study:  RO7234292 Q8W (RO7234292 Q8W arm), RO7234292 Q16W
(RO7234292 Q16W arm), and placebo Q8W (placebo arm) by IT injection.  To maintain 

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the study blind and integrity, patients in the RO7234292 Q16W arm will also receive 
placebo (i.e., alternating doses of active drug and placebo).
The 120-mg dose has been chosen for the Q8W dosing group based on the following:

In the chronic toxicology study in cynomolgus monkeys, the no-observed-adverse-
effect level was determined to be at least 35 mg/dose (the highest dose tested).  
Conservatively correcting for differences in CSF volume between cynomolgus 
monkeys (15 mL) and humans (150 mL) with a scaling factor of 10, the human 
equivalent dose corresponds to 350 mg, representing a 3-fold safety margin to the 
proposed 120-mg clinical dose.  

Both the 90-mg and 120-mg RO7234292 Q4W groups in the Phase I/IIa study 
(ISIS 443139-CS1) resulted in a median CSF mHTT protein reduction of 
approximately 40%, with individual cases reaching approximately 60% reduction at 
trough, well above the described preclinical threshold for efficacy.  The 120-mg dose 
group exhibited a more consistent decline compared with the 90-mg dose group. 

In the same Phase I/IIa study, 120 mg of RO7234292 administered intrathecally 
Q4W for four doses was safe and well tolerated compared with placebo.  See 
additional details in the RO7234292 Investigator's Brochure. 

In approximately 70% of patients (23 of 34 patients) assigned to receive 
RO7234292 in the Phase I/IIa study, CSF mHTT protein was declining at the last 
trough measurement (either Day 113 or 141), suggesting sustained reduction of 
CSF mHTT protein up to 2 months postdose (last timepoint assessed). 

In the 120-mg RO7234292 group in the Phase I/IIa study, CSF mHTT protein levels 
were reduced by at least 35% in all five cases for which a Day 141 sample was 
collected (i.e., 8 weeks after the last dose), in line with the observed Q8W OLE data. 

Data from the ongoing Phase II OLE Study BN40697 (ISIS 443139-CS2) showed 
that 120-mg doses administered in Q4W and Q8W regimens achieved 66% and 
47% median reductions of CSF mHTT from baseline at trough, respectively, after 9 
months.  Both results exceed the 20%40% target for CSF mHTT lowering at trough 
and steady state based upon efficacy data from nonclinical models, and exceed the 
result of approximately 40% median lowering observed in the completed Phase I/IIa 
study.  The observed effects on CSF mHTT lowering in the OLE after administration 
of three or four doses of 120 mg were also approximately 40%, consistent with 
results from the Phase I/IIa study (ISIS 443139-CS1).

Review of safety and tolerability data for RO7234292 from the Phase II OLE 
suggest that relative to the Q4W treatment regimen, the Q8W treatment regimen 
may be more suitable for chronic IT dosing.  This is supported by observations of 
fewer overall adverse events, decreased proportion of patients with moderate 
adverse events, and fewer adverse events considered possibly related to study drug 
in the Q8W regimen compared to the Q4W regimen (for details see the RO7234292 
Investigator’s Brochure).

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The 120-mg dose has been chosen for the Q16W dosing group based on the following: 

The nonclinical PK/PD model and updated clinical PK/PD model predicted the 
observed Q8W 9-month reductions.  From these models, a Q16W regimen is 
predicted to result in median CSF HTT trough lowering of 20%25%, within the 
range of the 20%40% target for CSF mHTT lowering at trough and steady state. 

Model predicted acute lowering for the 120-mg Q16W regimen is around 35%40%
CSF mHTT reduction, above observed threshold for efficacy based upon nonclinical 
models. 

Maintenance of trough lowering is not a necessary feature of this less frequent arm 
to test the primary hypothesis.   The hypothesis of this 120-mg Q16W arm (acute 
lowering, followed by more full recovery of target protein) is supported by nonclinical 
evidence that transient ASO-mediated lowering of HTT protein is associated with 
sustained phenotypic benefit in the BACHD model (Kordasiewicz et al. 2012).  
Efficacy in this model is sustained for 6 months even after a complete recovery of 
target mRNA and protein. 

Testing the less frequent regimen is of high interest to mitigate potential unknown 
long-term complications associated with a more frequent IT dosing of 120 mg Q8W.  
This approach could also mitigate the theoretical risks of suppression of wild-type
HTT and will provide a more patient-friendly long-term dosing regimen.
To date, RO7234292 has only been administered intrathecally in clinical trials.  IT bolus 
administration has been shown to overcome the challenges faced by ASOs, as they are 
unable to cross the blood-brain barrier and achieve adequate brain and spinal cord 
concentrations when administered systemically (Schoch and Miller 2017).  Therefore, 
the IT drug delivery method will be used in this trial, as presently no alternatives exist.  
A 25-month (2-year) study treatment length has been chosen because the 
signal-to-noise characteristics of the primary endpoint cUHDRS (TFC for U.S. FDA)as 
investigated in prospective observational cohort studies and in placebo groups of prior 
clinical trialssuggest that this length is optimal for trial efficacy.  A treatment duration of 
25 months will also enable demonstration of sustained, durable benefit on slowing
clinical progression as presumed to be achievable with RO7234292 (which is proposed 
to be administered as a chronic treatment to slow clinical progression).  Studies with a 
shorter treatment duration, such as 18 months, would require a dramatically larger 
sample size (i.e., 50%) under the 30% slowing of clinical progression assumption. This 
would result in a potential risk of signal dilution due to inherent variability of a larger 
number of sites and clinical raters, resulting in a potential increased risk of type II error.  
In summary, a 120-mg Q8W dosing regimen and the less frequent dosing regimen of 
120 mg Q16W have been selected for this Phase III study to maximize CSF mHTT 
protein lowering acutely and to test the hypothesis of clinical efficacy, as a function of 
more versus less frequent dosing, while mitigating theoretical risks of long-term IT 
dosing of 120 mg and of non-allele specific lowering of HTT.  The 25-month duration is 

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also considered appropriate for providing evidence of the benefitrisk profile of
RO7234292 and longer-term tolerability of IT administration.
3.3.2
Rationale for Patient Population
Patients with manifest HD (DCL score of 4 [i.e., motor abnormalities 99% likely to be 
due to HD]) who are ambulatory without assistance, verbal, and possess a CAGAge 
Product (CAP) score of 400 (Zhang et al. 2011; see Section 4.1.1) and an 
Independence Scale (IS) score of 70 will be included in this study.  This patient 
population represents manifest disease where disability might be more plausibly 
reversed or slowed in response to a therapeutic intervention compared with patients with 
more advanced disease (Penney et al. 1990).  This definition also corresponds to the 
patients most commonly recruited at present for clinical trials aiming to slow clinical 
progression.  Such cohorts are known to have a longitudinal decline in clinical measures 
(Paulsen et al. 2014) over a timeframe appropriate for clinical trials.
3.3.3
Rationale for Control Group
Patients will be randomly allocated to receive active treatment (RO7234292 Q8W or 
Q16W) or placebo in this double-blind study because there are no disease-modifying 
standard-of-care treatments for patients with HD.  The placebo arm will be compared 
with the RO7234292 treatment arms to enable a robust assessment of the primary 
endpoint and the benefit-risk profile.  As each patient completes the study or is 
prematurely discontinued by the Sponsor as a consequence of the changes to the study 
through Protocol Version 4, they will be given the option of receiving RO7234292 in an 
OLE study (BN40955), provided they meet eligibility criteria and the data from the 
ongoing RO7234292 program support continued development.  Approval of 
Study BN40955 must also be granted by the relevant competent authority and EC/IRB.  
3.3.4
Rationale for Biomarker Assessments
3.3.4.1
Cerebrospinal Fluid Biomarkers 
Measurement of protein levels in the CSF offers the potential to monitor molecular 
changes that take place in the CNS.  A toxic gain-of-function mechanism of mHTT
protein is widely considered to be the primary driver of disease pathophysiology in HD 
(Wild and Tabrizi 2017).  mHTT protein in human CSF is associated with disease stage 
and severity and with biomarkers of neuronal damage, including CSF NfL and CSF tau 
levels (Wild et al. 2015).  NfL levels in CSF predict progressive MRI measures of brain 
atrophy, as well as progressive clinical decline in patients (Wild and Tabrizi 2017).  
Longitudinal analysis of mHTT, NfL, tau, and other biomarkers related to HD, 
neurodegeneration, and inflammation in CSF may extend the current understanding of 
HD pathophysiology and progression and provide further data on how these putatively 
prognostic and potentially predictive biomarkers will respond to disease-modifying 
treatment.

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3.3.4.2
Blood Biomarkers
NfL levels in blood correlate with NfL levels in CSF and could serve as prognostic blood 
biomarkers of disease onset and progression in HD (Wild and Tabrizi 2017;
Johnson et al. 2018).  Longitudinal analysis of NfL and other biomarkers related to HD, 
neurodegeneration, and inflammation in blood may facilitate understanding of HD 
pathophysiology and progression.
3.3.4.3
Genetic Testing to Determine CAG Repeat Length
HD is caused by mutation in exon 1 of the HTT gene located on chromosome 4,
resulting in a polyglutamine (CAG) expansion in the huntingtin protein.  Above 35 CAG 
repeats, the age of HD onset is inversely correlated with the length of the expansion 
(Duyao et al. 1993).  CAG repeat length will be determined by direct DNA testing
performed centrally.  
3.3.4.4
Clinical Genotyping
Although CAG repeat length is inversely correlated to age of onset in HD, it only 
accounts for approximately 50% of the variance.  Identification of other genetic modifiers 
of disease severity and disease progression in HD could provide important insights, as 
has been recently shown in the Genetic Modifiers of Huntington's Disease Consortium 
(2015), where relatively common single nucleotide polymorphisms in the HD population 
were found to be associated with either an accelerated or delayed age of motor onset.  
A blood sample will be collected to detect individual single nucleotide polymorphisms, 
including SNP analysis of the huntingtin gene, to explore, for example, their influence on 
progression rates, age of onset, disease severity, or response to treatment.  
3.3.4.5
Magnetic Resonance Imaging
MRI is a non-invasive method to assess structure and function of the human brain and 
can provide insights into pathophysiological mechanisms of neurologic and 
neuropsychiatric disease. Several MRI techniques have shown sensitivity to detect 
abnormal structure and function within brains of individuals suffering from HD.  Structural 
MRI will be used to assess brain volume, diffusion-weighted MRI will be used to examine 
structural brain connectivity, and resting-state functional MRI will be employed to identify 
functional connectivity. All of the measures will be assessed at the whole-brain and
regional levels. The acquisition parameters of each sequence, structure, and length of 
each MRI session and image processing algorithms will be outlined in a separate MRI 
manual.
Structural Magnetic Resonance Imaging
Numerous structural MRI studies have demonstrated wide-spread brain atrophy,
including whole-brain, caudate, and ventricular changes in patients with premanifest and 
manifest HD (Douaud et al. 2006; Harrington et al. 2016).  Brain volume correlates with 
cognitive function (Peinemann et al. 2005).  Further, whole-brain, caudate, and 
ventricular volumes can predict and track progressive clinical decline in patients with HD 

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and can also be associated with molecular biomarkers of neurodegeneration, 
such as NfL (Tabrizi et al. 2012). 
Diffusion Magnetic Resonance Imaging
Widespread changes in basal gangliacortical structural connectivity have also been 
observed in patients with HD (Novak et al. 2015), including associations between 
striatum-sensorimotor cortex connections and UHDRS motor scale and TMS
(Bohanna et al. 2011), suggesting that the clinical phenotype in manifest HD may be a 
result of altered structural connectivity.
Resting-State Functional Magnetic Resonance Imaging
Resting-state functional MRI studies have generated evidence for functional connectivity 
alterations and their correlation to several clinical and cognitive measures in patients 
with HD (Werner et al. 2014; Dogan et al. 2015; Liu et al. 2016; Espinoza et al. 2018), 
implying that disrupted functional integrity of distinct brain networks may underlie clinical 
progression in HD.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 801 patients with HD will be enrolled in this global study from the 
implementation of Protocol Version 4 and onwards.  This is in addition to patients who 
enrolled prior to Version 4, who will be discontinued from this study and offered 
participation in OLE Study BN40955.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at baseline prior to randomization and study drug dosing):

Signed Informed Consent Form

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form and at 
the time of first dose administration

Manifest HD diagnosis, defined as a DCL score of 4 (see Appendix 8)

Independence Scale (IS) score 70 

Genetically confirmed disease by direct DNA testing with a CAP score 400 (Zhang 
et al. 2011), calculated as follows:
CAPAge(CAG repeat length 33.66)

Ability to read the words "red," "blue," and "green" in native language

Ability to walk unassisted without a cane or walker and move about without a 
wheelchair on a daily basis as determined at screening and baseline visit
-
Long-distance (e.g., 50 meters) use of wheelchairs for convenience or
transfer is permitted.

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
Body mass index 1632 kg/m2; total body weight 40 kg

Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no severe chorea 
or other condition that precludes MRI scans or renders scanning intolerable for the 
patient, no MRI-incompatible intrauterine devices, metallic dental braces, or other 
metal implants)

Ability to tolerate blood draws and lumbar punctures

Creatinine clearance (CrCl) 60 mL/min (Cockcroft-Gault formula)

Ability and willingness, in the investigator's judgment, to comply with all aspects of 
the protocol including completion of interviews and questionnaires for the duration of 
the study 

Ability and willingness, in the investigator's judgment, to carry a smartphone, wear a 
digital monitoring device, and complete smartphone-based tasks

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to 
screening and at the time of enrollment

Signed study companion consent for participation who fulfills all of the following 
criteria:
-
Age 18 years
-
Reliable and competent, in the investigator's judgment
-
Sufficiently knowledgeable of the patient's condition to complete study 
companion assessments of the patient, and likely to remain sufficiently 
knowledgeable throughout the study, in the investigator's judgment
-
Able to comment on study participant's symptoms and functioning experience, 
as required per Appendix 1
-
Able and willing to attend in person all clinical visits for completion of 
companion assessments and for input into the clinician-rated TFC scale
Note:  Companions must have no cognitive, behavioral or motor change, in the 
opinion of the investigator, that would question the validity of the acquired 
observer-reported data.
All effort should be made to retain the study companion; however, should this 
not be possible, a study companion should be replaced and new consent 
obtained.
A study companion is required for all patients who enroll after implementation of 
Version 5 of the protocol. The companion is optional but highly recommended 
for patients who enrolled under Protocol Versions 14.

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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, as defined below:
Women must remain abstinent or use two methods of contraception, including 
at least one method with a failure rate of 1% per year, during the treatment 
period and for 5 months after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices.  A vasectomized man must undergo a medical 
assessment that confirms the success of the surgery before he can be 
considered surgically sterile. 
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
5 months after the final dose of study drug to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal 
ideation) that required hospital visit and/or change in level of care within 12 months 
prior to screening
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
investigator.  If suicidal ideation is present, a risk assessment should be done 
by an appropriately qualified mental health professional to assess whether it is 

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safe for the patient to participate in the study.  Mild passive suicidal ideation 
(i.e., occasional thoughts that life is not worth living or is hard) without history of 
attempts or hospitalization over the past 12 months is generally acceptable for 
study participation, but final decision on participation should be made carefully 
and in consultation with an appropriately qualified mental health professional. 

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, or vital sign 
abnormality or claustrophobia at screening that, in the investigator's judgment,
precludes the patient's safe participation in and completion of the study

History known to the investigator or presence of an abnormal ECG that is clinically 
significant in the investigator's opinion, including complete left bundle branch block, 
second- or third-degree atrioventricular heart block, or evidence of prior myocardial 
infarction

Lifetime clinical diagnosis of chronic migraines

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 5 months after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test 
result at screening and a confirmatory urine pregnancy test prior to initiation of 
study drug.  

Presence of an implanted shunt for the drainage of CSF or an implanted CNS
catheter

Positive for hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) at 
screening

Known HIV infection

Current or previous use of an antisense oligonucleotide (including small interfering 
RNA)

Current or previous use of anti-psychotics prescribed for a primary independent 
psychotic disorder (i.e., schizophrenia, schizoaffective disorder, bipolar disorder 
type I, severe with psychotic features), cholinesterase inhibitors, memantine, 
amantadine, or riluzole within 12 weeks from initiation of study treatment

Current use of antipsychotics for motor symptoms or mood stabilization 
(i.e., irritability or aggressive behavior) and/or tetrabenazine, valbenazine, or 
deutetrabenazine at a dose that has not been stable for at least 12 weeks prior to 
screening or is anticipated to change between screening and treatment initiation

Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose that 
has not been stable for at least 6 weeks prior to screening or is anticipated to 
change during the study

Current use of an antidepressant or benzodiazepine at a dose that has not been 
stable for at least 12 weeks prior to screening or is anticipated to change between 
screening and treatment initiation

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
Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives 
prior to screening, whichever is longer

Antiplatelet or anticoagulant therapy within 14 days prior to screening or anticipated 
use during the study, including, but not limited to, aspirin (unless 81 mg/day), 
clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban

History of bleeding diathesis or coagulopathy

Platelet count less than the lower limit of normal  
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as 
the investigator confirms there is no evidence of current bleeding diathesis or 
coagulopathy.  

History of gene therapy, cell transplantation, or any experimental brain surgery

Concurrent or planned participation in any interventional clinical study, including 
explicit pharmacological and non-pharmacological interventions
Observational studies (e.g., ENROLL-HD prospective study) are acceptable. 

Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse 
or psychological or physiological dependency within 12 months prior to screening, 
as per the investigator's judgment
Abuse is defined as a maladaptive pattern of use that leads to failure to fulfill 
major work or social obligations or use in situations where it leads to physical 
danger or legal problems, and may be the focus of clinical attention.  

Poor peripheral venous access

Scoliosis or spinal deformity or surgery making IT injection not feasible in an 
outpatient setting and potentially interfering with distribution of RO7234292 up the 
neuraxis

An infection requiring oral or IV antibiotics within 14 days prior to screening and prior 
to randomization

Antiretroviral medications, including antiretroviral medication taken as prophylaxis
within 12 months of study enrollment

Malignancy within 5 years prior to screening, except basal or squamous cell
carcinoma of the skin or carcinoma in situ of the cervix that has been successfully 
treated

Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous 
malformation, meningiomas) as assessed by a centrally read MRI scan during the 
screening period
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
All patients who were enrolled prior to implementation of Protocol Version 4 and have 
not already discontinued for another reason will be prematurely discontinued and offered 
treatment in OLE Study BN40955.  The treatment assignments of these patients will 
remain blinded until at least after the entire cohort has been discontinued from 

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Study BN40423.  Patients will receive either the Q8W regimen or Q16W regimen in 
Study BN40955.  These patients will not be included in the primary analysis for Study 
BN40423.
Patients enrolled after implementation of Protocol Version 4 will be randomly allocated to 
receive 120 mg of RO7234292 Q8W, 120 mg of RO7234292 Q16W, or placebo Q8W.  
An independent interactive voice or web-based response system (IxRS) provider will 
conduct randomization and hold the treatment assignment code.
Effective 22 March 2021, all patients will be discontinued from study treatment and 
will follow the ETT schedule of assessments, outlined in Appendix 1b.  Patients who do 
not consent to version 6 of the protocol should be discontinued from the study.
Study site personnel and patients will remain blinded to treatment assignment during the 
study.  Following the Sponsor’s decision to permanently discontinue study treatment, 
the Sponsor will become unblinded to treatment assignment. Other individuals who 
require access to patient treatment assignments to fulfill their job roles during the clinical 
trial include the unblinding group, clinical supply chain managers, sample handling staff, 
operational assay group personnel, IxRS service provider, iDMC members, and iDCC 
members.
While PK and ADA samples must be collected from patients assigned to the placebo 
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patient treatment assignment in order to identify appropriate samples for 
analysis.  PK samples from patients assigned to the placebo arm will not be analyzed for 
study drug PK concentration except by request (e.g., to evaluate a possible error in 
dosing).  Baseline ADA samples will be analyzed for all patients.  Post-baseline ADA 
samples from patients assigned to the placebo arm will not be analyzed for ADAs except 
by request.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.

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As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment.  The investigator and patient
will remain blinded to treatment assignment.  Following the Sponsor’s decision to 
permanently discontinue study treatment, the Sponsor will become unblinded to 
treatment assignment including the Sponsor’s Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above).
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are RO7234292 and 
RO7234292 placebo. 
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
RO7234292
RO7234292 will be supplied by the Sponsor as sterile, preservative-free liquid in a 
20-mL single-use vial containing 10 mL of 6.0 mg/mL RO7234292 drug product for 
IT injection. For a 120-mg dose (20-mL dosing volume), two vials containing 10 mL of 
6.0 mg/mL RO7234292 will be pooled by drawing them up into the same injection 
syringe containing 20 mL of study drug.
For information on the formulation, preparation, and handling of RO7234292, refer to the 
pharmacy manual.
4.3.1.2
Placebo
RO7234292 placebo will be supplied by the Sponsor as a sterile, preservative-free liquid 
in a 20-mL single-use vial containing 10 mL RO7234292 placebo drug product for IT 
injection.  The liquid is no different in color than the active drug.
For a 20 mL dosing volume, two vials containing 10 mL of RO7234292 placebo will have 
to be pooled by drawing them up into the same injection syringe containing 20 mL of 
placebo drug product.
For information on the formulation, preparation, and handling of RO7234292 placebo, 
refer to the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along
with any associated adverse events, should be reported as described in Section 5.3.5.12

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Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
RO7234292 and Placebo
Each dose of RO7234292 (120 mg) and placebo will be administered as a single 
IT bolus injection of 20 mL by a qualified physician experienced in performing lumbar 
punctures.  In exceptional circumstances, study staff who are licensed physician 
assistants or nurse practitioners with extensive experience of performing lumbar 
punctures and administrating IMP for ASOs intrathecally may be acceptable with 
Sponsor approval.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO7234292 or placebo) will be provided 
by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by the 
Sponsor, using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to RO7234292
The Sponsor will offer continued access to Roche IMP (RO7234292) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (RO7234292) after completing the study if 
all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them

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A patient will not be eligible to receive Roche IMP (RO7234292) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for HD

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HD

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant HD therapy should constitute the optimal supportive care for the individual 
according to the investigator's own best clinical judgment.  Concomitant therapy consists 
of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from screening to the end-of-treatment visit for patients 
who enter OLE Study BN40955 or the safety follow-up visit for patients who do not enroll 
in the OLE study.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Contraceptive agents

Supplements (e.g., coenzyme Q10, vitamins, creatine) if the dose has been stable 
for at least 6 weeks prior to screening and the dose is not anticipated to change 
during the study

Antipsychotics only if prescribed for motor symptoms or for mood stabilization (i.e., 
irritability or aggressiveness) and/or tetrabenazine/deutetrabenazine/valbenazine if 
the dose has been stable for at least 12 weeks prior to screening and the dose is 
not anticipated to change between screening and the start of study treatment 
If clinically indicated, dose changes or medication stopping or starting can occur 
as per investigator judgment during the course of the study.

Antidepressant or benzodiazepine if the dose has been stable for at least 12 weeks 
prior to screening and the dose is not anticipated to change between screening and 
the start of study treatment 

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If clinically indicated, dose changes or medication stopping or starting can occur 
as per investigator judgment during the course of the study.

Anti-epileptics if given for mood stabilization, pain, restless legs, or insomnia

Aspirin at doses 81 mg/day

Local anesthesia for the lumbar puncture procedure, depending on institutional 
guidelines  
Sedation may not be used for lumbar puncture.
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited:

Experimental agents or marketed HD agents at experimental doses that are being 
tested for the treatment of HD, including, but not limited to, cholinesterase inhibitors, 
memantine, amantadine, and riluzole  

Antiplatelet or anticoagulant therapy, including, but not limited to, aspirin (unless 
81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and 
apixaban

Sedation for lumbar puncture or IT bolus procedures in the study
Depending on institutional guidelines, local anesthesia is permissible for the 
lumbar puncture procedure

Use of anti-anxiety medication is discouraged during scheduled MRI scans in the 
study. Anti-anxiety medication used to prevent movement disorder to allow 
successful MRI scan is not permitted in this study, as movement disorder too severe 
to scan under drug-free conditions is an overall study exclusionary criterion.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study and guidance on the order
these assessments can be performed are provided in Appendix 1a and Appendix 1b,
and Appendix 5, respectively.  All activities should be performed and documented for 
each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. Effective 22 March 
2021, patients will be discontinued from study treatment but will continue to be 
followed for safety and efficacy outcomes as outlined in Section 3.1.1.1, Appendix 1a
and Appendix 1b.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for patients and study companions will be maintained at the study site, 

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regardless of whether the patient is subsequently enrolled.  If a patient's capacity to 
consent is in question, the investigator should consult an appropriately qualified 
colleague who will independently assess capacity.  This additional assessment should 
also be documented.  If the patient’s capacity is confirmed, the investigator may proceed 
with signing of the Informed Consent Form.
All screening evaluations must be completed and reviewed to confirm that patients meet 
eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
A maximum of one re-screening will be allowed within 8 weeks of the initial screening 
failure for patients who fail the initial screening (e.g., as a consequence of abnormal 
laboratory values or general medical status not meeting inclusion or exclusion criteria).  
If re-screening is required, CAG repeat length testing from the initial screening does not 
need to be repeated (historical values will not be accepted). The screening MRI and 
viral serology from the initial screening, including from other Roche RO7234292 studies, 
may be acceptable as part of the re-screening assessments if performed within 12
weeks of the baseline visit.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, HD history (including 
past hospitalizations [i.e., number, duration, and reason]) over the last 2 years, 
reproductive status, smoking history, and use of alcohol and drugs of abuse will be 
recorded at baseline.  Alcohol and/or drug abuse is defined as a maladaptive pattern of 
use that leads to failure to fulfill major work or social obligations or use in situations 
where it leads to physical danger or legal problems, and may be the focus of clinical 
attention.  Daily use of any drug (i.e., cannabinoid, opioid, stimulant, hallucinogen, 
designer) or daily alcohol use that meets criteria for either abuse or psychological or 
physiological dependence is not permitted and is exclusionary.  Occasional use that 
does not meet the criteria for abuse is permissible in this study.  
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient from 
screening to the end-of-treatment visit for patients who enter OLE Study BN40955 or the 
safety follow-up visit for patients who do not enroll in the OLE study will be recorded.  At 
the time of each study drug administration and telephone safety follow-up calls, an
interval medical history should be obtained and any changes in medications and any 
physician visits for HD or general medical care should be recorded.
Demographic data will include age, sex, self-reported race/ethnicity, and education level 
based on the International Standard Classification of Education scale.  Demographic
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be collected for the study companion. Race/ethnicity is recorded because of the 
potential contribution of this variable to differences in observed pharmacokinetics, 
pharmacodynamics, toxicity, and/or response to treatment. 
A unique HD identification number (HDID) will be collected from patients who already 
have an HDID.  For patients without an HDID, the number will be created via a web 
portal (see Section 8.4).
4.5.3
Physical and Neurologic Examinations
A complete physical examination, performed at screening and other specified visits 
(see Appendix 1), should include an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems; genitourinary examinations may be performed 
if clinically indicated.  The physical examinations should be conducted in the same 
manner on each occasion to ensure comparability to previous examinations, including 
weight.  Height will be measured at screening and baseline only.
A neurologic examination, including fundoscopy, performed at screening and at every
clinical visit, should include assessment of mental status, level of consciousness, cranial 
nerve function, motor function, sensory function, reflexes, gait, and coordination (see
Appendix 9).  The neurologic examination should be conducted in the same manner on 
each occasion to ensure comparability to previous examinations.  Neurologic 
examinations should be performed before and after treatment on each dosing day or 
before the lumbar puncture, if there is no study treatment administration.  Weight 
should also be measured at each visit.
Any abnormality identified at baseline (Week 1) should be recorded on the General 
Medical History and Baseline Conditions eCRF.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
(i.e., beyond expected variation; normal age-related change; or HD-related clinical 
progression) should be recorded as adverse events on the Adverse Event eCRF.  
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse, temperature, and 
systolic and diastolic blood pressure while the patient is in a seated position after resting 
for approximately 5 minutes.  All data should be recorded on the appropriate eCRF.
4.5.5
Collection of Cerebrospinal Fluid (Lumbar Puncture 
Procedure)
Within 72 hours prior to performing each scheduled lumbar puncture, local laboratory 
analysis of coagulation factors (INR and/or PT, aPTT) and platelets must be conducted 
and the results reviewed.  The lumbar puncture should be performed at approximately 
the same time at each visit (ideally in the morning between 8:00 a.m. and 12:00 noon or 
in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal 

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variation of CSF parameters.  CSF fluid (20 mL) is to be collected for analyses using a 
lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a 
minimum of 5 mL should be collected over a maximum of 60 minutes, once CSF flow 
has been established.  The operator must confirm CSF flow is present prior to injecting 
drug.  A 24G atraumatic needle, as specified in the LP procedure and CSF collection 
guidelines, should be used to minimize risk of postlumbar puncture syndrome.  
Sedation may not be used.  Depending on institutional guidelines, local anesthesia 
should be used for the procedure.  Spinal ultrasound may be used for the lumbar 
puncture procedure if deemed necessary, but ultrasound is not required.  Ultrasound 
may be used if attempts at lumbar puncture without imaging are unsuccessful, if it is 
local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound 
with each lumbar puncture.  Fluoroscopy guidance can also be used, if local institutional 
guidelines dictate and local ECs and HAs have approved the use of the technique, but it 
is not required.  Where fluoroscopy is used, patients should also be informed and 
consent obtained.
For details on the lumbar puncture and IT bolus dosing procedure, please refer to the LP 
procedure and CSF collection guidelines and instructional video.  Effective
22 March 2021, no further study treatment will be administered.
When applicable, study treatment administration will occur via a lumbar puncture using 
a needle inserted into the L3/L4 space, although placement at a different level (either in 
the space above or the space below) is allowed if patient anatomy or clinical judgment 
dictates.  The left lateral position is mandatory in the first instance for the procedure for 
consistency of procedure practice across sites and within patients, unless patient-
specific factors require use of the upright, sitting position or the physician/operator has 
pre-existing experience using LP/intrathecal bolus dosing in the sitting position and 
prefers the use of the upright sitting position, as guided by the patient, his or her 
judgment.  Whichever position is used, once access is established to the IT space, the 
entire IT bolus procedure should be completed in the same position, to limit the risk of 
the needle losing position while the spinal needle is inserted.  Subsequent LP 
administrations should occur using the same position.
Patients will be discouraged from resting supine after the lumbar puncture procedure 
and will be encouraged to mobilize immediately by walking around at a minimum and, if 
feasible, walking briskly for approximately 30 minutes, after which the postdose 
neurological examination can occur (if study treatment was administered).  Patients 
should not perform any activity that is associated with a change in the ambient air 
pressure for at least 24 hours post-LP procedure (e.g., air travel, scuba diving, or hot air 
balloons).
Lumbar punctures will be performed as specified in the schedule of activities 
(see Appendix 1), with the last CSF sample obtained at the Week 101 end-of-treatment 

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visit.  After discontinuation of study treatment, LPs will be performed at the ETT and 
EoT for ETT visits (see Appendix 1a and Appendix 1b).  No study drug will be 
administered at these visits.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Coagulation:  INR and/or PT, aPTT, and platelet count

Urine pregnancy test
Urine pregnancy tests will be performed for women of childbearing potential at 
specified visits.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test (analyzed at a central laboratory).

CSF for safety:  cell count (RBCs and WBCs), glucose, and protein
The following samples will be sent to a central laboratory:

Hematology:  WBC count, RBC count, platelet count, hemoglobin, hematocrit, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes)

Serum chemistry panel:  bicarbonate or total carbon dioxide (if considered standard 
of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, 
ALP, ALT, AST, uric acid, gamma-glutamyl transferase, and CPK

Thyroid panel:  thyroid-stimulating hormone and free thyroxine (also known as T4) 
levels

Viral serology:  HBsAg and HCV antibody (or viral RNA if HCV antibody assay is 
positive)

Serum pregnancy test
Serum pregnancy tests will be performed for women of childbearing potential at 
screening.  At subsequent visits, it will be performed to confirm a positive urine 
pregnancy test (if applicable).

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
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination for all abnormal dipstick results (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria)

CSF and blood (plasma) samples for PK analyses and metabolite identification

Blood (plasma) samples for immunogenicity analyses

Blood sample for determination of CAG repeat length in HTT for patient eligibility 

Blood sample for clinical genotyping to look at factors influencing HTT function and 
severity of the disease

CSF samples for analysis of mHTT, NfL, and tau levels to evaluate the effects of 
RO7234292 compared with placebo (primary and secondary biomarker endpoints) 

Blood, plasma, and CSF samples for exploratory research on biomarkers and 
biomarker assay development
Exploratory biomarker research may include, but will not be limited to, total HTT protein, 
and other proteins related to HD, neurodegeneration, and inflammation.  Research may 
involve extraction of DNA and analysis of mutations, single nucleotide polymorphisms, 
and other genetic variations.  Research will not be aimed at distinguishing germline 
mutations from somatic mutations.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Blood, plasma, and CSF samples collected for biomarker research and biomarker 
assay development will be destroyed no later than 10 years after the final Clinical
Study Report has been completed.

Blood, plasma, and CSF samples collected for PK or immunogenicity analysis may
be needed for additional immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, these samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.

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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Magnetic Resonance Imaging
Structural MRI will be used to assess brain volume, diffusion-weighted MRI will be used 
to examine structural brain connectivity, and resting-state functional MRI will be 
employed to identify functional connectivity. All of the measures will be assessed at the 
whole-brain and regional levels.  All scans are mandatory unless a site does not have 
the capability to perform a resting-state functional MRI or diffusion-weighted 
MRI. For these cases, the Medical Monitor should be consulted; approval to continue 
without these scans would be required.
The MRI should be performed using a 3-Tesla (3T) magnet.  The acquisition parameters 
of each sequence, structure, and length of each MRI session, as well as image 
processing algorithms, will be outlined in a separate MRI manual.  MRI scans will be 
managed by a central laboratory to monitor and ensure the integrity and quality of the 
acquired data.  The screening MRI will be evaluated by the central laboratory to 
determine patient eligibility.  Local neuroradiologists will still be responsible for assessing 
MRI-related ongoing safety monitoring. During central review, the Sponsor and/or site 
staff will be notified of any unexpected findings requiring clinical follow-up.  
MRI should take place as early as possible within the screening window but may take 
place at any time during screening.  The MRI safety and efficacy screening scan will 
need to pass the central laboratory image QC and the results must be available before 
the patient can be enrolled in the study.  
After patient enrollment at specified timepoints, the MRI must be scheduled to occur 
before the lumbar puncture (see Appendix 1).  The MRI scan should be performed 
714 days prior to the lumbar puncture to allow time for re-scanning if the quality of the 
initial MRI is inadequate. If the re-scan cannot be performed prior to the lumbar 
puncture, then it can be conducted the day after the lumbar puncture, as long as there 
are no post-lumbar puncture contraindications and it occurs within 2 weeks of the 
original scan.
4.5.8
Electrocardiograms
Triplicate ECG recording will be obtained at specified timepoints, within approximately 
5 minutes of each other, as outlined in the schedule of activities (see Appendix 1), and 
may be obtained at unscheduled timepoints as clinically indicated.  For patients in 
Japan, additional triplicate ECG monitoring will be performed at 2 (± 30 minutes), 
4 (± 30 minutes), and 6 (± 30 minutes) hours following the first administration of study 
drug (Day 1).

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The ECG recordings must be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recording 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other invasive procedures scheduled at 
that same time (e.g., blood draws) and should not be obtained within 30 minutes after 
any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. All data should be 
recorded on the appropriate eCRF.
The ECG recordings may be electronically transferred to a central vendor.  The
investigator must review, sign, and date all ECG tracings.  Paper copies of ECG tracings 
will be kept as part of the patient's permanent study file at the site.  
4.5.9
Patient-Reported, Clinician-Reported, Study
Observer-Reported, and Performance Outcomes
Patient-reported outcome (PRO), clinician-reported outcome (ClinRO), 
observer-reported outcome (ObsRO), and performance outcome (PerfO) data will be
collected in the clinic to document the change from baseline over time.  To enable valid 
acquisition of all study companionrelated assessments, including the study companion 
input to the TFC scale, study companions are required to attend in person all study visits
when the TFC rating occurs.  Additionally, PRO, ObsRO, and PerfO data will be 
collected remotely.  The instruments, translated into the local language as appropriate,
will be completed in their entirety at specified timepoints during the study.  To ensure 
instrument validity and that data standards meet health authority requirements, 
instruments will be self-administered or administered by a trained rater (as appropriate).  
In-clinic data should be collected prior to the performance of the lumbar puncture 
procedure.
Patients, clinicians, and study companions will use an electronic device to capture 
outcome data during clinic visits, and scoring of ClinRO and PerfO measures will be 
supervised during acquisition and entry into a tablet to ensure instructions are given and 
appropriately followed.  Paper must not be used to capture clinical outcome data, unless 
it is for performance outcome measures (e.g., SWR, SDMT, and MoCA). Performance
measure outcomes must be completed in ink and not pencil.
Patients will use a smartphone and wrist-worn wearable to capture outcome data 
remotely and at specified visits (see Section 4.5.9.22).  Study companions will use an 
electronic device to capture data remotely and at specified visits.  The electronic devices
and/or instructions for completing the questionnaires electronically will be provided to 
patients and study companions by site staff.  Study companion device data will be 
transmitted to a centralized database maintained by the electronic device vendor.  The 
patient device data will be transmitted to a centralized database maintained by the 

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Sponsor.  The data will be available for access by appropriate study personnel.  If the 
device is lost, a replacement will be sent.  All devices are encrypted and password 
protected.  See Appendix 1 for the schedule of activities, and Appendix 2 and
Appendix 3 for a summary of timing and duration of each PRO, ClinRO, ObsRO, and 
PerfO assessment. Appendix 4 shows the order and approximate timing of 
assessments at each clinic visit, while Appendix 5 provides guidelines for the order of 
assessments.  Appendix 10 through Appendix 14 show relevant information for patients 
who enrolled in Study BN40423 before implementation of Protocol Version 4.
4.5.9.1
Composite Unified Huntington's Disease Rating Scale
The cUHDRS is a composite motor, cognitive, and global functional clinical outcome 
measure in patients with HD comprised of an equally weighted sum of Z scores of the 
TFC, the TMS, the SDMT, and the SWR scores from the UHDRS (Huntington Study 
Group 1996). It is a multidomain measure of clinical decline that tracks underlying 
progressive brain changes and is related to changes in daily functional ability 
(Schobel et al. 2017).  
The formula for cUHDRS scoring was originally developed for use in HD Stages 1 and 2 
(TFC 713) but has since been updated to encompass early HD Stage 3. This led to an 
update to the reference population (using ENROLL-HD data) from TFC713 to 
TFC513 (in both cases, a lower age cutoff of 20 years was used to limit the number of 
individuals included with juvenile-onset HD). The cUHDRS is scored using the following 
formula: 
	 =  −8.8
2.8
 −	 −34.4
17.4
 + 	 −25.2
12.4
 + 	 −58
21.2
 + 10.0
4.5.9.2
Total Functional Capacity Scale 
The TFC is a validated measure of global patient function in HD.   The TFC represents 
the investigator's assessment of the patient's capacity to perform a range of activities of 
basic daily living, including working, chores, managing finances, eating, dressing, and 
bathing.  The 5-item assessment is based on a brief interview with the patient and the 
study companion.  The TFC score ranges from 0 to 13, with a higher score representing 
better functioning.  A 1-point change in TFC score is a clinically meaningful change in 
patient function (e.g., a 1-point decline may indicate the loss of ability to work in a normal 
capacity) (Huntington Study Group 1996).  The TFC takes approximately 10 minutes to 
administer and will be completed at clinic visits.  Information for the TFC will be acquired 
from both the patient and companion, and input of the companion to the rating will be 
recorded electronically.  
4.5.9.3
Total Motor Score
The TMS is a holistic measure of motor function in HD that is linked to both functional 
capacity based on the TFC score, independence, and driving status 
(Beglinger et al. 2012; Schobel et al. 2017).  

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The TMS score is the sum of the individual motor ratings obtained from administration of 
the 31-item motor assessment portion of the UHDRS by the investigator.  The score 
ranges from 0 to 124, with a higher score representing more severe impairment.  The 
TMS takes approximately 15 minutes to administer and will be completed at clinic visits.
4.5.9.4
Symbol Digit Modalities Test
The SDMT is used to assess attention, visuoperceptual processing, working memory, 
and psychomotor speed.  It has been shown to have strong reliability and validity 
(Smith 1982).  The patient pairs abstract symbols with specific numbers according to a 
translation key.  The test measures the number of items correctly paired (maximum 
of 110 correct pairs) in 90 seconds.  The SDMT will be administered at clinic visits and 
can be completed in less than 5 minutes.  It will also be administered at specified 
timepoints indicated in Appendix 7 on the Roche HD mobile app (via electronic SDMT).
4.5.9.5
Stroop Word Reading Test 
The SWR Test is a measure of attention, processing, and psychomotor speed and 
depends upon quick verbal motor output.  Patients are presented with a page of color 
names (i.e., "BLUE," "RED," or "GREEN") printed in black ink and are asked to read 
aloud as many words as possible within a given amount of time (in 45 seconds).  The 
number of words read correctly is counted, with a higher score indicating better cognitive 
performance.  It will also be administered at specified timepoints indicated in Appendix 7
on the Roche HD mobile app (via electronic SWR).    
4.5.9.6
UHDRS Functional Assessment
The UHDRS Functional Assessment is a checklist of 25 common daily tasks.  The 
investigator indicates if the patient can perform the task by giving a score of 1 to all "yes" 
replies.  The checklist is then summed, and scores can range from 0 (inability to do any 
task) to 25 (ability to do all tasks on the checklist).  The UHDRS FA can be completed in 
15 minutes.  
4.5.9.7
Independence Scale
A patient's IS score is a measure of disease progression in functional disability and will 
be completed to evaluate a patient's degree of independence at screening and at 
specified timepoints.  It is a subscale of the UHDRS. The scale consists of 19 discrete 
levels ranging from 10 to 100 (by 5), in which a score of 100 indicates no special care is 
needed and a score of 10 indicates the patients is fed by tube and requires total bed 
care. 
4.5.9.8
HD Daily Activities Scale
The HD-DAS assesses patients' daily function.  Following a semi-structured interview 
with the patient and study companion, the patient's ability level to perform daily tasks 
such as eating or using a telephone will be recorded.  Each item is scored on a 4-point 
Likert-type scale, where 0 indicates no impact and 3 indicates severe impact.

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4.5.9.9
Clinical Global ImpressionSeverity and Change Scales
The CGI-S is a single-item measure of current global severity and is completed by the 
clinician at specified clinic visits.  The CGI-S is assessed using an 11-point numeric 
rating scale (NRS), where higher scores indicate greater severity.  The CGI-S can be 
completed in approximately 2 minutes.
The CGI-C is a single-item measure of change in global status (since starting the study) 
and is completed by the clinician at specified postbaseline visits.  The CGI-C has seven 
response options:  "very much worse," "much worse," "minimally worse," "no change," 
"minimally improved," "much improved," and "very much improved."  The CGI-C can be 
completed in approximately 2 minutes.  To assess the relevance of this change, a 
follow-up question with dichotomous response options ("yes" or "no") asks if the change 
has had a meaningful impact on the patient’s well-being.
4.5.9.10
Patient Global ImpressionSeverity and Change Scales
The PGI-S is a single-item measure of current global severity and is completed by the 
patient at specified clinic visits.  The PGI-S can be completed in approximately 
2 minutes.  The PGI-S is assessed using an 11-point NRS, where higher scores indicate 
greater severity.  
The PGI-C is a single-item measure of change in global status (since starting the study) 
and is completed by the patient at specified post-baseline visits.  The PGI-C has seven 
response options:  "very much worse," "much worse," "minimally worse," "no change," 
"minimally improved," "much improved," and "very much improved." To assess the 
relevance of this change, a follow-up question with dichotomous response options ("yes" 
or "no") asks if the change has had a meaningful impact on the patient's well-being.  The 
PGI-C can be completed in approximately 2 minutes.
4.5.9.11
Companion-Reported Global ImpressionSeverity and Change 
Scales
The Companion-Reported Global ImpressionSeverity (CrGI-S) is a single-item measure 
of current global severity and is completed by the companion (about the patient) at 
specified clinic visits.  The CrGI-S can be completed in approximately 2 minutes.  The 
CrGI-S is assessed using an 11-point NRS, where higher scores indicate greater 
severity.  
The Companion-Reported Global ImpressionChange (CrGI-C) is a single-item measure 
of change in global status (since starting the study) and is completed by the companion 
(about the patient) at specified post-baseline visits.  The CrGI-C has seven response 
options:  "very much worse," "much worse," "minimally worse," "no change," "minimally 
improved," "much improved," and "very much improved." To assess the relevance of this 
change, a follow-up question with dichotomous response options ("yes" or "no") asks if 
the change has had a meaningful impact on the patient's well-being.  The CrGI-C can be 
completed in approximately 2 minutes.  

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4.5.9.12
Montreal Cognitive Assessment
The MoCA is a patient-completed assessment used to detect cognitive impairment.  It 
contains a series of basic assessments, including attention and visuospatial tasks.  The 
total score ranges from 030, where lower scores indicate greater impairment.  It will be 
used in this study to characterize patients at screening and longitudinally to assess 
cognitive status at regular intervals throughout the study.  It takes approximately 
10 minutes to administer.
4.5.9.13
Work Productivity and Activity Impairment
The WPAI contains 6 items assessing the impact of disease on employment status 
(yes/no), hours missed due to disease, hours missed due to other reasons, hours 
worked, and impact on productivity and on daily activities (both using an 11-point NRS, 
where higher scores indicate greater impact).  The WPAI takes approximately 5 minutes 
to complete.  The WPAI will be completed by the patient (about him/herself) and by the 
study companion (about him/herself).  It will be completed at specified timepoints 
remotely by the patient on the Roche HD mobile app and by the study companion on an 
electronic device.
4.5.9.14
Apathy Evaluation Scale 
The AES is an 18-item assessment of apathy, including overt behavior, cognitive 
aspects of motivation, and emotional responsivity.  Each item is scored on a 4-point 
Likert scale, from 1 ("Not at all") to 4 ("A lot").  A total score is created by summing the 
18 items (scores range from 18 to 72; 3 items are reverse scored), with higher scores 
indicating greater apathy.  The AES takes approximately 10 minutes to complete and will 
be completed by the patient and study companion at specified clinic visits.
4.5.9.15
Neuro-Qol Cognition Function Short Form, Version 2
The Neuro-Qol Cognition Function Short Form contains 8 items (including "trouble 
concentrating" and difficulty "learning new tasks or instructions"), each assessed using a 
5-point Likert scale, where lower scores indicate greater difficulty (4 items) or greater 
frequency (4 items).  The raw sum score is converted to a T-score distribution 
(mean50, standard deviation10).  The Neuro-Qol Cognition Function Short Form 
takes approximately 5 minutes to complete and will be completed by the patient at 
specified clinic visits.
4.5.9.16
HD Speaking Difficulty Item
The HD-SDI includes a single question assessing difficulty speaking over the past 
7 days.  It is assessed using a 5-point Likert scale, where higher scores indicate a 
greater frequency of difficulty.  The HD-SDI can be completed in less than 1 minute and 
will be completed at specified timepoints remotely by the patient on the Roche HD 
mobile app.

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4.5.9.17
Symptoms of Major Depressive Disorder Scale 
The SMDDS is a newly developed, valid, and reliable self-report assessment of 
depression (McCarrier et al. 2016).  It contains 16 items, measuring concepts such as 
sadness, irritability, worry, and sleep disturbance.  Each item is assessed on a 5-point 
Likert scale, from "Not at all" to "Extremely" (9 items) and from "Never" to "Always" 
(7 items).  Item scores from 15 of the items (the least severe of the two eating items is 
not included) are summed to create a 060 score, where higher scores indicate more 
severe depressive symptomatology.  The SMDDS takes approximately 10 minutes to 
complete and will be completed by the patient at specified clinic visits.
The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.9.18
HD Companion-Reported Irritability and Angry Outbursts Scale 
The HD-CIAOS is a study companion-reported assessment of the patient's irritability and 
angry outbursts over the past 7 days and will be completed at specified timepoints 
remotely by the companion on an electronic device.  It consists of three items: frequency 
of irritable behavior (6-point Likert scale: "Not at all" to "Always"), frequency of angry 
outbursts (number of occurrences), and severity of the worst outburst (4-point Likert 
scale "Mild" to "Very severe").  The HD-CIAOS takes about 2 minutes to complete.
4.5.9.19
EuroQol 5-Dimension, 5-Level Questionnaire
The EQ-5D-5L is a validated self-report health status questionnaire used to calculate a 
health status utility score for use in health economic analyses (EuroQol Group 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There are two components to 
the EQ-5D-5L:  a 5-item health state profile that assesses mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, as well as a VAS that measures 
health state.  Published weighting systems allow for creation of a single composite score 
of the patient's health status (Index score) from the 5-item scores (i.e., does not include 
the VAS).  The EQ-5D-5L takes approximately 5 minutes to complete.  The Index score 
will be used in this study for informing pharmacoeconomic evaluations. The VAS score 
will be used to assess health-related quality of life (HRQoL). The EQ-5D-5L will be 
completed both by the patient (about him/herself) and by the study companion (about 
him/herself) at baseline and at specified post-baseline clinic visits on an electronic 
device.  In addition, it will be completed remotely at specified timepoints by the patient 
on the Roche HD mobile app and by the study companion on an electronic device.
4.5.9.20
Health Utilities Index Mark 2 and Mark 3
The HUIis a multi-attribute system of health status (Feeny et al. 1995).  The HUI2 and 
HUI3 questionnaire (commonly referred to as HUI2/3) contains 15 items with Likert-type 
response options.  From these items, two scores can be produced:  HUI2 (7 items) and 
HUI3 (8 items).  Both scores are health utility indexes, where 0death, and 1perfect 
health.

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The HUI2/3 will be completed by the companion, both about him/herself and as a proxy 
report of the patient’s HRQoL.  The HUI2/3 will be completed at specified timepoints at 
clinic visits and remotely on an electronic device.
4.5.9.21
Columbia-Suicide Severity Rating Scale
The C-SSRS is a structured tool to assess suicidal ideation and behavior.  
Four constructs are measured:  severity of ideation, intensity of ideation, behavior, and 
lethality of actual suicide attempts.  Binary (yes/no) data are collected for 10 categories, 
and composite endpoints based on the categories are followed over time to monitor 
patient safety (Posner et al. 2011).  It maps to the Columbia-Classification Algorithm for 
Suicide Assessment and meets the criteria listed in the U.S. FDA draft guidance for 
assessment of suicidality in clinical trials (FDA 2012).  The C-SSRS will be used to 
assess eligibility for the study (full version at baseline, requiring approximately 20 
minutes to administer) and to monitor the patients throughout the study at clinic visits 
(follow-up version, requiring approximately 5 minutes to administer, assuming absence 
of suicidal ideation and no change in clinical status from previous administration).
The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.9.22
Optional Exit Interviews
Optional exit interviews will be conducted with a subset of patients (up to 60 patients) at 
select sites within approximately 1 week after the end-of-treatment visit.  The 
semi-structured interviews will be conducted by an external vendor and can be 
conducted by telephone but may be completed by an in-clinic videotaped session.  The
interviews will enable patients to provide details about changes they observe in their
symptoms, as well as any impacts on daily life.
Interviews will be transcribed verbatim, and themes emerging from these transcripts will 
be interpreted in relation to changes in patients' clinical outcome assessment scores. All 
participants in this optional study interview will be asked which arm they thought they 
were assigned to (120 mg Q8W, 120 mg Q16W, or placebo).  Of note, patients and staff
will remain blind to patient treatment assignment during the study. Following 
the Sponsor’s decision to permanently discontinue study treatment, the Sponsor will 
become unblinded to treatment assignment, as outlined in Section 4.2.
Additional consent for this optional portion of the study will be included in the relevant 
Informed Consent Form.
4.5.9.23
Roche HD Mobile Application:  Remote Testing (Smartphone 
and Wrist-Worn Wearable)
Smartphones and wrist-worn wearables have high-quality sensors that enable the 
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symptoms (Maetzler et al. 2013; Andrzejewski et al. 2016; Adams et al. 2017; Lipsmeier 
et al. 2018).  Each patient will receive a preconfigured smartphone and wrist-worn 
wearable with installed software for the Roche HD mobile app assessments.  The 
devices and software will monitor motor symptoms, non-motor symptoms, and activities 
associated with routine daily living throughout the course of the study.  Additional details 
are available in the Roche HD mobile app (Smartphone) manual.
Patients will be provided with devices and trained on their use during screening.  
Patients will also have in-clinic assessments of the digital platform that are supervised as 
indicated in Appendix 7.  Outside of the clinic, patients will be instructed to conduct an 
"active test" every day at approximately the same time (ideally in the morning, after 
breakfast).  The active test consists of a short, preconfigured schedule of tasks that 
assess motor symptoms (upper and lower body movements, upper limb dexterity, voice) 
and non-motor symptoms (processing speed, voice).  Testing will usually last 
approximately 5 minutes in total on a typical day of testing.  Not all tests are daily.  
Additional information on the tasks and schedule is specified in Appendix 7.  
For "passive monitoring," patients will be instructed to carry the smartphone in a manner 
convenient to them (e.g., in a pocket or in a Sponsor-provided pouch) and wear the 
wrist-worn wearable throughout the day as they go about their daily routines.  
Companions will receive their own independent electronic device at screening, which is 
different from the patient smartphone.  
Patients will be encouraged to adhere to the daily schedule of tasks as much as 
possible; however, patients will not be excluded from the study for poor adherence, nor 
will missing a daily test be considered a protocol deviation. 
Device sensor data will be recorded continuously, throughout the active tests and 
passive monitoring.  Sound will only be recorded during selected active test tasks.  Data 
will be encrypted and uploaded to secure servers when the smartphone is connected 
to Wi-Fi.  Patients will be asked to charge the devices overnight.  If patients have a Wi-Fi 
network at home, they will be encouraged to connect their smartphone to enable data 
transfer.  If no Wi-Fi network is available, the sensor data will be transferred during clinic 
visits or after the devices have been returned.
Roche HD mobile app "baseline" data will consist of all data collected prior to and 
including the baseline visit (up to 28 days).  Baseline data will be collected for at least 
the 7 days up to and including Day 1. 
4.5.9.24
Roche HD Mobile Application:  In-Clinic Assessments
Patients will be instructed to bring the smartphone and wearable to every clinic visit to 
check adherence and technical status of the devices.  At specified clinic visits, patients 
will be asked to conduct the "active test" tasks under the supervision of trained site staff, 
as shown in Appendix 7.  

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The smartphone and wearable must be returned to the clinic in cases where the patient 
does not meet eligibility criteria, at the end of the study, or upon early termination from 
the study.  At the time of study completion or early termination, patients will be asked to 
complete a pen-and-paper satisfaction survey about their experience using the 
smartphone and wrist-worn wearable.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of 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.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
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 Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10)
will not be applicable at that site.
4.5.10.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7234292, the HTT 
protein, HD or other diseases, or drug safety:

Blood and serum samples collected at baseline and at Weeks 37, 69, and 101

Leftover blood, plasma, and CSF samples and any derivatives thereof 
(e.g., proteins, peptides)

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The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researchers' understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples 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 and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.

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4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.10.7
Monitoring and Oversight
RBR samples 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.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 

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and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
Due to the Sponsor’s decision to discontinue the 120-mg Q4W dosing regimen and 
replace this with a 120-mg Q16W dosing regimen in Protocol Version 4, all patients who 
enrolled prior to implementation of Protocol Version 4 will be prematurely discontinued 
from the study by the Sponsor and will complete their end-of-treatment visit prior to entry 
into Study BN40955. 
Effective 22 March 2021, all patients will be discontinued from study treatment.
Patients who discontinue study treatment and do not withdraw consent for continued 
participation in the study will follow the existing ETT schedule of assessments, 
outlined in Appendix 1a and Appendix 1b.  Patients who do not consent to version 6 of 
the protocol should be discontinued from the study.
An excessive rate of withdrawals (either study treatment discontinuation or withdrawal 
from the study) can render the study results non-interpretable.  Therefore, all efforts 
should be taken to motivate patients to comply with all study-specific procedures and to 
be followed until the end of the 101-week, placebo-controlled treatment period. 
Investigators should explore all possible options to contact patients for visits, especially 
end-of-treatment visits.  The site must document all attempts to try to contact the patient 
in the patient's medical records and source documents.
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Loss of capacity to consent, if legal guardian consent is not possible
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be
replaced.
All patients who discontinue study treatment prematurely but do not withdraw consent for 
continued participation in the study will return to the clinic for study visits at Weeks 53 
and 69 (if not already completed) for collection of clinical outcome data for the primary 

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and secondary endpoints (see Sections 2.1.1, 2.1.2, 2.2, and Appendix 1b).  If the early 
treatment termination visit falls within 30 days of either scheduled visits at Week 53 or 
Week 69, then only early treatment termination will be considered.  Patients will also 
attend the scheduled end-of-treatment (EoT for ETT) visit at Week 101. Further 
clarification on the ETT schedule is provided in Section 3.1.1.1 and Appendix 1b.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be
replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)

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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
RO7234292 is not approved and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with RO7234292 in completed and 
ongoing studies.  The known safety risks for the lumbar puncture procedure and 
RO7234292 are outlined below in Sections 5.1.1 and 5.1.2, respectively.  Please refer to 
the RO7234292 Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this 
study, including the eligibility criteria.  Patients will undergo safety monitoring during the 
study, including assessment of the incidence and severity of adverse events.  Guidelines 
for managing adverse events, including criteria for treatment interruption or 
discontinuation, are provided below.
5.1.1
Known Risks Associated with Lumbar Puncture
Postlumbar puncture syndrome, spinal hematoma, and meningitis (see 
Sections 5.1.1.1 through 5.1.1.3) are potential risks associated with lumbar puncture. 
In the completed Phase I/IIa study, the most commonly reported adverse events across 
all treatment groups (RO7234292, n34; placebo, n12) were procedural pain (54% of 
patients) and postlumbar puncture syndrome (37% of patients).
In the recently completed Phase II OLE study BN40697, potential LP procedure-
associated selected AEs were reported with similar incidence across the cohorts despite 
the difference in dosing frequency (16 patients [69.6%] in the Q4W cohort and 
17 patients [73.9%] in the Q8W cohort).  Overall, the most frequently reported event 
was procedural pain (41.3%).  In the ongoing Phase III study BN40423, patients 
enrolled under Protocol Versions 13 (receiving Q4W blinded treatment) were 
discontinued following discontinuation of the Q4W dosing.  These patients’ treatment 
assignments are now unblinded and hereby referred to as original design cohort (ODC).  
In the ODC, potential LP procedure associated selected AEs were reported with similar 
incidence across the three cohorts (17 patients [47.2%] in the placebo cohort, 
14 patients [40%] in the Q4W cohorts, and 17 patients [47.2%] in the Q8W cohort).  
Overall, the events reported with highest incidence were procedural pain and post-LP 
syndrome (14% each).
As of 7 August 2020, in the ongoing Study BN40955, potential LP procedure 
associated selected AEs were reported in 30 patients [22.9%] in the Q8W cohort and 
11 patients [15.1%] in the Q16W cohort.  Overall the most frequently reported event 
was procedural pain (9.2% in the Q8W cohort and 4.1% in the Q16W cohort).
Many of the complications associated with lumbar puncture can be avoided by the 
mandatory use of a 24G atraumatic needle with a stylet, adherence to procedural 

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guidelines (see lumbar puncture manual and instructional video), and careful 
assessment of the patient, including neurologic examination with fundoscopy both prior 
to and postlumbar puncture procedure.  Lumbar puncture should be avoided when a 
contraindication is present.
CSF leakage is more likely with larger bore needles.  To minimize this risk, a 
24G atraumatic needle will be used.  Training for use of the 24G atraumatic needle in 
this study will be provided prior to initiation of lumbar puncture, as will a review of 
extension tubing use and the need to gently aspirate CSF for timely collection.  If 
headache with characteristics of low-pressure syndrome is present after the procedure
and persists despite standard-of-care treatment, a blood patch should be considered.  
Formation of a subarachnoid epidermal cyst (i.e., when a skin plug is introduced into the 
arachnoid space) can be avoided by use of a needle with stylet, which is mandatory.  
Rarely, brain herniation can occur in the setting of lumbar puncture and increased 
intracranial pressure.  
There are specific contraindications to performing lumbar puncture.  These include 
unstable cardiorespiratory status, where positioning patient for lumbar puncture may not 
be tolerated, signs of cerebral herniation or incipient cerebral herniation, signs of 
increased intracranial pressure, or focal neurological findings on examination.  In those 
patients, lumbar puncture (and IT treatment administration) should not be performed and 
appropriate diagnostic work-up should be initiated.  On a case-by-case basis and 
following discussion with the Medical Monitor, such patients may be able to resume 
treatment.  Previous lumbar surgery is an exclusion criterion for this study.   
In the setting of HD, for the purposes of lumbar puncture and IT bolus injection of
RO7234292, moderate to severe truncal chorea may also be prohibitive.  
5.1.1.1
PostLumbar Puncture Syndrome
RO7234292 is delivered directly to the CNS by IT lumbar puncture injection.  
Postlumbar puncture syndrome (e.g., headaches, nausea, vomiting, infection, 
hemorrhage, nerve irritation pain) can occur with IT administration.  Experience to date 
with postlumbar puncture syndrome, as reported in the completed Phase I/IIa study, 
includes headache, which occurred after 10% of procedures and was transient and mild 
in the vast majority of patients.  
In the recently completed Phase II OLE Study BN40697, post-LP syndrome events 
(such as post-LP syndrome, headache, migraine, nausea, vomiting or procedural 
headache) occurring within 5 days of LP were reported in 9 patients (39.1%) in the 
Q4W cohort and 13 patients (56.5%) in the Q8W cohort.
In Study BN40423 ODC, post-LP syndrome events (post-LP syndrome, headache, 
migraine, nausea, vomiting or procedural headache) occurring within 5 days of LP were 

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reported in 14 patients (38.9%) in the placebo cohort, 8 patients (22.9%) in the Q4W 
cohort and 14 patients (38.9%) in the Q8W cohort.
As 7 August 2020, in the ongoing Study BN40955, post-LP syndrome events (such as 
post-LP syndrome, headache, migraine, nausea, vomiting or procedural headache) 
occurring within 5 days of LP were reported in 7 patients (5.3%) in the Q8W cohort 
and 2 patients (2.7%) in the Q16W cohort. 
The majority of these events were mild or moderate and non-serious.  No events led to 
treatment interruption or discontinuation.
Patients should walk postlumbar procedure (see Section 4.3.2.1). However, if a patient 
develops a headache after the lumbar puncture with characteristic features, which 
makes walking intolerable, the patient should be encouraged to first sit down and if the 
headache persists then the patient should lie in a comfortable position, which is most 
likely in the supine position owing to the postural nature of the symptoms.  Supportive 
treatment may include rehydration, consumption of caffeinated drinks, simple 
analgesics, opioids, and antiemetics.  If these conservative measures fail, more specific 
measures may be indicated.
5.1.1.2
Spinal Hematoma
Postlumbar puncture spinal hematoma is a very rare but important potential risk that 
can present as persistent back pain, radicular pain, new sensory or motor symptoms, 
sphincter disturbance, or meningism.  Prompt MRI scanning should be performed if 
suspicion of spinal hematoma arises.  Patients with susceptibility to bleeding, patients 
with coagulopathy, and patients receiving anticoagulant therapy are at an increased risk 
of spinal hematoma and will be excluded from the study (see Section 4.1.2).  
Management of spinal hematomas should include consultation with neurosurgical 
colleagues.
5.1.1.3
Meningitis
Meningitis is a rare potential risk of lumbar puncture.  Patients may present with 
headache, meningism, photophobia, neck stiffness, and pyrexia.  Guidelines for 
management of patients with suspected meningitis are provided in Table 3. 
5.1.2
Potential Risks Associated with RO7234292
The potential risks identified below have been considered in relation to clinical data 
available as of 7 August 2020, including the completed Phase I/IIa study and its
Phase II OLE Study (BN40697), Study BN40423 (ODC), and the ongoing Study 
BN40955.  
5.1.2.1
Neurologic Changes
In cynomolgus monkeys, acute, transient deficits in lower spinal reflexes (patellar reflex 
in particular) were typically observed 2 to 8 hours following dosing, in the 13-week and in 

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the chronic toxicity studies.  The transient changes in patellar reflex were observed in all 
treatment groups, including controls, with a slightly higher incidence in the high-dose 
groups.  These findings were fully reversible within 24 hours following dosing.  No other 
treatment-related changes in general sensory and motor function parameters nor 
changes in the cerebral reflexes were observed.
In the Phase I/IIa MAD study (ISIS 443139-CS1), no adverse trends in neurological 
examinations were detected and only a few drug-related neurological adverse events 
were observed in 2 patients.  See the RO7234292 Investigator’s Brochure for more 
information.
In the other completed and ongoing studies, among events associated with peripheral 
nervous system, 2 cases of asymptomatic lumbar radiculopathy that were characterized 
by loss of ankle reflexes without changes in motor or sensory function and one serious 
adverse event (SAE) of radiculopathy and hyporeflexia (suspected unexpected serious 
adverse reaction [SUSAR] case) have been observed in the Phase II OLE study 
BN40697 at the Q4W 120 mg cohort.  In Study BN40423 ODC, one case of lumbar 
radiculopathy (post traumatic, considered not related to study drug by the investigator) 
was reported in the Q8W cohort.  In Study BN40955, no treatment emergent 
radiculopathy cases have been reported. 
Among reflex change events in Study BN40697, areflexia and reflexes abnormal were 
reported in 1 patient each in the Q4W cohort and hyporeflexia was reported in 1 patient 
each in the Q4W and Q8W cohorts, respectively.  In Study BN40955, treatment 
emergent areflexia was reported in 1 patient in the Q8W cohort, and none were 
reported in the Q16W cohort.  No reflex change AEs have been reported in Study 
BN40423 ODC.  For details, see the RO7234292 Investigator’s Brochure.
Among events associated with the central nervous system in Study BN40697, 
dysarthria was reported in 2 patients in the Q4W cohort; coordination abnormal was 
reported in 1 patient in the Q4W cohort; pleocytosis was reported in 1 patient in the 
Q4W arm; and ataxia was reported in 1 patient each in the Q4W and Q8W cohorts, 
respectively.  An SAE of cerebrovascular accident was reported in 1 patient in the Q4W 
cohort, which was considered by the investigator not to be related to study drug by the 
investigator.  SAEs of hemiparesis, myelitis, and neuritis (SUSAR cases) were reported 
in another patient in the Q4W cohort.  In Study BN40423 ODC, ataxia (SUSAR case) 
and dysarthria were reported in 1 patient each in the Q4W cohort.  In Study BN40955, 
treatment-emergent event of ataxia was reported in 1 patient each in the Q8W and 
Q16W cohorts, respectively, pleocytosis was reported in 1 patient in the Q8W cohort, 
and two neurological SUSAR cases were reported in 2 patients in the Q8W cohort (1 
patient each for arachnoiditis and aseptic meningitis).  For details see the RO7234292 
Investigator’s Brochure.

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Following LP administration and post-LP mobilization, neurologic examinations should 
be conducted.  In addition, patients should be observed in clinic for any complications or 
complaints post-LP and intrathecal bolus injection of RO7234292.
5.1.2.2
Elevations in CSF WBCs and Protein
The CSF WBC elevations were also observed in the chronic non-human primate study 
with slight increases over time.  Increases were mild, and there was no apparent dose 
dependency.
CSF protein and WBC increases have been observed in the RO7234292 program. 
In Study BN40697, one patient was diagnosed with chemical meningitis (SUSAR case) 
in the Q4W cohort.  As of 4 October 2020, in the ongoing Study BN40955, one patient 
experienced aseptic meningitis (clinically not infectious) and one patient experienced 
arachnoiditis, in the Q8W cohort.  
For details on CSF proteins and WBC laboratory values and non-serious AEs of CSF 
WBC and protein increases, please refer to the RO7234292 Investigator’s Brochure.
5.1.2.3
Thrombocytopenia
Reductions in platelet count have been observed after systemic administration of some 
2'-MOE chimeric ASOs to clinical trial subjects.  However, no clinically significant 
reductions in platelet counts have been observed in clinical studies for RO7234292 to 
date.  In one 13-week and one 9-month IT toxicity studies of RO7234292 in the 
cynomolgus monkey, there were no effects on hematology or coagulation parameters.
No clinically significant reduction in platelet counts has been observed in the completed 
and ongoing studies in the RO7234292 program to date.
Platelet counts will be monitored at each study visit prior to lumbar puncture.  See 
Table 3 for patient stopping and treatment discontinuation rules.
5.1.2.4
Kidney Effects
Reductions in renal function have been observed after administration of some 2'-MOE 
containing chimeric ASOs to clinical trial subjects.  In the 13-week and 9-month toxicity 
studies of RO7234292 in cynomolgus monkeys, there were no test articlerelated 
histologic findings in the visceral organs or effects on clinical chemistries.
No clinically significant reduction in kidney function was observed in the completed 
RO7234292 Phase l/IIa study. Among the other completed and ongoing studies, in the 
recently completed Phase II OLE study BN40697, one case of moderate and non-serious
proteinuria was reported in the Q4W cohort, which resolved without any intervention, 
was considered by the investigator to be related to the study treatment, and the patient 
continued study drug administration. No other clinically significant kidney abnormality 
has been observed.

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Kidney function will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased renal function are provided in Table 3.
5.1.2.5
Liver Effects
Elevations in liver enzymes have been observed after administration of some 2'-MOE 
chimeric ASOs to clinical trial subjects. However, no clinically significant elevation in liver 
enzymes have been observed in the clinical studies for RO7234292 to date.
In the 13-week and 9-month toxicity studies of RO7234292 in cynomolgus monkeys, 
there were no drugrelated histologic findings in the visceral organs, including the liver, 
or effects on clinical chemistry test levels. No clinically significant elevations in liver 
enzymes were observed in the completed RO7234292 Phase I/IIa study. Among the 
other completed and ongoing studies, in the recently completed Phase II OLE study 
BN40697, one mild AE of hepatic enzyme increase was reported in 1 patient in the 
Q4W cohort, which resolved without any intervention and was considered by the 
investigator not related to RO7234292. No other clinically significant hepatic 
abnormality has been observed.
Liver enzymes will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased liver function are provided in Table 3.
5.1.2.6
Hydrocephalus
Hydrocephalus is included as a warning in the labelling of one marketed IT-administered 
2'-MOE chimeric ASO.  
Ventricular volume expansion has been described in the RO7234292 Investigator’s 
Brochure and is being monitored in all RO7234292 studies.
An SAE of hydrocephalus following chemical meningitis was reported in a patient who 
has undergone shunting in the Q4W cohort of the recently completed Phase II OLE 
Study BN40697.  In ongoing blinded Study BN40423, 1 patient with symptomatic 
communicating hydrocephalus has been shunted (SUSAR case) and 1 patient with a 
medical history of hydrocephalus had an event of hydrocephalus (verbatim: worsening 
hydrocephalus) that was considered by the investigator not to be related to the study 
treatment. 
For details and description of non-serious AEs, refer to the RO7234292 Investigator’s 
Brochure; for management guidelines, see Section 5.1.3.3.
5.1.2.7
Neuropsychiatric Changes
RO7234292 is directly administered to the CNS, with limited clinical experience.
Nonclinical studies in animals did not show any adverse effects on the CNS.  Though a 
single case of completed suicide has occurred in the ongoing Phase II OLE study 
(BN40697), when weighing all available details of the case, the investigator has 
concluded that this event was not related to RO7234292.  Patients should be closely 

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monitored for signs and symptoms of neuropsychiatric changes in addition to routine 
monitoring with the Columbia-Suicide Severity Rating Scale (C-SSRS) and the Montreal 
Cognitive Assessment battery.
5.1.2.8
Potential Risk due to Reduction of Target Protein HTT
By specifically targeting mRNA from both HTT alleles, RO7234292 lowers levels of both 
mHTT protein and normal wild-type huntingtin (wtHTT) protein in all patients, regardless 
of genetic variations.  The ASO modality provides partial, transient, reversible, and 
titratable HTT lowering.  Partial HTT lowering is safe and well tolerated in normal rodents 
and non-human primates, as shown in multiple studies using ASOs and non-reversible 
approaches.  Furthermore, no safety signals of concern emerged during the completed
Phase I/IIa study of RO7234292 in adults with HD (see RO7234292 Investigator's 
Brochure), in which partial lowering was achieved.
Transgenic mice expressing human mHTT develop progressive HD-like phenotypes that 
recapitulate many aspects of HD in humans.  ASO-mediated mHTT lowering provides 
therapeutic benefits and often restores normal functioning in transgenic and fully 
humanized animal models of HD, with generally similar results regardless of whether 
wtHTT is also lowered. Moreover, no detrimental effects of partial wtHTT lowering in 
animal models have been reported in multiple studies using ASOs and non-reversible 
approaches.
Still, the current understanding of the diverse cellular functions of HTT suggests potential 
theoretical risks associated with reducing total HTT levels in people with HD. More than 
two decades of research findings implicate HTT in a wide array of cellular functions, 
including microtubule-based transport, F-actin-based trafficking, Rab-based trafficking, 
brain-derived neurotrophic factor transport, ciliogenesis, transcription, chromatin 
modification, post-transcriptional gene-expression regulation, neurogenesis, 
synaptogenesis, synaptic plasticity, signaling pathways, cell stress responses, cell 
survival, selective macro-autophagy and DNA damage repair, as detailed in a recent 
review article (Liu and Zeitlin 2017).
Although functional HTT (mutant or wild-type) is essential for embryogenesis, 
near-complete genetic ablation of HTT has little or no reported neurological effect in 
normal adult animals. However, complete ablation of wtHTT protein expression 
throughout life results in a worsening motor phenotype and, in male transgenic mice, 
age-dependent emergence of brain atrophy and decreased testicular size (Van 
Raamsdonk et al. 2005).  In contrast, decreases in mHTT protein expression ameliorate 
disease, and increases in mHTT protein exacerbate disease in animal models of HD, 
regardless of concomitant changes in wtHTT protein levels.
No clinically significant new neurologic events were observed in the completed 
Phase l/IIa study.  As a precaution, a full neurologic examination will be conducted at 

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each study visit (on dosing days before and after dosing), and additional monitoring of 
cognition will be conducted throughout the study using the MoCA.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Dose Modifications
No dose modifications are permitted in this study, whether by varying the amount of 
study drug volume injected or the frequency of procedure per protocol (i.e., all 
participants will receive 20 mL of blinded study drug per injection on a Q8W basis).
5.1.3.2
Treatment Interruption
Study drug may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  If study drug has been withheld for 60 days, 
from the date of the first missed dose, because of signs of persistent drug-induced 
toxicity or if the scheduled dose has been missed, the investigator should consult the 
Medical Monitor to determine if discontinuation from study drug is warranted.  Study drug
may be suspended for reasons other than toxicity (e.g., surgical procedures) with 
Medical Monitor approval.  The investigator and the Medical Monitor will determine the 
acceptable length of treatment interruption.
5.1.3.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 3.  
Additional guidelines are provided in the subsections below.
Initial clinical laboratory tests with results meeting criteria for withholding study drug must 
be repeated on new specimens as soon as possible, and results must be available prior 
to administering the next dose of study drug. In general, patients who do not reach the 
stopping rule may continue dosing; however, the investigator and Sponsor should confer 
as to whether additional close monitoring of the patient is indicated.

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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events
Event
Action to Be Taken
Elevations in CSF WBC 
count or proteins or 
suspected meningitis, 
radiculitis, arachnoiditis, 
hydrocephalus, or other 
acute neurologic symptoms

Withhold study drug if diagnosis of meningitis, radiculitis,
arachnoiditis, hydrocephalus, or acute neurologic symptoms is 
suspected and initiate appropriate diagnostic work-up as 
indicated. 

Clinical signs and symptoms of hydrocephalus (e.g., new 
onset of persistent or worsening gait disturbance, change 
in level of consciousness/cognition, changes in continence, 
or a combination of all three signs) are required for 
diagnosis of suspected hydrocephalus.  

Clinical signs and symptoms of meningitis (e.g., headache, stiff 
neck, fever) plus confirmatory WBC count are required for 
diagnosis of suspected meningitis; and clinical signs and 
symptoms are required for diagnosis of radiculitis, arachnoiditis, 
or acute neurologic symptoms.  Isolated low-level (e.g., 550/L
WBC count) elevations in CSF WBC count without clinical 
symptoms does not meet criteria for diagnosis of suspected 
meningitis.  

The Medical Monitor should be consulted in all cases where 
CSF WBC count elevations above 10/L are present, or a 
change from baseline in CSF proteins greater than twice 
baseline or where there is uncertainty to discuss next steps of 
patient management in the study.

If diagnosis of suspected meningitis, radiculitis, arachnoiditis, 
hydrocephalus, or other acute neurologic symptoms is refuted, 
the study drug may be resumed after consultation with the 
Medical Monitor.

In the event meningitis, radiculitis, arachnoiditis, hydrocephalus, 
or acute neurologic symptom diagnosis is confirmed, standard-
of-care therapies should be instituted as indicated.

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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Thrombocytopenia

If platelet count is 100,000/mm3:
o
Monitor platelet count weekly

If platelet count is 75,000/mm3 and 50,000/mm3 in the 
absence of major bleeding or clinically relevant non-major 
bleeding:
o
Withhold study drug until the platelet count has recovered 
to 100,000/mm3.  
o
The suitability of the patient for continued dosing and 
frequency of monitoring should be discussed with the 
Medical Monitor. 

If platelet count is 50,000/mm3:
o
Permanently discontinue study drug. 
o
Monitor platelet counts daily until two successive values 
show improvement.  Then monitor every 23 days until 
platelet count is stable, and at least weekly until platelet 
count returns to normal.
o
Treatment per standard of care should be considered for 
patients whose platelet count is 25,000/mm3.
Decreased renal function

Withhold study drug in the event of a persistent (2 weeks) 
decrease in eGFR or CrCl or increase in creatinine, as defined
below:
o
eGFR or CrCl (using Cockcroft-Gault) 60 mL/min
o
Creatinine level increase of 2.0 above baseline

Study drug may be resumed when follow-up test results show 
that the patient no longer meets the dose interruption criteria.
Elevated liver enzymes

ALT or AST is 3ULN:
o
Monitor weekly until ALT and AST return to 1.2ULN.
o
Further investigation into the liver enzyme elevations may 
include hepatitis serologies and other diagnostic tests at 
the discretion of the investigator in consultation with the 
Medical Monitor.

Withhold study drug in the event of liver enzymes that meet the 
following criteria without an alternative explanation (as 
discussed with the Medical Monitor):
o
ALT or AST 5ULN 
o
ALT or AST 3ULN, combined with total 
bilirubin 2ULN or INR 1.5
o
ALT or AST 3ULN coinciding with new appearance of
fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or concomitant eosinophilia.
o
Discontinue study drug permanently if levels do not return 
to baseline after 30 days.
CrClcreatinine clearance; CSF cerebrospinal fluid; eGFRestimated glomerular filtration rate; 
ULNupper limit of normal.

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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

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
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 5 months after the 
final dose of study drug or until the patient receives his or her first dose in the OLE study 
(BN40955), at which time reporting will occur per the new study requirements.  For 
patients consented to version 6 of the protocol, who have discontinued study treatment 
and have entered the ETT schedule of assessments, AEs will be reported until 5 months 
after the last dose of study drug or until the EoT for ETT Week 101 visit (whichever is 
longer).  For patients consented to version 6 of the protocol, who have received their
last dose of study treatment less than 5 months before the scheduled Week 101 EoT for 
ETT visit, an additional safety telephone call should be performed 5 months after the 
last dose.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 

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5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale indicated in Table 4 will be used for assessing 
adverse event severity.  Laboratory values determined as an adverse event should be 
graded as per Appendix 6, which is based on the NCI CTCAE (v5.0).
Table 4
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 Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event

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Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of IT bolus-related reaction or anaphylactic reaction.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 

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severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.

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

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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2 ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). This 
includes death attributed to progression of HD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of HD, "Huntington's disease progression" 
should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.

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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Huntington's Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours

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5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
RO7234292 or placebo, adverse events associated with special situations should be 
recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with RO7234292 or placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF 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 two
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one

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entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived by the Sponsor from PRO, ObsRO, or digital 
wearable device (HD mobile app) data, and safety analyses will not be performed using 
PRO or ObsRO or digital wearable device data.  Sites are not expected to review the 
PRO or ObsRO or digital wearable device data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on patient 
management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
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.

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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 5 months after the final dose of study drug or until the EoT 
for ETT Week 101 visit (whichever is longer). Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 5 months after the final 
dose of study treatment are provided in Section 5.6.

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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 

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recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
greater than 5 months after the final dose of study drug), if the event is believed to be 
related to prior study drug treatment.  These events should be reported through use of 
the Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 

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scanning and emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO7234292 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
All patients enrolled prior to Version 4 of the protocol will not be included for any efficacy 
analysis.  The safety data collected for these patients up to and including the end of 
treatment visit in Protocol BN40423 will be analyzed separately.  
The primary efficacy analysis will be conducted at the end of the study (see Section 3.2).  
Treatment assignments will be unblinded to the Sponsor at the end of the study after the 
data have been cleaned and verified and the database has been locked.
Details of the planned statistical analyses mentioned below will be fully specified in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to the locking and 
unblinding of the study database.
Unless otherwise specified, all the p-values considered in Section 6 are two-sided.
6.1
ANALYSIS POPULATIONS
The intent-to-treat (ITT) population will consist of all patients enrolled after 
implementation of Protocol Version 4 who received any study treatment. Randomized 
patients who receive incorrect therapy from that intended will be summarized in the 
group according to their planned randomized treatment.  The ITT population will be the 
primary population for all analyses of primary and secondary efficacy variables.

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The safety population for the trial will consist of all patients who enroll after 
implementation of Version 4 of the protocol and also receive any study treatment.  The 
safety population will be the primary population for all safety analyses.  For the purpose 
of all safety analyses, it will be assessed whether patients received a treatment different 
from the one they were randomized to at any time during the course of the study.  In 
case the number and duration of such “treatment switches” warrants it, the safety 
population may be redefined by reallocating individual patients to the treatment actually 
received, as opposed to which treatment they were randomized to.
The PK population will include all patients randomized after implementation of Protocol 
Version 4 who received at least one dose, and had sufficient sampling to permit PK 
evaluation.
6.2
DETERMINATION OF SAMPLE SIZE
The planned sample size is adequate to capture meaningful clinical decline on both the 
TFC and cUHDRS and was estimated on the basis of data available from 
non-interventional studies (TRACK-HD, COHORT, ENROLL-HD) and a randomized 
placebo-controlled study (2CARE).  Based on these data, using the anticipated trial 
population, a meta-analysis for the change from baseline at 24 months in TFC score 
suggested a natural decline of 1.36 points and a corresponding pooled standard 
deviation of 1.78.  A conservative treatment discontinuation rate at Week 101 for 
patients receiving placebo or active is assumed to be 20% and 15%, respectively.  Using 
these assumptions, the simulation described below was performed to estimate the 
sample size.  
Description of Simulations to Derive the Sample Size
The design used for the simulation was simplified to consider only 2 treatment arms 
(placebo and active) and 2 postbaseline timepoints (Week 49 and Week 101).  These 
simplifications are justifiable given that:

The overall alpha level 5% will be split to 2.5%, such that each active treatment will 
be tested against placebo independently. Within each testing chain, a hierarchical 
procedure will be used to test the primary endpoint and secondary endpoints (see 
Section 6.3).

The difference on the derived sample size for considering more than two 
postbaseline timepoints would be minimal. 
The following algorithm was run and repeated 500,000 times:
1. Generate change from baseline values in TFC at Week 49 and Week 101 for 
N active patients according to the following bivariate normal distribution: 
 _ 49
_ 101 = " #$ = #0.47
0.82% , ' = #1.56)
1.8
1.8
1.78)%%

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where y_wk49 and y_wk101 is the change from baseline in TFC, respectively, at 
Week 49 and Week 101, is the assumed true change at those two timepoints, 
and ∑ is the variance-covariance matrix.  Subsequently:

set to missing, due to study drugrelated (SDR) reasons, both values at 
Week 49 and Week 101 for 5% of the N patients.  Set to missing, due to 
nonstudy drugrelated (NSDR) reasons, both values at Week 49 and 
Week 101 for additional 2.5% of the N active patients.

set to missing, due to SDR reasons, only the value at Week 101 for 
additional 5% of the N active patients.  Set to missing, due to NSDR
reasons, only the value at Week 101 for additional 2.5% of the N active 
patients.
2. Generate change from baseline values in TFC at Week 49 and Week 101 for 
N placebo patients according to the following bivariate normal distribution: 
 _ 49
_ 101 = " #$ = #0.79
1.36% , ' = #1.56)
1.8
1.8
1.78)%%
where y_wk49 and y_wk101 is the change from baseline in TFC, respectively, at 
Week 49 and Week 101, is the assumed true change at those two timepoints, 
and ∑ is the variance-covariance matrix.  Subsequently:

set to missing both values at Week 49 and Week 101 for 10% of the 
N placebo patients

set to missing only the value at Week 101 for additional 10% of the 
N placebo patients
Given how missing data will be imputed, it is not relevant to differentiate missing 
data into SDR versus NSDR reasons for placebo patients.
3. Apply multiple imputations and derive 20 complete datasets.  Missing data on 
placebo patients were imputed from the placebo arm.  Missing data on active 
patients, depending on if due to NSDR or SDR reasons, were imputed 
respectively from the active or the placebo arm. 
4. Use a t-test to compare active versus placebo at Week 101 for each completed 
dataset and pool the result (Rubin 1987) to derive an estimate of the treatment 
effect, including a p-value.
Across the 500,000 simulations, the power achieved, with the N patients per arm was 
calculated by dividing the number of times the p-value (in above Step 4) was below 2.5% 

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by 500,000.  The above procedure was repeated by only changing the N until the 
calculated power was close to 80%.
It was estimated that 267 patients per arm will provide approximately 80% power, at a 
two-sided 0.025 level, to detect a 40% slowing of clinical decline for RO7234292 as 
compared with placebo at 101 weeks.  This treatment effect translates into an expected 
average decline of ~0.82 points at 101 weeks for the RO7234292 arms.  The minimal 
detectable difference with these assumptions is ~0.38 points.  
6.3
TESTING STRATEGY AND MULTIPLICITY ADJUSTMENT 
The overall alpha level 5% will be split to 2.5% for testing each active treatment against 
placebo. A hierarchical approach will be used for multiple adjustments that accounts for 
multiple endpoints (the primary and secondary endpoints).  
Within each testing chain (RO7234292 Q8W and RO7234292 Q16W), the endpoint will 
be tested only if the preceding endpoint is significant at the alpha level 2.5%.  Details of 
the order for secondary endpoints will be detailed in the SAP. 
6.4
SUMMARIES OF CONDUCT OF STUDY
The numbers of patients who enroll in the study, discontinue from the study, and
complete the study will be summarized overall and by treatment arm.  Reasons for 
premature study withdrawal will be listed and summarized.  Enrollment and major 
protocol deviations will be listed and evaluated for their potential effects on the 
interpretation of study results.
6.5
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, CAG repeat length, CAP, 
HD stage, education) will be summarized using means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.  Summaries will be presented overall and by treatment group.
6.6
EFFICACY ANALYSES
To ensure the treatment groups under comparison are concurrent and that treatment 
regimens are comparable across the entire dosing period of the 25-month study, for all 
efficacy analyses, patients enrolled prior to implementation of Protocol Version 4 will not 
be included and will be offered the option to enroll into Study BN40955 before reaching 
the primary endpoint assessment in the current study.    

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6.6.1
Estimands
Following the very recent estimand framework outlined in the ICH-E9 draft addendum
(FDA 2017), the attributes of the estimand for the primary endpoint are defined as 
follows:

Population: ITT population (see Section 6.1)

Variable:  Change from baseline in cUHDRS score at Week 101  
–
Note: cUHDRS scale will be replaced by TFC scale for the FDA.

Intercurrent events (ICEs): 
–
Treatment discontinued for study drugrelated reasons (e.g., treatment-related 
adverse event or lack of efficacy):
–
After treatment discontinuation, the actual off-treatment values will be 
used in the analysis. 
–
Treatment discontinued for NSDR reasons (e.g., lost to follow-up): 
–
After treatment discontinuation, imputed hypothetical values as if patients 
had continued receiving study drug will be used in the analysis. In this 
instance, any data collected after treatment discontinuation will not be 
included in the analysis. 

Population level summary:  Difference in mean change from baseline at Week 101 
between each active arm and the placebo arm 
The primary estimand is a combination of a treatment-policy strategy and a hypothetical 
strategy (FDA 2017) to account for the different assumptions for each type of ICE. 
The Sponsor will emphasize to investigators the importance of collecting data for the 
primary endpoint through Week 101, even if patients discontinue study drug but do not 
withdraw study consent, as well as the importance of providing detailed reasons for 
treatment discontinuation. The primary estimator, described by the statistical model in 
Section 6.6.2, will be applied on the dataset produced after multiple imputation of any 
missing value.  In principle,

missing data as well as off-treatment data from patients who discontinued treatment 
for NSDR reasons will be imputed from patients with available data from the same 
treatment arm collected while on treatment

missing data from patients who discontinued treatment for SDR reasons will be 
imputed from: 
-
patients with available data from the placebo arm collected either while on 
treatment or off treatment and
-
patients with available data from the same treatment arm collected while off 
treatment

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Multiple imputation of missing data values will be performed as follows:
1. Imputation step:  Missing data values will be imputed "m" times leading to "m" 
complete datasets.  
2. Analysis step:  Each of the resulting "m" datasets will be analyzed using the 
statistical model described in Section 6.6.2, which will provide an estimate of 
treatment difference.  
3. Pooling step:  The results from the "m" datasets will be combined (Rubin 1987) 
leading to an overall estimate of the treatment effect and associated 95% confidence 
intervals and p-values.
Full details of the algorithm for multiple imputation (e.g., which reference population to 
use for each missing data pattern, number of imputed datasets, method for imputation, 
etc.) will be provided in the SAP.
A supplementary estimand may be considered (and will be defined in the SAP). 
6.6.2
Primary Efficacy Analysis
The primary efficacy endpoint is the change from baseline in cUHDRS score at 
Week 101.  This is defined as the attribute "variable" of the primary estimand in Section 
6.6.1.
Note: The primary efficacy endpoint for the U.S. FDA will be change from baseline in 
the TFC score at Week 101. TFC will be analyzed the same way as the cUHDRS.
The primary efficacy analysis for this study will compare each active treatment arm, 
RO7234292 Q8W and RO7234292 Q16W, against the placebo arm.  
To account for the multiple comparison, an appropriate procedure will be used to 
maintain the overall two-sided type I error at 5% (details will be given in the SAP). 
The analysis of the primary endpoint will be performed by means of analysis of 
covariance (ANCOVA).  The model will include the corresponding endpoint baseline 
score, CAG repeat length, baseline CAP score (defined in Section 4.1.1), and treatment 
as covariates.  On the basis of this analysis, least squares mean for the treatment 
differences at Week 101 and corresponding 95% CIs will be derived.  
The robustness of the primary method of estimation described above may be explored 
by alternative sensitivity estimators based on varying assumptions underlying the 
multiple imputation strategy. These sensitivity analyses will be described in the SAP.
6.6.3
Secondary Efficacy Analyses
The secondary efficacy endpoints are identified in Section 2.1.2.

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Similar hypotheses as for the primary efficacy endpoint will be tested for the secondary 
continuous efficacy endpoints. 
Categorical endpoints, such as CGI-C and the proportion of progressors, will be 
analyzed by means of logistic regression and will include treatment (categorical), CAG 
repeat length, and CAP score as covariates.   
Methods for controlling type I error in the testing of the secondary endpoints will be 
described in the SAP. 
6.6.4
Subgroup Analyses
The results of selected efficacy variables will be summarized within subgroups using 
descriptive statistics.  The following variables will be used to define subgroups:

Sex (male vs. female)

Age at baseline (45 vs. 45 years)

CAG repeat length (43 vs. 43)

Stage at baseline (I, II, III)
–
Stage III will be considered only if there are enough patients.
Additional exploratory analyses of efficacy results may be performed using an ANCOVA 
model, similar to the primary analysis, based on change from baseline for the variable of 
interest, with baseline score (not for analysis by baseline stage), CAP score, CAG repeat 
length (not for analysis by CAG repeat length), treatment, subgroup, and treatment-by-
subgroup interaction as covariates.
6.6.5
Exploratory Efficacy Analysis
The exploratory efficacy endpoints are identified in Section 2.1.3.
The exploratory endpoints will be summarized using tables, listings, and graphs, as 
appropriate.  Additional statistical modeling may be considered (e.g., ANCOVA, logistic 
regression).
6.6.6
Historical Controls
Should the treatment discontinuation rate in the placebo arm be significantly higher than 
expected, the Sponsor may consider the use of historical controls for efficacy analysis.  
In this scenario, the use of historical controls will be deemed supportive analyses. 
Prior to database lock, the Sponsor may select historical controls from ENROLL-HD.  
These historical controls may be selected to match patients with regard to important 
baseline characteristics (e.g., gender, CAG, age, IS, International Standard 
Classification of Education).  The objective for use and exact algorithm for selecting 
historical controls will be specified in the SAP.  If implemented, the actual selection will 

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be made before database lock and unblinding of treatment allocation and will be 
documented and stored in the Sponsor's database.   
Whether the Sponsor will decide to use those the historical controls, the exact algorithm 
for borrowing and for deriving an overall treatment effect will be described in the SAP 
before unblinding.
Additionally, given that some of the patients who will be enrolled in this study may have 
been part of ENROLL-HD, the Sponsor may explore a within-patient comparison for the 
rate of decline in cUHDRS or TFC score, before treatment with RO7234292 (prior to 
randomization, using ENROLL-HD registry data) and after treatment with RO7234292
(after randomization, using study data), for patients who were randomized to the active 
arm and had follow-up in ENROLL-HD of at least 1 year's duration prior to randomization
into this study.
6.7
SAFETY ANALYSES
The safety population (see Section 6.1) will be the primary population for all analyses of 
safety data.  Incorrect treatment assignments (patients who received a treatment 
different than their planned randomized treatment) will be summarized and the impact on 
the safety assessment will be discussed.
For all safety analyses, patients enrolled prior to implementation of the Version 4 of the 
protocol will be summarized separately.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms.  The 
adverse event severity grading scale indicated in Table 4 will be used for assessing 
adverse event severity.  Laboratory values determined as an adverse event should be 
graded as per Appendix 6, which is based on the NCI CTCAE (v5.0).
All safety data, including adverse events, laboratory tests, CSSR-S, MoCA, ECG, and 
vital signs will be reported in individual listings and summarized by treatment for each 
assessment time using descriptive statistics. For continuous variables, both the original 
value as well as the change from baseline will be reported. 
The incidence of adverse events will be summarized on the basis of body systems and 
dictionary preferred terms. The incidence of adverse events by severity and relationship 
to study drug or study procedure and incidence of marked abnormal laboratory test 
results will be provided. 
The iDMC will review safety data throughout the study. Analyses required for the iDMC 
data review will be performed as described in the iDMC Charter.

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6.8
PHARMACOKINETIC ANALYSES
For all patients in the PK population (Section 6.1), CSF and plasma concentrations of 
RO7234292 will be presented descriptively, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation.  Nonlinear 
mixed-effects modeling will be used to analyze the concentrationtime data for
RO7234292 in CSF and plasma following IT administration. A covariate analysis will be 
conducted to evaluate the effect of covariates such as body weight, age, and sex on 
RO7234292 exposure.   
Population and individual estimates of primary PK parameters (e.g., clearance, 
distribution volume) and secondary PK parameters (e.g., area under the plasma 
concentrationtime curve, average trough plasma concentration) will be computed and 
used to explore exposure-response relationship on primary and key secondary
endpoints, as well as safety measures.  The data from this study may be pooled with 
data from other studies conducted with RO7234292 to support the population PK/PD 
modeling.
Details of this mixed-effects modeling and exploration of exposure-response analysis 
and results will be described and reported in a document separate from the Clinical 
Study Report.
6.9
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) will be summarized by treatment group. For those who 
are ADA-positive, titers will be estimated as well as antibody subtype.  In addition, the 
numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized for patients on active treatment only. When determining 
post-baseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more post-baseline samples is at least is at least 4-fold 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all post-baseline samples are negative, or if they are ADA positive 
at baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample (treatment unaffected). 

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The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.10
BIOMARKER ANALYSES
The biomarker endpoints are described in Section 2.5. 
A mixed-effects model repeat measurement model will be used to model the change in 
each primary and secondary biomarker endpoint, adjusting for the baseline endpoint, 
CAG repeat length, CAP score, treatment, visit, and treatment-by-visit interaction (the 
final list of covariates and details of the model will be specified in the SAP).
6.11
HEALTH STATUS UTILITY ANALYSIS
The health status utility endpoints are described in Section 2.6.
The health status utility endpoints will be summarized using tables, listings, and graphs, 
as appropriate.  Additional statistical modeling may be considered.
6.12
OPTIONAL INTERIM ANALYSES 
The Sponsor may choose to conduct one or more interim analyses for efficacy.  Below 
are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an iDCC and reviewed by the iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC Charter.
The decision to conduct an interim analysis, along with the rationale, specification of the 
endpoint (e.g., clinical and/or biomarker endpoint), number of patients, and statistical 
details for each analysis, will be introduced via a future protocol amendment, which will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC Charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of an interim analysis, and the iDMC Charter will be 
made available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of an 
interim analysis of efficacy data, the type I error rate will be controlled to ensure 
statistical validity is maintained.  Additional criteria for recommending that the study be 
stopped for positive efficacy will be added to a future protocol amendment.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 

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eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data electronic data 
from clinic visits (see Section 7.3) and electronic data obtained from the Roche HD 
mobile app (see Section 7.4) will be sent directly to the Sponsor, using the Sponsor's 
standard procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT-, CLINICIAN-, AND 
OBSERVER-REPORTED OUTCOME DATA
Electronic devices will be used to capture PRO, ClinRO, ObsRO, and PerfO data.  The 
devices are designed for entry of data in a way that is attributable, secure, and accurate, 
in compliance with U.S. FDA regulations for electronic records (21 CFR Part 11).  The 
data will be transmitted to a centralized database maintained by the electronic device 
vendor.
The electronic data will be available for view access only, via a secure vendor web 
portal. Only identified and trained users may view the data, and their actions will 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 

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study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
ELECTRONIC DATA OBTAINED BY THE ROCHE HD DIGITAL 
MONITORING PLATFORM
During "active tests" and "passive monitoring," the smartphone and wrist-worn wearable 
record movement and location data.  Data on the technical status and connectivity of the 
devices is also recorded.  Patients can choose to pause location data recording.  
No patient identifiable information is stored on the devices.  For selected "active test" 
tasks, touch and sound is also recorded.  Video is not recorded.
Roche HD mobile app (smartphone and wrist-worn wearable) sensor data are encrypted 
and uploaded to secure servers whenever the smartphone is connected to Wi-Fi. All 
sensor data will be managed by the Sponsor who will monitor and ensure the integrity 
and quality of the acquired data.  This includes, but is not limited, to the analysis of 
sensor data together with protocol-specified assessments and activities associated with 
routine daily living.  The data will not be analyzed for efficacy until study end, unless they 
are chosen to be a part of a pre-specified interim analysis along with other clinical and/or 
biomarker endpoints.
7.5
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.7.

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To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.6
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.7
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO, ClinRO, ObsRO (if applicable), and 
PerfO data (if applicable), Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 

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European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms) will be provided to each site.  If applicable, it will be provided in a certified 
translation of the local language.  The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the "Consent Forms") before 
IRB/EC submission.  The final IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study. The study companion must also sign and date a consent form 
prior to participation in the study.  The case history or clinical records for each patient 
shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.  If the patient 
should lose capacity to consent during the study (i.e., after enrollment), as judged by the 
investigator, a legally authorized representative may sign on behalf of the patient.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.

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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 

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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. Linking 
of data will be facilitated by the HDID number (see Section 4.5.2). The HDID is a unique 
coded identifier for persons participating in studies in HD.  This HDID will stay the same 
for a person throughout all trials.  The use of the unique identifier will assure that people 
are only enrolled once in large observational studies like Enroll-HD, REGISTRY, 
COHORT, PREDICT, and TRACK-HD and will also allow approved comparison and 
combination of data between studies.  The HDID is a 9-digit number created by a secure 
one-way algorithm, based on unchanging information (date of birth, birth name, place of 
birth and mother’s maiden name). The identifying data are used for the split second 
needed by the algorithm needed to generate the HDID and are never stored 
electronically on the web portal or in the study database. For patients without a 
pre-existing HDID number in the source notes, the investigator should store the original 
data and the newly generated HDID in the patient’s source documents and in the 
investigator file.  The HDID can be generated within the web portals of the observational 
studies or in the specially defined portal for the HDID generation under: 
https://hdid.enroll-hd.org. In addition, redacted clinical study reports and other summary 
reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 

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governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
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 patient safety and data integrity.  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.  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.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 110 sites globally, which may include The Republic of China, will
participate to enroll approximately 801 patients after implementation of Version 4 of the 
protocol.  Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.

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An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details) and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials
Data at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.

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9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
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Appendix 1a
Schedule of Activities for Patients Enrolled after Implementation of Protocol 
Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT b
Safety 
Follow-Up 
Calls ee
ETT b
SFU
Month
1
3
5
7
9
11
13
15
17
19
21
23
25
25
29
Week
4 to 1
1
5
13
21
29
37
45
53
61
69
77
85
93
101
101
117
Day (Window)
28 to 2
1
1
(3
(7) dd
(7)
(7)
(56)
Signed informed consent c
x
Review of inclusion and 
exclusion criteria 
x
Demographic data
x
Medical history and baseline 
conditions d
x
xe
Blood sample for CAG repeat 
length
x
Viral serology f
x
Thyroid panel g
x
Vital signs h
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical examination i
x
xe
x
x
x
x
x
x
Neurologic examination j
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG k
x
xe
x
x
x
x
x
x
x
Hematology l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test n
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
127/Protocol BN40423, Version 6
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT b
Safety 
Follow-Up 
Calls ee
ETT b
SFU
Month
1
3
5
7
9
11
13
15
17
19
21
23
25
25
29
Week
4 to 1
1
5
13
21
29
37
45
53
61
69
77
85
93
101
101
117
Day (Window)
28 to 2
1
1
(3
(7) dd
(7)
(7)
(56)
Local INR and/or PT, aPTT, 
platelet count x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for PK
x
x
x
x p 
x
x
x
x
x
Plasma sample for 
immunogenicity testing
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for biomarkers
x
x
x
x
x
x
x
x
x
x
x
Blood sample for clinical 
genotyping
xe
CSF sample for 
PK/safety/biomarkers
x
x
x
x
x
x
x
x
x
x
x
x
x
xy
x
x
MRI q
x
x
x
x
x
x
HD-DAS
x
x
x
x
x
x
x
Independence Scale
x
x
x
x
x
x
x
x
x
x
x
MoCA
x
x
x
x
x
x
x
x
x
x
x
C-SSRS r
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
UHDRS FA
x
x
x
x
x
x
x
x
x
x

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
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128/Protocol BN40423, Version 6
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT b
Safety 
Follow-Up 
Calls ee
ETT b
SFU
Month
1
3
5
7
9
11
13
15
17
19
21
23
25
25
29
Week
4 to 1
1
5
13
21
29
37
45
53
61
69
77
85
93
101
101
117
Day (Window)
28 to 2
1
1
(3
(7) dd
(7)
(7)
(56)
TFC s
x
x
x
x
x
x
x
x
x
x
TMS s, cc
x
x
x
x
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
CGI-C
x
x
x
x
x
x
x
x
x
SDMT s
x
x
x
x
x
x
x
x
x
x
SWR s
x
x
x
x
x
x
x
x
x
x
AES
x
x
x
x
x
x
x
x
x
SMDDS
x
x
x
x
x
x
x
x
x
NeuroQoL
x
x
x
x
x
x
x
x
x
x
EQ-5D-5L (in-clinic)
x
x
x
x
x
x
x
x
x
x
PGI-S
x
x
x
x
x
x
x
x
x
x
PGI-C
x
x
x
x
x
x
x
x
x
Roche HD mobile app in-clinic 
assessments
x
x
x
x
x
x
x
Roche HD mobile app remote 
data collection
Continuous remote data collection t
x
Optional exit interview u
x
x
CRQ: EQ-5D-5L, HUI-self, HUI-
proxy, CrGI-S
x
x
x
x
x
x
x
x
x
x

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
129/Protocol BN40423, Version 6
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT b
Safety 
Follow-Up 
Calls ee
ETT b
SFU
Month
1
3
5
7
9
11
13
15
17
19
21
23
25
25
29
Week
4 to 1
1
5
13
21
29
37
45
53
61
69
77
85
93
101
101
117
Day (Window)
28 to 2
1
1
(3
(7) dd
(7)
(7)
(56)
CRQ: AES
x
x
x
x
x
x
x
x
x
CRQ: CrGI-C
x
x
x
x
x
x
x
x
x
Remote data collection of CRQ 
(EQ-5D-5L, HUI-self, HUI-
proxy, HD-CIAOS, WPAI)
Remote data collection (see Appendix 4)
x
Blood sample for RBR DNA 
(optional) v
x
Blood sample for RBR RNA
(optional) v
x
x
x
x
x
Serum sample for RBR
(optional) v
x
x
x
x
x
Change in medical information 
since previous visit w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lumbar puncture x
x
x
x
x
x
x
x
x
x
x
x
x
x
x y
x y
x y
Study drug administration
x
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
Concomitant medications aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events bb
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; AESApathy Evaluation Scale; BLbaseline; CGI-C Clinical Global Impression, Change; CGI-S Clinical Global 
Impression, Severity; CrGI-CCompanion-Reported Global Impression, Change; CrGI-SCompanion-Reported Global Impression, Severity;
CRQCompanion-reported questionnaire; CSFcerebrospinal fluid; CSSRS Columbia-Suicide Severity Rating Scale; cUHDRS composite 

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
130/Protocol BN40423, Version 6
Unified Huntington's Disease Rating Scale; DCLdiagnostic confidence level; eCRF electronic Case Report Form; EoT end of treatment; EQ-
5D-5LEuroQol 5-Dimension, 5-Level Questionnaire; ETT early treatment termination; FAFunctional Assessment; HBsAghepatitis B surface 
antigen; HCVhepatitis C virus; HDHuntington disease; HD-CIAOSHuntington's Disease Companion-Reported Irritability and Angry Outbursts 
Scale; HD-DASHD Daily Activities Scale; HUIHealth Utilities Index; LP lumbar puncture; MoCA Montreal Cognitive Assessment; 
MRI magnetic resonance imaging; Neuro-Qol Quality of Life in Neurological Disorders; PGI-C Patient Global Impression, Change; PGI-
S Patient Global Impression, Severity; PKpharmacokinetic; Q8W every 8 weeks; RBR Research Biosample Repository; SDMT Symbol 
Digit Modalities Test; SFU safety follow-up; SMDDS Symptoms of Major Depressive Disorder Scale; SWR Stroop Word Reading; TFC Total 
Functional Capacity Scale; TMS Total Motor Score; UHDRSUnified Huntington's Disease Rating Scale.
Notes:  All assessments should be performed at the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be 
performed prior to dosing, unless otherwise specified.  
a A maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for patients who fail the initial screening (e.g., as a 
consequence of abnormal laboratory values or general medical status not meeting inclusion or exclusion criteria).  If re-screening is required, 
CAG repeat length testing from the initial screening does not need to be repeated (historical values will not be accepted). The screening MRI and 
viral serology from the initial screening, including for other Roche studies, may be acceptable as part of the re-screening assessments, if 
performed within 12 weeks of the baseline visit.  
b Patients who complete the treatment period will return to the clinic for a treatment completion visit at Week 101 (i.e., the EoT visit).  All patients 
enrolled in Study BN40423 who discontinue study treatment prematurely but do not withdraw consent for continued participation in the study 
(including all patients from 22 March 2021) will follow the ETT visit schedule (see Appendix 1b and Section 3.1.1.1). Study visits should be 
planned as per the study schedule, however under exceptional circumstances, a time window of 7 days can be utilized. The ETT visit should 
take place within 56 days of the decision to discontinue the study treatment.
Patients enrolled prior to implementation of Version 4 of the protocol: all patients will be prematurely discontinued from the Study BN40423 and 
will complete their EoT visit for early treatment termination prior to entry into Study BN40955.
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
d Medical history, including clinically significant diseases, surgeries, HD history (including past hospitalizations [i.e., number, duration, and 
reason]), over the last 2 years, reproductive status, smoking history, and use of alcohol and drugs of abuse will be recorded at baseline.
e Assessments may take place on Day 1 or Day 1.
f
Viral serology: HBsAg and HCV antibody (or viral RNA if HCV antibody assay is positive)
g Thyroid panel:  thyroid-stimulating hormone and free thyroxine (also known as T4) levels. 
h Vital signs include respiratory rate, pulse, temperature, and systolic and diastolic blood pressure while the patient is in a seated position after 
resting for approximately 5 minutes.  All data should be recorded on the appropriate eCRF.

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
131/Protocol BN40423, Version 6
i
A complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary 
examinations may be performed if clinically indicated.   The physical examinations should be conducted in the same manner on each occasion to 
ensure comparability to previous examinations. Changes from baseline abnormalities should be recorded in patient notes.  New or worsened 
clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as adverse events on the 
Adverse Event eCRF.  Height will be measured at screening and baseline only.
j
A neurologic examination (including fundoscopy), performed at screening and at every clinical visit, should include assessment of mental status, 
level of consciousness, cranial nerve function, motor function, sensory function, reflexes, gait, and coordination.  The neurologic examinations 
should be conducted in the same manner on each occasion to ensure comparability to previous examinations.  Neurologic examinations should 
be performed before and after treatment on each dosing day.  At visits when an LP is performed and study treatment is not administered, the 
neurological examination should be performed prior to the LP. Weight should also be measured at each visit. Any abnormality identified at 
baseline (Week 1) should be recorded on the General Medical History and Baseline Conditions eCRF.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related 
change) should be recorded as adverse events on the Adverse Event eCRF.  
k Triplicate ECG are to be performed within approximately 5 minutes of each other, after the patient has been in a supine position for 
approximately 10 minutes.  ECGs for each patient should be obtained from the same machine whenever possible.  At screening, baseline 
(Day 1 or Day 1) and other visits, pre-dose ECG should be performed prior to any blood draws and where applicable before the lumbar 
puncture.  For patients in Japan, additional triplicate ECG monitoring will be performed at 2 (± 30 minutes), 4 (± 30 minutes), and 
6 (± 30 minutes) hours following the first administration of study drug (Day 1).
l
Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).
m Serum chemistry panel:  includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, 
gamma-glutamyl transferase, and CPK.
n All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination for all abnormal dipstick results 
(sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria).  
p At the Week 37 visit, PK samples will be collected prior to dosing and at 1, 2, and 4 hours post-dose.  All patients will remain in clinic at least 
4 hours after lumbar puncture.
q MRI should take place as early as possible within the screening window but may take place at any time during screening.  The MRI safety and 
efficacy screening scan will need to pass the central laboratory image QC and the results must be available before the patient can be enrolled in 
the study.  At Weeks 13, 37, 69, 101 and at the EoT for ETT visit the MRI should be scheduled to occur before the lumbar puncture.  The MRI 
scan should be performed 714 days prior to the lumbar puncture to allow time for re-scanning if the quality of the initial MRI is inadequate. If the 

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
132/Protocol BN40423, Version 6
re-scan cannot be performed prior to the lumbar puncture, then it can be conducted the day after the lumbar puncture, as long as there are no 
post-lumbar puncture contraindications and it occurs within 2 weeks of the original scan.
r
The C-SSRS will be used to assess eligibility for the study (full version at screening, requiring approximately 20 minutes to administer) and to 
monitor the patients throughout the study at clinic visits (follow-up version, requiring approximately 5 minutes to administer, assuming absence of 
suicidal ideation and no change in clinical status from previous administration).
s The cUHDRS is a composite motor, cognitive, and global functional clinical outcome measure in patients with HD comprised of the TFC, the 
TMS, the SDMT, and the SWR scores.
t
The electronic devices for remote data collection will be supplied to patients at screening and must be returned to the clinic in cases where the 
patient does not meet eligibility criteria, at the end of the study, or upon early termination from the study.  
u
Optional exit interviews will be conducted for patients who consent from the selected sites within approximately 1 week after the EoT visit; these 
interviews can be conducted by telephone but may be completed by an in-clinic videotaped session.  
v Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.
w At the time of each study drug administration, non-dosing visit, and safety follow-up telephone calls, an interval medical history should be 
obtained and any changes in medications, any major procedures or hospitalizations, and any physician visits for HD or general medical care 
should be recorded.

Appendix 1a:  Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
133/Protocol BN40423, Version 6
x Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets must 
be conducted and the results reviewed.  Collection for these local laboratory tests may occur at any time in the 72 hours prior to the lumbar 
puncture.  The lumbar puncture should be performed at approximately the same time at each visit (ideally in the morning between 8:00 a.m. and 
12:00 noon or in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters.  CSF fluid 
(20 mL) is to be collected for analyses using a lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a minimum 
of 5 mL should be collected over a maximum of 60 minutes, once CSF flow has been established. The operator must confirm CSF flow is 
present prior to injecting drug.  A 24G atraumatic needle, as specified in the LP procedure and CSF collection guidelines, should be used.  
Depending on institutional guidelines, local anesthesia should be used for the procedure.  Sedation may not be used.  Spinal ultrasound may be 
used for the lumbar puncture procedure if deemed necessary, but is not required.  Ultrasound guidance may be used if attempts at lumbar 
puncture without imaging are unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound with each 
lumbar puncture.  Patients will be discouraged from resting supine after the lumbar puncture procedure and will be encouraged to mobilize 
immediately by walking around at a minimum and, if feasible, walking briskly for approximately 30 minutes.  Patients should not perform any 
activity that is associated with a change in the ambient air pressure for at least 24 hours post-LP procedure (e.g., air travel, scuba diving, or hot 
air balloons).  In the case of a failed IT bolus dosing or a failed CSF collection procedure (e.g., due to an inadequate establishment of access to 
the IT space), a second attempt may occur up to 7 days after the originally scheduled attempt. For this additional visit, safety and tolerability 
evaluations on the day of LP administration will be performed, including neurological examination (predose and postdose, or pre-procedure if no 
study treatment is being administered), vital signs, and a review of adverse events and concomitant medication.  If the second attempt occurs 
more than 3 days after the first attempt, local laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets need to be 
conducted again and results reviewed prior to the LP attempt.
y CSF samples will be obtained at the Week 101 EoT, Week 101 EoT for ETT, and ETT visits, but no study drug will be administered.
z Patients in Q16W arm will receive placebo at these visits.
aa Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from screening to the study completion/discontinuation visit.
bb After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 5 months after the final dose of study drug.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment.  
cc The DCL will be assessed at screening only (i.e., without the full TMS assessment).  The TMS scale will be assessed (excluding the DCL) at all 
other timepoints.
dd Excluding MRIs, which have a visit window of 14 to 7 days.
ee During the treatment period, a safety follow-up telephone call will be conducted for the months in which no clinic visits are. A safety follow-up 
call will also be conducted approximately 2 months after the Week 101 visit. Telephone safety follow-up calls will assess any changes to ongoing 
adverse events or occurrence of new adverse events and changes to concomitant medication.  Unscheduled visits can occur based on the 
outcome of this safety follow-up call.

RO7234292F. Hoffmann-La Roche Ltd
134/Protocol BN40423, Version 6
Appendix 1b
Schedule of Activities for Early Treatment Termination (Applicable to all 
Patients from 22 March 2021)
Visit
ETT a
FU Week 53 a FU Week 69 a
EoT for ETT
(Week 101) a
Safety Follow-
Up Calls b
Month
13
17
25
Window (days)
56 days after the decision to 
discontinue study treatment
(7)
(7)
(7) c
(7)
Vital signs d
x
Complete physical examination e
x
Neurologic examination f
x
x
ECG g
x
x
Hematology h
x
x
Chemistry i
x
x
Pregnancy test j
x
x
Local INR and/or PT, aPTT, platelet count k
x
x
Urinalysis l
x
x
Plasma sample for PK
x
Plasma sample for immunogenicity testing
x
x
Plasma sample for biomarkers
x
x
CSF sample for safety/biomarkers
x
x
MRI m
x
Independence Scale
x
x
x
x
MoCA
x
x
x
x
C-SSRS n
x
x
x
x
UHDRS FA
x
x
x
x

Appendix 1b: Schedule of Activities for Early Treatment Termination (Applicable to all Patients from 22 March 
2021) (cont.)
RO7234292F. Hoffmann-La Roche Ltd
135/Protocol BN40423, Version 6
Visit
ETT a
FU Week 53 a FU Week 69 a
EoT for ETT
(Week 101) a
Safety Follow-
Up Calls b
Month
13
17
25
Window (days)
56 days after the decision to 
discontinue study treatment
(7)
(7)
(7) c
(7)
TFC o
x
x
x
x
TMS o
x
x
x
x
CGI-S
x
x
x
x
CGI-C
x
x
x
x
SDMT o
x
x
x
x
SWR o
x
x
x
x
AES
x
SMDDS
x
NeuroQoL
x
x
EQ-5D-5L (in-clinic)
x
x
PGI-S
x
x
PGI-C
x
x
Roche HD mobile app in-clinic assessments
x
x
Roche HD mobile app remote data collection
Continuous remote data collection p
Optional exit interview 
x
CRQ: EQ-5D-5L, HUI-self, HUI-proxy, CrGI-S
x
x
CRQ: AES
x
CRQ: CrGI-C
x
x
Remote data collection of CRQ (EQ-5D-5L, 
HUI-self, HUI-proxy, HD-CIAOS, WPAI)
Remote data collection

Appendix 1b: Schedule of Activities for Early Treatment Termination (Applicable to all Patients from 22 March 
2021) (cont.)
RO7234292F. Hoffmann-La Roche Ltd
136/Protocol BN40423, Version 6
Visit
ETT a
FU Week 53 a FU Week 69 a
EoT for ETT
(Week 101) a
Safety Follow-
Up Calls b
Month
13
17
25
Window (days)
56 days after the decision to 
discontinue study treatment
(7)
(7)
(7) c
(7)
Blood sample for RBR RNA (optional) r
x
Serum sample for RBR (optional) r
x
Change in medical information since previous 
visit s
x
x
x
x
Lumbar puncture k
x t
x t
Concomitant medications u
x
x
x
x
Adverse events v
x
x
x
x
AES Apathy Evaluation Scale; CGI-C Clinical Global Impression, Change; CGI-S Clinical Global Impression, Severity; CrGI-
CCompanion-Reported Global Impression, Change; CrGI-SCompanion-Reported Global Impression, Severity; CRQCompanion-reported 
questionnaire; CSF cerebrospinal fluid; CSSRS Columbia-Suicide Severity Rating Scale; cUHDRS composite Unified Huntington's 
Disease Rating Scale; eCRF electronic Case Report Form; EoT end of treatment; EQ-5D-5L EuroQol 5-Dimension, 5-Level Questionnaire; 
ETT early treatment termination; FA Functional Assessment; FU follow-up; HD Huntington disease; HD-CIAOSHuntington's 
Disease Companion-Reported Irritability and Angry Outbursts Scale; HUI Health Utilities Index; LP lumbar puncture; MoCA Montreal 
Cognitive Assessment; MRI magnetic resonance imaging; Neuro-Qol Quality of Life in Neurological Disorders; PGI-C Patient Global 
Impression, Change; PGI-S Patient Global Impression, Severity; PK pharmacokinetic; RBR Research Biosample Repository; 
SDMT Symbol Digit Modalities Test; SMDDS Symptoms of Major Depressive Disorder Scale; SWR Stroop Word Reading; TFC Total 
Functional Capacity Scale; TMS Total Motor Score; UHDRS Unified Huntington's Disease Rating Scale.
Notes:  Unscheduled safety assessments (MRI, ECG, safety laboratory assessments, vital signs) can be performed if clinically indicated.
a All patients who discontinue study treatment prematurely but do not withdraw consent for continued participation in the study (this 
includes all patients from 22 March 2021) will attend a minimum of two and up to four in-clinic visits depending on which visits have 
already been completed at the time of study drug discontinuation (see Figure 3).  Patients will complete an ETT visit within 56 days (8 
weeks) of the decision to discontinue study treatment (i.e., 22 March 2021).  Patients will also return to the clinic for FU study visits at 
Weeks 53 and 69 (if not already completed) for collection of clinical outcome data for the primary and secondary endpoints (see Sections 2.1.1, 
2.1.2, 2.2 and the table above).  If the ETT visit falls within 30 days of either scheduled visits at Week 53 or Week 69, then only the ETT 
visit should be performed.  Patients will also attend the scheduled EoT for ETT visit at Week 101.  Study visits should be planned as per the 
study schedule, however under exceptional circumstances, a time window of 7 days can be utilized where shown. 

Appendix 1b: Schedule of Activities for Early Treatment Termination (Applicable to all Patients from 22 March 
2021) (cont.)
RO7234292F. Hoffmann-La Roche Ltd
137/Protocol BN40423, Version 6
b
After study treatment discontinuation, a safety follow-up telephone call should be conducted every 8 weeks between the clinic visits.  For 
patients consented to version 6 of the protocol who received their last dose of study treatment less than 5 months before the scheduled Week 
101 EoT for ETT visit, an additional safety telephone call should be performed 5 months after the last dose.  Telephone safety follow-up calls 
will assess any changes to ongoing adverse events or occurrence of new adverse events and changes to concomitant medication which should 
be documented in the eCRF.  Unscheduled visits can occur based on the outcome of this safety follow-up call.
c
Excluding MRIs, which have a visit window of 14 to 7 days.
d Vital signs include respiratory rate, pulse, temperature, and systolic and diastolic blood pressure while the patient is in a seated position after 
resting for approximately 5 minutes.  All data should be recorded on the appropriate eCRF.
e
The complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be performed if 
clinically indicated.   Changes from baseline abnormalities should be recorded in patient notes.  New or worsened clinically significant 
abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as adverse events on the Adverse Event eCRF.  
f
A neurologic examination (including fundoscopy) should include assessment of mental status, level of consciousness, cranial nerve function, 
motor function, sensory function, reflexes, gait, and coordination.  The neurologic examinations should be conducted in the same manner on 
each occasion to ensure comparability to previous examinations.  At visits when an LP is performed and study treatment is not administered, 
the neurological examination should be performed prior to the LP. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as 
adverse events on the Adverse Event eCRF.  
g Triplicate ECG are to be performed within approximately 5 minutes of each other, after the patient has been in a supine position for 
approximately 10 minutes.  ECGs for each patient should be obtained from the same machine whenever possible.  The ECG should be 
performed prior to any blood draws and before the lumbar puncture.  
h Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).
i
Serum chemistry panel:  includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, 
gamma-glutamyl transferase, and CPK.
j
Urine pregnancy tests will be performed at specified visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test.

Appendix 1b: Schedule of Activities for Early Treatment Termination (Applicable to all Patients from 22 March 
2021) (cont.)
RO7234292F. Hoffmann-La Roche Ltd
138/Protocol BN40423, Version 6
k Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets 
must be conducted and the results reviewed.  Collection for these local laboratory tests may occur at any time in the 72 hours prior to the 
lumbar puncture.  The lumbar puncture should be performed at approximately the same time at each visit (ideally in the morning between 
8:00 a.m. and 12:00 noon or in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal variation of CSF 
parameters.  CSF fluid (20 mL) is to be collected for analyses using a lumbar puncture collection kit.  If there are difficulties in collecting 
20 mL of CSF fluid, a minimum of 5 mL should be collected over a maximum of 60 minutes, once CSF flow has been established. A 24G 
atraumatic needle, as specified in the LP procedure and CSF collection guidelines, should be used.  Depending on institutional guidelines, 
local anesthesia should be used for the procedure.  Sedation may not be used.  Spinal ultrasound may be used for the lumbar puncture 
procedure if deemed necessary, but is not required.  Ultrasound guidance may be used if attempts at lumbar puncture without imaging are 
unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound with each lumbar puncture.  
Patients will be discouraged from resting supine after the lumbar puncture procedure and will be encouraged to mobilize immediately by 
walking around at a minimum and, if feasible, walking briskly for approximately 30 minutes.  Patients should not perform any activity that is 
associated with a change in the ambient air pressure for at least 24 hours post-LP procedure (e.g., air travel, scuba diving, or hot air 
balloons).  In the case of a failed CSF collection procedure (e.g., due to an inadequate establishment of access to the IT space), a second 
attempt may occur up to 7 days after the originally scheduled attempt. For this additional visit, safety and tolerability evaluations on the day 
of LP administration will be performed, including a pre-procedure neurological examination, vital signs, and a review of adverse events and 
concomitant medication.  If the second attempt occurs more than 3 days after the first attempt, local laboratory analysis of coagulation factors 
(INR and/or PT, aPTT) and platelets need to be conducted again and results reviewed prior to the LP attempt.
l
Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination for all abnormal dipstick 
results (sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria).  
m The MRI should be scheduled to occur before the lumbar puncture.  The MRI scan should be performed 714 days prior to the lumbar 
puncture to allow time for re-scanning if the quality of the initial MRI is inadequate. If the re-scan cannot be performed prior to the lumbar 
puncture, then it can be conducted the day after the lumbar puncture, as long as there are no post-lumbar puncture contraindications and it 
occurs within 2 weeks of the original scan.
n The C-SSRS will be used to monitor the patients (follow-up version, requiring approximately 5 minutes to administer, assuming absence of 
suicidal ideation and no change in clinical status from previous administration).
o The cUHDRS is a composite motor, cognitive, and global functional clinical outcome measure in patients with HD comprised of the TFC, the 
TMS, the SDMT, and the SWR scores.
p The electronic devices for remote data collection will be supplied to patients at screening and must be returned to the clinic in cases where the 
patient does not meet eligibility criteria, at the end of the study, or upon early termination from the study.  
q
Optional exit interviews will be conducted for patients who consent from the selected sites within approximately 1 week after the EoT for 
ETT visit; these interviews can be conducted by telephone but may be completed by an in-clinic videotaped session.  
r
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.

Appendix 1b: Schedule of Activities for Early Treatment Termination (Applicable to all Patients from 22 March 
2021) (cont.)
RO7234292F. Hoffmann-La Roche Ltd
139/Protocol BN40423, Version 6
s
An interval medical history should be obtained at each clinic visit and safety telephone call and any changes in medications, any major 
procedures or hospitalizations, and any physician visits for HD or general medical care should be recorded.
t
CSF samples will be obtained at the Week 101 EoT for ETT, and ETT visits but no study drug will be administered.
u Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from screening to the study completion/discontinuation visit.
v All adverse events will be reported until 5 months after the final dose of study drug.  After this period, all deaths, regardless of cause, should 
be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study drug treatment (see Section 5.6).

RO7234292F. Hoffmann-La Roche Ltd
140/Protocol BN40423, Version 6
Appendix 2 Clinician-Reported Outcomes for Patients Enrolled after Implementation of Protocol 
Version 4
Assessment
Name
Items
Concepts
Approx. 
Duration
Timing
FA
UHDRS Functional 
Assessment
25
Daily function
15 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
IS
Independence Scale
1
Functional disability
3 min
Screening, baseline, and Weeks 5, 
21, 37, 53, 69, 85, and 101 and 
ETT visits
TFC
Total Functional 
Capacity Scale
5
Overall function
10 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
TMS
Total Motor Score
31
Motor function
15 min
DCL only: Screening
TMS without DCL: Baseline and 
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits
C-SSRS
Columbia-Suicide 
Severity Scale
5
Suicidal ideation 
and behavior
20 min full 
version; 
5 min follow-up 
version
Full version at screening in clinic; 
follow-up version at baseline and all 
post-baseline clinic visits 
CGI-S
Clinical Global 
ImpressionSeverity
1
Overall severity of 
patient status
2 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
CGI-C
Clinical Global 
ImpressionChange
1
Overall change in 
patient status
2 min
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits 
HD-DAS
Huntington's 
Disease Daily 
Activities Scale 
25
Daily function
25 min
Screening and Weeks 13, 29, 45, 
61, 77, and 93
DCLdiagnostic confidence level.

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Appendix 3 Patient-Reported, Observer-Reported, and Performance Outcomes
and Roche HD Mobile Application for Patients Enrolled after Implementation of Protocol 
Version 4
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
AES
Apathy Evaluation 
Scale
18
Apathy
10
PROObsRO
Baseline and 
Weeks 13, 29, 45, 61, 
77, 93, and 101
In-clinic
Roche HD 
mobile app 
Roche HD mobile app 
with daily Active Test 
and Passive 
Monitoring
NA
Tasks (“active test”) that assess 
motor symptoms (upper and 
lower body movements, upper 
limb dexterity, voice) and 
non-motor symptoms 
(processing speed/voice); 
continuous passive monitoring
5
Sensor data, 
PRO, PerfO
Dailyat clinic visits 
(Screening, baseline 
and Weeks 5, 53, and 
101 and ETT visits) 
Roche HD 
mobile app
CrGI-C
Companion-Reported 
Global Impression, 
Change
1
Overall change in patient status
2
ObsRO
Weeks 5, 21, 37, 53, 
69, 85, and 101 and 
ETT visits
In-clinic on 
electronic 
device
CrGI-S
Companion-Reported 
Global Impression, 
Severity
1
Overall severity of patient status
2
ObsRO
Baseline and Weeks 5, 
21, 37, 53, 69, 85, and 
101 and ETT visits
In-clinic on 
electronic 
device
EQ-5D-5L
EuroQol 5-Dimension, 
5-Level Questionnaire
6
Health utilities
5
PROObsRO
Baseline and Weeks 5, 
21, 37, 53, 69, 85, and 
101 and ETT visits
In-clinic
Weekly
Roche HD 
mobile app; 
electronic 
device

Appendix 3:  Patient-Reported, Observer-Reported, and Performance Outcomes
and Roche HD Mobile Application for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
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Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
HD-SDI
Huntington's 
Disease Speaking 
Difficulty Item 
1
Speech
1
PRO
Weekly
Roche HD 
mobile app
HD-CIAOS
Huntington's 
Disease Companion-
Reported Irritability 
and Angry Outbursts 
Scale
3
Irritability and angry 
outbursts
2
ObsRO
Weekly
Electronic 
device
HUI
Health Utilities Index
15
Health-related quality of 
life
10
ObsRO
Baseline, Weeks 5, 21, 37, 
53, 69, 85, and 101 and ETT
In-clinic
Weekly
Electronic 
device
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10
PerfO
Screening, baseline, 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT
In-clinic
Neuro-Qol 
Cog Func
Neuro-Qol Cognitive 
Function Short Form
8
Cognition
5
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 
In-clinic
PGI-C
Patient Global 
ImpressionChange
1
Overall change in 
patient status
2
PRO
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
PGI-S
Patient Global 
ImpressionSeverity
1
Overall severity of 
patient status
2
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 and 
ETT
In-clinic

Appendix 3:  Patient-Reported, Observer-Reported, and Performance Outcomes
and Roche HD Mobile Application for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
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Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
SDMT/
eSDMT
Symbol Digit 
Modalities Test
Max 
number in 
90 seconds
Cognitive
5
PerfO
SDMT at baseline and 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits 
In-clinic
eSDMT monthly + at clinic 
visits (screening, baseline, 
Weeks 5, 53,101, and ETT )
Roche HD 
mobile app 
(eSDMT)
SMDDS
Symptoms of Major 
Depressive 
Disorder Scale
16
Depression, anxiety, 
irritability, sleep
10
PRO
Baseline and Weeks 13, 29, 
45, 61, 77, 93, and 101 
In-clinic
SWR/eSWR
Stroop Word 
Reading Test
Max 
numbers in 
45 seconds
Cognitive
5
PerfO
SWR at baseline and 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
eSWR monthly + at clinic 
visits (screening, baseline, 
Weeks 5, 53, and 101 and 
ETT)
Roche HD 
mobile app 
(eSWR)
WPAI
Work Productivity 
and Activity 
Impairment
6
Work productivity
5
PROObsRO
Baseline and then monthly 
Roche HD 
mobile app 
and electronic 
device
appapplication; ETT early treatment termination; HD Huntington disease; ObsRO observer-reported outcome; PerfO performance outcome; 
PROpatient-reported outcome.

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Appendix 4 Clinical Assessments Order and Duration for
Patients Enrolled after Implementation of Protocol Version 4
Table 1
Screening Visit Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Diagnostic Confidence Level a
Huntington's Disease Daily Activities Scale
Independence Scale
MoCA
C-SSRS 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Roche HD mobile application
~20
Qualified 
study 
personnel
C-SSRSColumbia-Suicide Severity Rating Scale; DCL Diagnostic Confidence Level;
HDHuntington disease; MoCAMontreal Cognitive Assessment; TMS Total Motor Score.
a
The DCL will be assessed at screening only (i.e., without the full TMS assessment).  The 
TMS scale will be assessed (excluding the DCL) at all other timepoints.

Appendix 4:  Clinical Assessments Order and Duration for Patients 
Enrolled after Implementation of Protocol Version 4 (cont.)
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Table 2
Baseline and Week 101 Clinical Assessments (for Primary 
Analysis)
Block
Assessments
Total 
Duration 
(minutes)
Site Staff Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic 
Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
(post-baseline visits only)
~60
Qualified study physician
Break (if needed)
~2030
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified study 
personnel
Break (if needed)
~10
3 a
Apathy Evaluation Scale (patient and 
companion)
Symptoms of Major Depressive Disorder 
Scale
~20
Qualified study 
personnel
Break (if needed)
~1020
4 a
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level 
Questionnaire (patient and companion)
Health Utilities Index (companion: self and 
proxy)
Patient/Companion-reported Global 
ImpressionSeverity
Patient/Companion-reported Global 
ImpressionChange (post-baseline visits 
only)
~20
Qualified study 
personnel
Break (if needed)
~1020
5 a
Roche HD mobile application
~20
Qualified study 
personnel
HDHuntington disease; MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in 
Neurological Disorders; UHDRSUnified Huntington's Disease Rating Scale.
a At the baseline visit and at Week 101, Blocks 3, 4, and 5 can be completed on the same day 
after Blocks 1 and 2, or on the following day, but must be completed predose at the baseline 
visit.  

Appendix 4:  Clinical Assessments Order and Duration for Patients 
Enrolled after Implementation of Protocol Version 4 (cont.)
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Table 3
Follow-Up Clinical Assessments at Weeks 5, 21, 37, 53, 69, 
and 85
Block
Assessments
Total 
Duration 
(minutes)
Site Staff 
Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified 
study 
personnel
Break (if needed)
~10
3
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level Questionnaire (patient
and companion)
Health Utilities Index (companion: self and proxy)
Patient/Companion-reported Global ImpressionSeverity
Patient/Companion-reported Global ImpressionChange 
~30
Qualified 
study 
personnel
4
Roche HD mobile application a
~20
Qualified 
study 
personnel
MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in Neurological Disorders; 
UHDRSUnified Huntington's Disease Rating Scale
a
These assessments will take place only at Weeks 5 and 53.

Appendix 4:  Clinical Assessments Order and Duration for Patients 
Enrolled after Implementation of Protocol Version 4 (cont.)
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Table 4
Follow-Up Clinical Assessments at Weeks 13, 29, 45, 61, 77, 
and 93
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1 a
Apathy Evaluation Scale (patient and companion)
Symptoms of Major Depressive Disorder Scale
~20
Qualified 
study 
personnel
Break (if needed)
~10
2
Huntington's Disease-Daily Activities Scale
~25
Qualified 
study 
physician
a To be completed prior to safety assessments.

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Appendix 5 Guidelines for Order of Assessments
This guidance is in addition to what is mandated throughout this protocol, including from
Section 4.5.9.

Screening Visits: Screening assessments can be performed over several days 
through the 28-day screening period.  Blood sample for CAG repeat testing and the 
MRI scans should be taken as early as possible to enable the results to be available 
in time for randomization.  The electronic clinical outcome assessments (eCOAs) 
can be done after eligibility has been confirmed for all other parameters, so that 
patients and sites are not spending unnecessary time on eCOAs before knowing if 
the patient will fulfill all the other eligibility criteria.

All eCOA blocks should always be done in a sequential order as per Appendix 2, 
Appendix 3, and Appendix 4.  One block cannot be done before the previous block 
is completed (i.e., the blocks should be completed sequentially as Block 1, Block, 2, 
Block 3, Block 4, and Block 5).

Within a block, the protocol order should be kept to prevent bias.  All the 
assessments have been ordered by importance for the primary and secondary study 
endpoints.

eCOA blocks can be split over 2 consecutive days.  When eCOA blocks are split 
over 2 consecutive days, Blocks 1 and 2 should always be completed together on 
the same day.  As such, either Blocks 15 or just 1 and 2 can be done the day 
before dosing.  

The same methodology should be kept for an individual patient’s eCOAs, to prevent 
intra-patient variability. For example, if the blocks are done all together, they should 
be performed that way for all visits, but at a minimum for baseline and Week 101 
visits.

The same timings should be kept for each patient’s eCOAs at each visit, but 
especially for Day 1 and Week 101 visits.

Blood sampling (all or just coagulation) can be done before Block 1 or after Block 5 
or between blocks, but only as follows:
o
The eCOAs are separated into 2 consecutive days
o
The blood sampling should be done after Block 2 but should not be done 
before Block 3 on the following day.  
Therefore, blood sampling can occur the day before (before Block 1, after Block 2, or 
after Block 5) depending on which eCOAs are done the day before dosing. Alternatively, 
blood sampling can be done before Block 1 on the day of dosing.  Again the same 
methodology should be used for the patient throughout the study but in particularly for 
the Day 1 and Week 101 visits.

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Appendix 6 Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities for All Patients
The following grading recommendations for adverse events relating to lab test 
abnormalities are based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0.
LLNlower limit of normal; ULNupper limit of normal.

Appendix 6:  Grading Scale for Adverse Events Relating to Laboratory Abnormalities for 
All Patients (cont.)
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LLNlower limit of normal; ULNupper limit of normal.

Appendix 6:  Grading Scale for Adverse Events Relating to Laboratory Abnormalities for 
All Patients (cont.)
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Appendix 7 Roche HD Mobile Application for Patients Enrolled 
after Implementation of Protocol Version 4:  Active Test
The following tasks are part of the "active tests" conducted on the Roche Huntington's Disease 
(HD) mobile application by the patient. 
Daily Questions
Two daily single-item questions on mood and physical energy will be assessed, asking patients 
about their mood and physical health at the time they are performing the “Active” tests. The 
assessments aim to capture daily mood fluctuations and will be used as a control for the other 
motor and cognitive assessments. 
Cognitive Test (eSDMT)
The Cognitive Test asks participants to match symbols with numbers according to a key as 
quickly and accurately as possible. The key, symbols, numbers are all displayed on a 
smartphone screen. The test assesses visuo-motor integration, and measures visual attention 
and motor speed.  It is modelled on the pen and paper Symbol Digit Modalities Test (SDMT) 
(Smith, 1968). The SDMT has been shown to be sensitive to symptom changes in early HD 
patients (Tabrizi 2012) and is part of the Unified Huntington's Disease Rating Scale (UHDRS)
assessment (Huntington’s Study Group, 1996).
Word Reading Test (eSWR)
The Word Reading Test asks participants to read aloud color words written in black font on a 
smartphone screen. Their voice will be recorded. The test assesses cognitive processing speed, 
and is modelled on the Stroop Word Reading (SWR) (Ridley 1935). The "Word Reading" part of 
the SWR Test has been shown to be sensitive to symptom changes in patients with early HD 
(Tabrizi 2012) and is part of the UHDRS assessment (Huntington’s Study Group 1996). 
Speeded Tapping Test
The Speeded Tapping Test asks participants to tap the smartphone screen as fast and regularly 
as possible, using the index finger of both the left and right hands. The test assesses 
bradykinesia. Performance will also be impacted by chorea and dystonia. It is modelled on 
tapping tests shown to be sensitive to symptom changes in early HD (Bechtel et al. 2010; Tabrizi 
et al. 2012). A similar finger tapping task is also included as part of the UHDRS assessment 
(Huntington’s Study Group 1996).
Draw a Shape Test
The Draw a Shape Test asks participants to trace a series of increasingly complex shapes on the 
smartphone screen. The shapes include lines, a square, a circle, an eight, and a spiral. This test 
is designed to assess visuomotor coordination and fine motor impairment in early HD patients. It 
is modelled on circle tracing tasks that have been shown to be sensitive to symptom changes in 
early HD (Say et al. 2011; Tabrizi et al. 2013). 
Chorea Test
The Chorea Test asks participants to hold the smartphone still in their hand with their arm
outstretched, and wear the wrist-worn wearable. As a dual task, participants will also need to 
count backwards aloud. To ensure correct execution, voice will be recorded. The test is 
designed to assess chorea. It draws on other sensor-based approaches to measure chorea 
(Reilmann et al. 2010, 2011; Kegelmeyer et al. 2017). A chorea assessment is also part of the 
UHDRS (Huntington’s Study Group 1996). 
Balance Test
The Balance Test asks participants to stand still while wearing the smartphone and wrist-worn 
wearable. It is an assessment for patients’ static balance function. Sensor-based approaches for 
measuring static balance have been shown to be sensitive to differences in symptoms in early 

Appendix 7:  Roche HD Mobile Application for Patients Enrolled after Implementation of 
Protocol Version 4:  Active Test (cont.)
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HD (Dalton et al. 2013). The test is also part of established scales like the Berg Balance Scale 
(Berg et al. 1992), which are used in HD (Busse et al. 2009; Rao et al. 2009). The test is 
anchored to the UHDRS assessments for maximal dystonia, maximal chorea, and tandem 
walking (Huntington Study Group 1996).
U-Turn Test
The U-Turn Test asks participants to walk and turn safely between two points that are at least 
four steps apart, while wearing the smartphone and wrist-worn wearable. They need to make at 
least five turns. The test is designed to assess gait and lower-body bradykinesia, which are also 
assessed by the UHDRS. It is modelled on the Timed Up and Go Test, which has been clinically 
validated for the HD population (Busse et al. 2009; Rao et al. 2009). The test is anchored to the 
UHDRS gait, bradykinesia body, and tandem walking items (Huntington Study Group 1996). 
Walk Test
The Walk Test asks participants walk as fast as is safely possible for 200 meters or 2 minutes 
every day. Ideally, the test is done in a straight path with no obstacles (e.g., in a park). 
Sensor-based approaches for measuring gait have been shown to be sensitive to differences in 
symptoms in early HD (Dalton et al. 2013). The test is anchored to the UHDRS gait, bradykinesia 
body, and tandem walking items (Huntington Study Group 1996).
Tasks are automatically scheduled as shown below in Figure 1 and take no more than 5 minutes 
per day.  If the patient does not complete the active test on a certain day, scheduled tasks that 
occur less frequently than every second day (i.e., EuroQol 5-Dimension, 5 Level Questionnaire, 
Work Productivity and Activity Impairment, Huntington's Disease Speaking Difficulty Item, 
2-Minute Walk Test) are rolled over to the next time the active test is completed.
References
Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest 
and symptomatic Huntington disease. Neurology 2010;75:215060.
Berg KO, Wood-Dauphinee SL, Williams JI, et al. Measuring balance in the elderly: validation of 
an instrument. Can J Public Health 1992;83(Suppl 2):S711.
Busse ME, Wiles CM, Rosser AE. Mobility and falls in people with Huntington's disease. J Neurol 
Neurosurg Psychiatry 2009;80:8890.
Dalton A, Khalil H, Busse M, et al. Analysis of gait and balance through a single triaxial 
accelerometer in presymptomatic and symptomatic Huntington’s disease. Gait Posture 
2013;37:4954.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.Kegelmeyer et al. 2017
Rao AK, Muratori L, Louis ED, et al. Clinical measurement of mobility and balance impairments in 
Huntington's disease: validity and responsiveness. Gait Posture 2009;29:4336.
Reilmann R, Bohlen S, Kirsten F, et al. Assessment of involuntary choreatic movements in 
Huntington's disease—toward objective and quantitative measures. Mov Disord 
2011;26:226773.

Appendix 7:  Roche HD Mobile Application for Patients Enrolled after Implementation of 
Protocol Version 4:  Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
154/Protocol BN40423, Version 6
Reilmann R, Bohlen S, Klopstock T, et al. Grasping premanifest Huntington's disease - shaping 
new endpoints for new trials. Mov Disord 2010;25:285862.
Say MJ, Jones R, Scahill R, et al. Visuomotor integration deficits precede clinical onset in 
Huntington's disease. Neuropsychologia 2011;49:26470.
Smith A. The symbol-digit modalites test: a neuropsychologic test of learning and other cerebral 
disorders. In: Helmuth J, editor. Learning disorders. Seattle: Special Child Publications; 
1968:83–91.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:64362.
Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and 
early Huntington's disease in the TRACK-HD study: analysis of 24 month observational 
data. The Lancet Neurology 2012;11.1:4253.
Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in 
premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-
month observational data. Lancet Neurol 2013;12:63749.

Appendix 7:  Roche HD Mobile Application for Patients Enrolled after Implementation of Protocol Version 4:  Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
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Figure 1
Timing of Assessments
EQ-5D-5LEuroQol 5-Dimension, 5 Level Questionnaire; eSDMT electronic Symbol Digit Modalities Test; HD-SDIHuntington's Disease
Speaking Difficulty Item; Lleft; PROpatient-reported outcome; Rright; WPAI=Work Productivity and Activity Impairment Questionnaire. 

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Appendix 8 Diagnostic Confidence Level for All Patients
The Diagnostic Confidence Level is calculated as shown below (from UHDRS 
Total Motor Score Scale, Item 17):
DIAGNOSIS CONFIDENCE LEVEL
To what degree are you confident that this person meets the operational 
definition of the unequivocal presence of an otherwise unexplained 
extrapyramidal movement disorder
(e. g., chorea, dystonia, bradykinesia, rigidity) in a subject at risk for HD?
0normal (no abnormalities)
1non-specific motor abnormalities (less than 50% confidence)
2motor abnormalities that may be signs of HD (50%89% confidence)
3motor abnormalities that are likely signs of HD (90%98% confidence)
4motor abnormalities that are unequivocal signs of HD (99% confidence)
Copyright 1999
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.

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Appendix 9 Guidance for Neurological Examination for 
All Patients
Perform the neurological examination in the same way every time at screening and at 
every clinic visit.  At dosing visits, perform examination predose and postdose after the 
participant has walked for 30 minutes postdrug injection.
Neurological Examination

Mental status (appearance, level of consciousness, behavior, 
speech)

Cranial Nerves II (including Visual Acuity and Fundoscopy)XII

Motor examination (bulk, tone, and strength)

Coordination

Abnormal movements

Gait

Reflexes

Sensation (vibration, light touch, pin prick/temperature)
Note:  The neurological examination should be followed at the 
non-dosing clinic visits, end-of-treatment visit, and safety follow-up 
visit.  At visits when a lumbar puncture is performed and study 
treatment is not administered, the neurological examination 
should be performed prior to the lumbar puncture.

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Appendix 10 Schedule of Activities for Patients Enrolled before Implementation of Protocol 
Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
Signed informed 
consent c
x
Review of inclusion and 
exclusion criteria 
x
Demographic data
x
Medical history and 
baseline conditions d
x
xe
Blood sample for CAG 
repeat length
x
Viral serology f
x
Thyroid panel g
x
Vital signs h
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical 
examination i
x
xe
x
x
x
x
x
x
Neurologic examination j
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ECG k
x
xe
x
x
x
x
x
x
x
Hematology l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
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Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
Chemistry m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test n
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Local INR, aPTT, PT
platelet count x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for PK
x
x
x
x p 
x
x
x
x
x
Plasma sample for 
immunogenicity testing
x
x
x
x
x
x
x
x
x
x
Plasma sample for 
biomarkers
x
x
x
x
x
x
x
x
x
x
Blood sample for clinical 
genotyping
xe
CSF sample for 
PK/safety/biomarkers
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xy
x
MRI q
x
x
x
x
x
x
HD-DAS
x
x
x
x
x
x
x
Independence Scale
x
x
x
x
x
x
x
x
x
x
x
MoCA
x
x
x
x
x
x
x
x
x
x
x
C-SSRS r
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
160/Protocol BN40423, Version 6
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
UHDRS FA
x
x
x
x
x
x
x
x
x
x
TFC s
x
x
x
x
x
x
x
x
x
x
TMS s, cc
x
x
x
x
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
CGI-C
x
x
x
x
x
x
x
x
x
SDMT s
x
x
x
x
x
x
x
x
x
x
SWR s
x
x
x
x
x
x
x
x
x
x
AES
x
x
x
x
x
x
x
x
x
SMDDS
x
x
x
x
x
x
x
x
x
NeuroQoL
x
x
x
x
x
x
x
x
x
x
EQ-5D-5L (in-clinic)
x
x
x
x
x
x
x
x
x
x
HUI(in-clinic)
x
x
x
x
x
x
x
x
x
x
PGI-S
x
x
x
x
x
x
x
x
x
x
PGI-C
x
x
x
x
x
x
x
x
x
Roche HD mobile app 
in-clinic assessments
x
x
x
x
x
x
x
x
Roche HD mobile app 
remote data collection 
Continuous remote data collection t

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
161/Protocol BN40423, Version 6
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
Optional exit interview u
x
x
Blood sample for RBR 
DNA (optional) v
x
Blood sample for RBR 
RNA (optional) v
x
x
x
x
x
Serum sample for RBR
(optional) v
x
x
x
x
x
Change in medical 
information since 
previous visit w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lumbar puncture x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x y
x y
Study drug 
administration
x
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
xz
x
xz
Concomitant 
medications aa
x
x
x
x
x
x
x
x
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 bb
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; AESApathy Evaluation Scale; BLbaseline; CGI-C Clinical Global Impression, Change; CGI-S Clinical Global 
Impression, Severity; CSF cerebrospinal fluid; CSSRS Columbia-Suicide Severity Rating Scale; cUHDRS composite Unified Huntington's 
Disease Rating Scale; DCLdiagnostic confidence level; eCRF electronic Case Report Form; EoT end of treatment; EQ-5D-5LEuroQol 
5-Dimension, 5-Level Questionnaire; ETT early treatment termination; FAFunctional Assessment; HBsAghepatitis B surface antigen; 
HCVhepatitis C virus; HD Huntington disease; HD-DASHD Daily Activities Scale; HUIHealth Utilities Index; MoCA Montreal Cognitive 
Assessment; MRI magnetic resonance imaging; Neuro-Qol Quality of Life in Neurological Disorders; PGI-C Patient Global Impression, 

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
162/Protocol BN40423, Version 6
Change; PGI-S Patient Global Impression, Severity; PKpharmacokinetic; Q8W every 8 weeks; RBR Research Biosample Repository; 
SDMT Symbol Digit Modalities Test; SFU safety follow-up; SMDDS Symptoms of Major Depressive Disorder Scale; SWR Stroop Word 
Reading; TFC Total Functional Capacity Scale; TMS Total Motor Score; UHDRSUnified Huntington's Disease Rating Scale.
Notes:  All assessments should be performed at the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be 
performed prior to dosing, unless otherwise specified.  
a A maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for patients who fail the initial screening (e.g., as a 
consequence of abnormal laboratory values or general medical status not meeting inclusion or exclusion criteria).  If re-screening is required, 
CAG repeat length testing does not need to be repeated and the screening MRI and viral serology from the initial screening may be acceptable 
as part of the re-screening assessments, if performed within 12 weeks of the baseline visit.  
b Patients who complete the treatment period will return to the clinic for a treatment completion visit at Week 101 (i.e., the EoT visit).  All patients 
who discontinue study treatment prematurely but do not withdraw consent for continued participation in the study will return to the clinic for study 
visits at Weeks 53 and 69 (if not already completed) and at Week 101 (i.e., the EoT for ETT visit) for collection of at least the data for the primary 
and secondary endpoints (see Sections 2.1.1, 2.1.2, and 2.2).  If the ETT visit falls within 30 days of either scheduled visits at Week 53 or 
Week 69, then only ETT will be considered.  The ETT visit should be performed 28 days (3 days) after the last dose.  Patients will also attend 
the scheduled EoT for ETT visit at Week 101 for limited assessments including the collection of the primary and secondary endpoints (see 
Sections 2.1.1, 2.1.2, and 2.2).  Study visits should be planned as per the study schedule, however under exceptional circumstances, time 
window of 3 days can be utilized. 
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
d Medical history, including clinically significant diseases, surgeries, HD history (including past hospitalizations [i.e., number, duration, and 
reason]), over the last 2 years, reproductive status, smoking history, and use of alcohol and drugs of abuse will be recorded at baseline.
e Assessments may take place on Day 1 or Day 1.
f
Viral serology: HBsAg and HCV antibody
g Thyroid panel:  thyroid-stimulating hormone and free thyroxine (also known as T4) levels. 
h Vital signs include respiratory rate, pulse, temperature, and systolic and diastolic blood pressure while the patient is in a seated position after 
resting for approximately 5 minutes.  Record abnormalities observed at baseline (Day -1 or Day 1) on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
A complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems (including fundoscopy); 
genitourinary examinations may be performed if clinically indicated.   The physical examinations should be conducted in the same manner on 
each occasion to ensure comparability to previous examinations. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as 
adverse events on the Adverse Event eCRF.  Height will be measured at screening only.

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
163/Protocol BN40423, Version 6
j
A neurologic examination, performed at screening and at every clinical visit, should include assessment of mental status, level of consciousness, 
cranial nerve function, motor function, sensory function, reflexes, and coordination.  The neurologic examinations should be conducted in the 
same manner on each occasion to ensure comparability to previous examinations. Neurologic examinations should be performed before and 
after treatment on each dosing day.  Weight should also be measured at each visit. 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 patient notes.  New or 
worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as adverse 
events on the Adverse Event eCRF.  
k Triplicate ECG are to be performed after the patient has been in a supine position for approximately 10 minutes.  ECGs for each patient should 
be obtained from the same machine whenever possible.  At screening, baseline (Day 1 or Day 1) and other visits, pre-dose ECG should be 
performed prior to any blood draws and where applicable before the lumbar puncture.  
l
Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).
m Serum chemistry panel:  includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, 
gamma-glutamyl transferase, and CPK.
n All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).  
p At the Week 37 visit, PK samples will be collected prior to dosing and at 1, 2, and 4 hours post-dose.  All patients will remain in clinic at least 
4 hours after lumbar puncture.
q At Weeks 13, 37, and 69 and at the EoT visit, the MRI should be scheduled to occur before the lumbar puncture.  It can be scheduled in the days 
prior to the lumbar puncture (provided it occurs within the visit window).  After patient enrollment, the MRI scan should be performed 714 days 
prior to the lumbar puncture to allow time for re-scanning if the quality of the initial MRI is inadequate. MRI should take place as early as 
possible within the screening window but may take place at any time during screening.  Results must be available before the patient can be 
enrolled in the study.
r
The C-SSRS will be used to assess eligibility for the study (full version at baseline, requiring approximately 20 minutes to administer) and to 
monitor the patients throughout the study at clinic visits (follow-up version, requiring approximately 5 minutes to administer, assuming absence of 
suicidal ideation and no change in clinical status from previous administration).
s The cUHDRS is a composite motor, cognitive, and global functional clinical outcome measure in patients with HD comprised of the TFC, the 
TMS, the SDMT, and the SWR scores.
t
The electronic devices for remote data collection will be supplied to patients at screening and must be returned to the clinic in cases where the 
patient does not meet eligibility criteria, at the end of the study, or upon early termination from the study.  

Appendix 10: Schedule of Activities for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
164/Protocol BN40423, Version 6
u
Optional exit interviews will be conducted within approximately 1 week after the EoT visit; these interviews can be conducted by telephone.  
v Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.
w At the time of each study drug administration, an interval medical history should be obtained and any changes in medications, any major 
procedures or hospitalizations, and any physician visits for HD or general medical care should be recorded.
x Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR, aPTT, PT) and platelets must be 
conducted and the results reviewed.  Collection for these local laboratory tests may occur at any time in the 72 hours prior to the lumbar 
puncture.  The lumbar puncture should be performed at approximately the same time at each visit (ideally in the morning between 8:00 a.m. and 
12:00 noon or in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters.  CSF fluid 
(20 mL) is to be collected for analyses using a lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a minimum 
of 5 mL should be collected over a maximum of 60 minutes.  If only 5 mL is collected after 60 minutes, the operator must confirm CSF flow is 
present prior to injecting drug at 60 minutes.  A 24G Whitacre (atraumatic) needle should be used.  Depending on institutional guidelines, local 
anesthesia should be used for the procedure.  Sedation may not be used.  Spinal ultrasound may be used for the lumbar puncture procedure if 
deemed necessary, but is not required.  Ultrasound guidance may be used if attempts at lumbar puncture without imaging are unsuccessful, if it 
is local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound with each lumbar puncture.  Patients will be discouraged 
from resting supine after the lumbar puncture procedure and will be encouraged to mobilize immediately by walking around at a minimum and, if 
feasible, walking briskly.
y The last CSF sample will be obtained at the Week 101 EoT visit, but no study drug will be administered.
z Patients in Q8W arm will receive placebo at these visits.
aa Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from screening to the study completion/discontinuation visit.
bb After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 5 months after the final dose of study drug.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment.  
cc The DCL will be assessed at screening only (i.e., without the full TMS assessment).  The TMS scale will be assessed (excluding the DCL) at all 
other timepoints.
dd Excluding MRIs, which have a visit window of 14 days.

RO7234292F. Hoffmann-La Roche Ltd
165/Protocol BN40423, Version 6
Appendix 11
Clinician-Reported Outcomes for Patients Enrolled before Implementation of 
Protocol Version 4
Assessment
Name
Items
Concepts
Approx. 
Duration
Timing
FA
UHDRS Functional 
Assessment
25
Daily function
15 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
IS
Independence Scale
1
Functional disability
3 min
Screening, baseline, and Weeks 5, 
21, 37, 53, 69, 85, and 101 and 
ETT visits
TFC
Total Functional 
Capacity Scale
5
Overall function
10 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
TMS
Total Motor Score
31
Motor function
15 min
DCL only: Screening
TMS without DCL: Baseline and 
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits
C-SSRS
Columbia-Suicide 
Severity Scale
5
Suicidal ideation 
and behavior
20 min full 
version; 
5 min follow-up 
version
Full version at screening in clinic; 
follow-up version at baseline and all 
post-baseline clinic visits 
CGI-S
Clinical Global 
Impression
Severity
1
Overall severity of 
patient status
2 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
CGI-C
Clinical Global 
Impression
Change
1
Overall change in 
patient status
2 min
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits 
HD-DAS
Huntington's 
Disease Daily 
Activities Scale 
25
Daily function
25 min
Screening and Weeks 13, 29, 45, 
61, 77, and 93
DCLdiagnostic confidence level.

RO7234292F. Hoffmann-La Roche Ltd
166/Protocol BN40423, Version 6
Appendix 12 Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD 
Mobile Application for Patients Enrolled before Implementation of Protocol Version 4
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
AES
Apathy Evaluation 
Scale
18
Apathy
10
PROObsRO
Baseline and Weeks 13, 
29, 45, 61, 77, 93, and 
101
In-clinic
Roche HD 
mobile app 
Roche HD mobile app 
with daily Active Test 
and Passive 
Monitoring
NA
Tasks (“active test”) that assess 
motor symptoms (upper and 
lower body movements, upper 
limb dexterity, voice) and 
non-motor symptoms 
(processing speed/voice); 
continuous passive monitoring
5
Sensor data, 
PRO, PerfO
Dailyat clinic visits 
(Screening, baseline 
and Weeks 25, 49, 73, 
and 101 and ETT visits) 
Roche HD 
mobile app
CrGI-C
Companion-Reported 
Global Impression, 
Change
1
Overall change in patient status
2
ObsRO
Weeks 5, 21, 37, 53, 
69, 85, and 101 and 
ETT visits
In-clinic on 
electronic 
device
CrGI-S
Companion-Reported 
Global Impression, 
Severity
1
Overall severity of patient status
2
ObsRO
Baseline and Weeks 5, 
21, 37, 53, 69, 85, and 
101 and ETT visits
In-clinic on 
electronic 
device
EQ-5D-5L
EuroQol 5-Dimension, 
5-Level Questionnaire
6
Health utilities
5
PROObsRO
Baseline and Weeks 5, 
21, 37, 53, 69, 85, and 
101 and ETT visits
In-clinic
Weekly
Roche HD 
mobile app; 
electronic 
device

Appendix 12: Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients Enrolled 
before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
167/Protocol BN40423, Version 6
Assessment
Name
Item
s
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
HD-SDI
Huntington's 
DiseaseSpeaking 
Difficulty Item 
1
Speech
1
PRO
Weekly
Roche HD 
mobile app
HD-CIAOS
Huntington's 
DiseaseCompanion
-Reported Irritability 
and Angry Outbursts 
Scale
3
Irritability and angry 
outbursts
2
ObsRO
Weekly
Electronic 
device
HUI
Health Utilities Index
15
Health-related quality of 
life
10
ObsRO
Baseline, Weeks 5, 21, 37, 
53, 69, 85, and 101 and ETT
In-clinic
Weekly
Electronic 
device
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10
PerfO
Screening, baseline, 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT
In-clinic
Neuro-Qol 
Cog Func
Neuro-Qol Cognitive 
Function Short Form
8
Cognition
5
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 
In-clinic
PGI-C
Patient Global 
ImpressionChange
1
Overall change in 
patient status
2
PRO
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
PGI-S
Patient Global 
ImpressionSeverity
1
Overall severity of 
patient status
2
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 and 
ETT
In-clinic

Appendix 12: Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients Enrolled 
before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
168/Protocol BN40423, Version 6
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
SDMT/
eSDMT
Symbol Digit 
Modalities Test
Max 
number in 
90 seconds
Cognitive
5
PerfO
SDMT at baseline and 
Weeks 5, 21, 37, 53, 61 69, 
85, and 101 and ETT visits 
In-clinic
eSDMT at screening, 
baseline, and 
Week 101 in last block 
post-SDMT assessment
Roche HD 
mobile app 
(eSDMT)
SMDDS
Symptoms of Major 
Depressive 
Disorder Scale
16
Depression, anxiety, 
irritability, sleep
10
PRO
Baseline and Weeks 13, 
29, 45, 61, 77, 93, and 101 
In-clinic
SWR/eSWR
Stroop Word 
Reading Test
Max 
numbers in 
45 seconds
Cognitive
5
PerfO
SWR at baseline and 
Weeks 5, 21, 37, 53, 61 69, 
85, and 101 and ETT visits
In-clinic
eSWR at screening, 
baseline, and Week 101 in 
last block post-SWR 
assessment
Roche HD 
mobile app 
(eSWR)
WPAI
Work Productivity 
and Activity 
Impairment
6
Work productivity
5
PROObsRO
Monthly 
Roche HD 
mobile app 
and electronic 
device
appapplication; ETT early treatment termination; HD Huntington disease; ObsRO observer-reported outcome; PerfO performance outcome; 
PROpatient-reported outcome.

RO7234292F. Hoffmann-La Roche Ltd
169/Protocol BN40423, Version 6
Appendix 13 Clinical Assessments Order and Duration for 
Patients Enrolled before Implementation of Protocol Version 4
Table 1
Screening Visit Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Diagnostic Confidence Level
Huntington's Disease Daily Activities Scale
Independence Scale
MoCA
C-SSRS 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Roche HD mobile application
~20
Qualified 
study 
personnel
C-SSRSColumbia-Suicide Severity Rating Scale; HDHuntington disease; MoCAMontreal 
Cognitive Assessment.

Appendix 13: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
170/Protocol BN40423, Version 6
Table 2
Baseline and Week 101 Clinical Assessments (for Primary 
Analysis)
Block
Assessments
Total 
Duration 
(minutes)
Site Staff Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic 
Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
(post-baseline visits only)
~60
Qualified study physician
Break (if needed)
~2030
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified study 
personnel
Break (if needed)
~10
3 a
Apathy Evaluation Scale (patient and 
companion)
Symptoms of Major Depressive Disorder 
Scale
~20
Qualified study 
personnel
Break (if needed)
~1020
4 a
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level 
Questionnaire (patient and companion)
Health Utilities Index (companion: self and 
proxy)
Patient/Companion-reported Global 
ImpressionSeverity
Patient/Companion-reported Global 
ImpressionChange (post-baseline visits 
only)
~20
Qualified study 
personnel
Break (if needed)
~1020
5 a
Roche HD mobile application
~20
Qualified study 
personnel
HDHuntington disease; MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in 
Neurological Disorders; UHDRSUnified Huntington's Disease Rating Scale.
a At the baseline visit and at week 101, Blocks 3, 4, and 5 can be completed on the same day 
after Blocks 1 and 2, or on the following day, but must be completed predose at the baseline 
visit.  

Appendix 13: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
171/Protocol BN40423, Version 6
Table 3
Follow-Up Clinical Assessments at Weeks 5, 21, 37, 53, 69, 
and 85
Block
Assessments
Total 
Duration 
(minutes)
Site Staff 
Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified 
study 
personnel
Break (if needed)
~10
3
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level Questionnaire (patient 
and companion)
Health Utilities Index (companion: self and proxy)
Patient/Companion-reported Global ImpressionSeverity
Patient/Companion-reported Global ImpressionChange 
~30
Qualified 
study 
personnel
MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in Neurological Disorders; 
UHDRSUnified Huntington's Disease Rating Scale
Table 4
Follow-Up Clinical Assessments at Weeks 13, 29, 45, 61, 77, 
and 93
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1 a
Apathy Evaluation Scale (patient and companion)
Symptoms of Major Depressive Disorder Scale
~20
Qualified 
study 
personnel
Break (if needed)
~10
2
Huntington's Disease-Daily Activities Scale
~25
Qualified 
study 
physician
a To be completed prior to safety assessments.

Appendix 13: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
172/Protocol BN40423, Version 6
Table 5
Digital Monitoring Platform Assessment Supervised by Study 
Staff in Clinic at Weeks 25, 49, 73
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Roche HD mobile application
~20
Qualified 
study 
personnel
HDHuntington disease.

RO7234292F. Hoffmann-La Roche Ltd
173/Protocol BN40423, Version 6
Appendix 14
Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4:  Active 
Test
The following tasks are part of the "active tests" conducted on the Roche Huntington's Disease 
(HD) mobile application by the patient. 
Daily Questions
Two daily single-item questions on mood and physical energy will be assessed, asking patients 
about their mood and physical health at the time they are performing the “Active” tests. The 
assessments aim to capture daily mood fluctuations and will be used as a control for the other 
motor and cognitive assessments. 
Cognitive Test (eSDMT)
The Cognitive Test asks participants to match symbols with numbers according to a key as 
quickly and accurately as possible.  The key, symbols, numbers are all displayed on a 
smartphone screen.  The test assesses visuo-motor integration, and measures visual attention 
and motor speed.  It is modelled on the pen and paper Symbol Digit Modalities Test (SDMT) 
(Smith, 1968).  The SDMT has been shown to be sensitive to symptom changes in early HD 
patients (Tabrizi 2012) and is part of the Unified Huntington's Disease Rating Scale (UHDRS) 
assessment (Huntington’s Study Group, 1996).
Word Reading Test (eSWR)
The Word Reading Test asks participants to read aloud color words written in black font on a 
smartphone screen. Their voice will be recorded.  The test assesses cognitive processing speed, 
and is modelled on the Stroop Word Reading (SWR) (Ridley 1935).  The "Word Reading" part of 
the SWR Test has been shown to be sensitive to symptom changes in patients with early HD 
(Tabrizi 2012) and is part of the UHDRS assessment (Huntington’s Study Group 1996). 
Speeded Tapping Test
The Speeded Tapping Test asks participants to tap the smartphone screen as fast and regularly 
as possible, using the index finger of both the left and right hands.  The test assesses 
bradykinesia. Performance will also be impacted by chorea and dystonia.  It is modelled on 
tapping tests shown to be sensitive to symptom changes in early HD (Bechtel et al. 2010; Tabrizi 
et al. 2012). A similar finger tapping task is also included as part of the UHDRS assessment 
(Huntington’s Study Group 1996).
Draw a Shape Test
The Draw a Shape Test asks participants to trace a series of increasingly complex shapes on the 
smartphone screen. The shapes include lines, a square, a circle, an eight, and a spiral.  This test 
is designed to assess visuomotor coordination and fine motor impairment in early HD patients.  It 
is modelled on circle tracing tasks that have been shown to be sensitive to symptom changes in 
early HD (Say et al. 2011; Tabrizi et al. 2013). 
Chorea Test
The Chorea Test asks participants to hold the smartphone still in their hand with their arm
outstretched, and wear the wrist-worn wearable.  As a dual task, participants will also need to 
count backwards aloud.  To ensure correct execution, voice will be recorded.  The test is 
designed to assess chorea.  It draws on other sensor-based approaches to measure chorea 
(Reilmann et al. 2010, 2011; Kegelmeyer et al. 2017). A chorea assessment is also part of the 
UHDRS (Huntington’s Study Group 1996). 
Balance Test
The Balance Test asks participants to stand still while wearing the smartphone and wrist-worn 
wearable.  It is an assessment for patients’ static balance function.  Sensor-based approaches for 

Appendix 14: Roche HD Mobile Application for Patients Enrolled before Implementation of 
Protocol Version 4:  Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
174/Protocol BN40423, Version 6
measuring static balance have been shown to be sensitive to differences in symptoms in early 
HD (Dalton et al. 2013).  The test is also part of established scales like the Berg Balance Scale 
(Berg et al. 1992), which are used in HD (Busse et al. 2009; Rao et al. 2009).  The test is 
anchored to the UHDRS assessments for maximal dystonia, maximal chorea, and tandem 
walking (Huntington Study Group 1996).
U-Turn Test
The U-Turn Test asks participants to walk and turn safely between two points that are at least 
four steps apart, while wearing the smartphone and wrist-worn wearable.  They need to make at 
least five turns.  The test is designed to assess gait and lower-body bradykinesia, which are also 
assessed by the UHDRS.  It is modelled on the Timed Up and Go Test, which has been clinically 
validated for the HD population (Busse et al. 2009; Rao et al. 2009).  The test is anchored to the 
UHDRS gait, bradykinesia body, and tandem walking items (Huntington Study Group 1996). 
Walk Test
The Walk Test asks participants walk as fast as is safely possible for 200 meters or 2 minutes 
every day.  Ideally, the test is done in a straight path with no obstacles (e.g., in a park).  
Sensor-based approaches for measuring gait have been shown to be sensitive to differences in 
symptoms in early HD (Dalton et al. 2013).  The test is anchored to the UHDRS gait, bradykinesia 
body, and tandem walking items (Huntington Study Group 1996).
Tasks are automatically scheduled as shown below in Figure 1 and take no more than 5 minutes 
per day.  If the patient does not complete the active test on a certain day, scheduled tasks that 
occur less frequently than every second day (i.e., EuroQol 5-Dimension, 5 Level Questionnaire, 
Work Productivity and Activity Impairment, Huntington's Disease Speaking Difficulty Item, 
2-Minute Walk Test) are rolled over to the next time the active test is completed.
References
Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest 
and symptomatic Huntington disease. Neurology 2010;75:215060.
Berg KO, Wood-Dauphinee SL, Williams JI, et al. Measuring balance in the elderly: validation of 
an instrument. Can J Public Health 1992;83(Suppl 2):S711.
Busse ME, Wiles CM, Rosser AE. Mobility and falls in people with Huntington's disease. J Neurol 
Neurosurg Psychiatry 2009;80:8890.
Dalton A, Khalil H, Busse M, et al. Analysis of gait and balance through a single triaxial 
accelerometer in presymptomatic and symptomatic Huntington’s disease. Gait Posture 
2013;37:4954.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.Kegelmeyer et al. 2017
Rao AK, Muratori L, Louis ED, et al. Clinical measurement of mobility and balance impairments in 
Huntington's disease: validity and responsiveness. Gait Posture 2009;29:4336.
Reilmann R, Bohlen S, Kirsten F, et al. Assessment of involuntary choreatic movements in 
Huntington's disease—toward objective and quantitative measures. Mov Disord 
2011;26:226773.

Appendix 14: Roche HD Mobile Application for Patients Enrolled before Implementation of 
Protocol Version 4:  Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
175/Protocol BN40423, Version 6
Reilmann R, Bohlen S, Klopstock T, et al. Grasping premanifest Huntington's disease - shaping 
new endpoints for new trials. Mov Disord 2010;25:285862.
Say MJ, Jones R, Scahill R, et al. Visuomotor integration deficits precede clinical onset in 
Huntington's disease. Neuropsychologia 2011;49:26470.
Smith A. The symbol-digit modalites test: a neuropsychologic test of learning and other cerebral 
disorders. In: Helmuth J, editor. Learning disorders. Seattle: Special Child Publications; 
1968:83–91.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:64362.
Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and 
early Huntington's disease in the TRACK-HD study: analysis of 24 month observational 
data. The Lancet Neurology 2012;11.1:4253.
Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in 
premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-
month observational data. Lancet Neurol 2013;12:63749.

Appendix 14: Roche HD Mobile Application for Patients Enrolled before Implementation of Protocol Version 4:  Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
176/Protocol BN40423, Version 6
Figure 1
Timing of Assessments
EQ-5D-5LEuroQol 5-Dimension, 5 Level Questionnaire; eSDMT electronic Symbol Digit Modalities Test; HD-SDIHuntington's Disease 
Speaking Difficulty Item; Lleft; PROpatient-reported outcome; Rright; WPAI.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
PROs
2 Daily Questions (Physical, Mood)
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
EQ-5D-5L
o
o
o
o
WPAI
o
HD-SDI
o
o
o
o
Cognitive Tests
eSDMT
o
Word reading test
o
Motor tests
Speeded tapping Test (L+R)
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
Draw shape Test (L+R)
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
Chorea Test (L+R)
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
Balance Test
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
U-Turn Test
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
o
Walking
2 Minute Walk Test
o
o
o
o
Screening, 
Month 6, 12, 18
Baseline, 
Month 25
Timing of assessments in 4-week rotation (day)

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  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.
RO7234292—F. Hoffmann-La Roche Ltd
Protocol BN40423, Version 4
PROTOCOL
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III CLINICAL 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF INTRATHECALLY ADMINISTERED 
RO7234292 (RG6042) IN PATIENTS WITH 
MANIFEST HUNTINGTON'S DISEASE
PROTOCOL NUMBER:
BN40423
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002987-14
IND NUMBER:
137873
TEST PRODUCT:
RO7234292
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  18 September 2018
DATES AMENDED:
Version 2 (European Union):  13 December 2018
Version 3 (VHP):  24 January 2019
Version 4:  See electronic date stamp below
 
16-Apr-2019 22:13:46
Title
Approver's Name
Company Signatory
Date and Time (UTC)

RO7234292—F. Hoffmann-La Roche Ltd
2/Protocol BN40423, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
The Study BN40423 protocol has been amended following a 9-month data review from 
the ongoing open-label extension (OLE) Study BN40697 (ISIS 443139-CS2).  
Preliminary dataincluding cerebrospinal fluid (CSF) mutant huntingtin (mHTT) protein, 
exploratory fluid biomarkers, and safety/tolerabilityshow that a 120 mg every-8-week 
(Q8W; every 2 months) dosing regimen of RO7234292 achieves 47% median CSF 
mHTT lowering at trough (i.e., sample taken immediately before the next dose) and the 
120 mg every-4-week (Q4W; monthly) dosing regimen achieves 66% median lowering at 
trough. Both results exceed the 20%40% target for CSF mHTT lowering at trough and 
steady state based upon efficacy data from nonclinical models, and exceed the result of 
~40% median lowering observed in the completed Phase I/IIa study.
Safety and tolerability data for RO7234292 from the Phase II OLE Study BN40697 
suggest that relative to the Q4W treatment regimen, the Q8W treatment regimen may be 
more suitable for chronic intrathecal (IT) dosing, as evidenced by improved adherence to
the less frequent regimen. There have been no acute safety concerns meriting a 
change to the ongoing Study BN40697.  However, given the 9-month CSF mHTT 
results, which suggest a longer than anticipated duration of effect of RO7234292 on CSF 
mHTT lowering, it is not necessary to use Q4W paradigm to test the existing 
dose rationale in this study.
The existing dose rationale tests a more frequent dosing regimen, which is anticipated to 
maintain trough CSF mHTT reduction of at least ~40% (i.e., Q8W 120 mg arm from 
present data), and a less frequent regimen, which is still anticipated to lower mHTT 
acutely, but will allow greater recovery of HTT levels between doses (from present data 
trough CSF mHTT reduction of ~20% is maintained in a 120-mg Q16W 
paradigm). Thus, this protocol for the 25-month pivotal Phase III study (BN40423) has 
been amended to replace the Q4W arm with an every-16-week (Q16W; every 4 months) 
arm, while continuing the Q8W arm and placebo.
Changes to the protocol, along with a rationale for each change, are summarized below:

The Q4W dosing regimen has been removed from this study design based on
preliminary data from Study BN40697.  The 120-mg Q8W arm will be continued in
the protocol, and a less frequent regimen of 120 mg Q16W has been added. The
underlying dose rationale remains the same for the program, namely testing a more
frequent dosing regimen that maintains a higher magnitude trough reduction of
at least ~40% (i.e., Q8W 120-mg arm from present data) versus a less frequent
dosing regimen that allows for a lower magnitude trough reduction, which is still
anticipated to lower mHTT acutely, but will allow more recovery of HTT levels
between doses (from present data trough CSF mHTT reduction of ~20% is
maintained in a 120-mg Q16W paradigm (Sections 1.2, 3.1, 3.3.1, 4.6, and 6).  The
timings of study assessments have been updated accordingly (Appendix 1).

RO7234292—F. Hoffmann-La Roche Ltd
3/Protocol BN40423, Version 4

Treatment regimen descriptions have been updated.  Patients who enrolled in
Study BN40423 before this amendment (Version 4) will be given the option of
enrolling in the long-term OLE Study BN40955 after approval of the OLE study by
the relevant competent authority and Ethics Committee/Investigational Review
Board (Sections 3.1, 3.3.3, and 4.2).  Those patients will be discontinued from
Study BN40423 at the point of enrollment into Study BN40955.

Description of study companion requirements has been revised (Section 4.1.1).

Exclusion criteria have been revised to further describe drug and/or alcohol abuse
(Sections 4.1.2 and 4.5.2). In addition, clarification has been made for exclusions
for scoliosis and antiretroviral medications (Section 4.5.5).

Additional details have been provided for administration of study drug by lumbar
puncture (Section 4.3.2.1).  Clarification has also been made that patients should
not perform any activity associated with a change in the ambient air pressure for at
least 72 hours poststudy drug administration (Section 4.5.5).

Sedation and anti-anxiety medication have been further detailed in the prohibited
therapy section (Section 4.4.2).

A CSF sample for differential cell counts, where feasible, has been added to the
local laboratory samples section (Section 4.5.6).

Preservation of biomarkers samples has been updated from 5 years to 10 years
(Section 4.5.6).

Loss of capacity to consent (if legal guardian consent is not possible) has been
added as a possible reason for study treatment discontinuation (Section 4.6.1).

The potential risks section has been updated to include hydrocephalus based upon
observed findings from another intrathecal bolusadministered 2’MOE ASO and
changes in CSF protein observed with RO7234292.  Additional updates from the
ongoing Study BN40697 have been made.  The safety monitoring plan and
management guidelines for patients who experience adverse events have been
further clarified but principally remain the same (Section 5.1).

The name and contact phone number for the Medical Monitor has been revised
(Section 5.4.1).

Language has been added to clarify that, after withdrawal of consent for
participation in the RBR, remaining RBR samples will be destroyed or will no longer
be linked to the patient (Section 4.5.10.6).

Text has been modified to account for the fact that special situations (i.e., accidental
overdoses and medication errors) are not required to be reported within 24 hours
(Sections 5.3.5.12 and 5.4).  Note that serious adverse events associated with
special situations are still required to be reported within 24 hours.

Language has been added to indicate that the study will comply with applicable local,
regional, and national laws (Section 8.1).

RO7234292—F. Hoffmann-La Roche Ltd
4/Protocol BN40423, Version 4

Language has been revised to clarify that data posting will not be limited to two
clinical trial registries and to clarify that redacted CSRs are provided only if
requirements of Roche's global policy on data sharing have been met (Section 9.5).

Appendices 14 and 6 describe study assessments relevant solely to patients
enrolled after implementation of Protocol Version 4. Appendices 913 describe
study assessments relevant solely to patients enrolled before implementation of
Protocol Version 4.

Guidance for neurological examination has been added as Appendix 8.
This amendment includes cumulative changes to the protocol from Versions 2 (EU) 
and 3 (VHP), which were created following comments from the Voluntary Harmonization 
Process (VHP) review.  Protocol Versions 2 and 3 were previously only implemented in 
EU countries, as they were local amendment requests following the European Medicines 
Agency (EMA) review.
Changes brought forward from the Version 2 amendment are summarized below:

Additional wording has been added as per Clinical Trial Facilitation Group guidance
to clarify that a vasectomized man must undergo a medical assessment of surgical
success before he can be considered surgically sterile (Section 4.1.1).

The inclusion criterion referring to the estimated glomerular filtration rate has been
corrected by using the correct unit (mL/min) (Section 4.1.1).

The exclusion criterion regarding current use of antidepressants or benzodiazepine
has been amended to change from 112 weeks to 12 weeks (Section 4.1.2).

Additional information has been provided in the statistical section around the testing
strategy for the primary endpoint, how missing data will be imputed, clarity around
the use of historical controls, and details on how the sample size has been
calculated, as requested (Sections 6.2, 6.3, and 6.6).
Changes brought forward from the Version 3 amendment are summarized below:

Clarification has been added to Section 6.12.  An Interim Analysis (IA) will be
performed only after a future protocol amendment outlining a detailed plan of the IA.
Additional minor changes have been made to improve clarity and consistency. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.

RO7234292F. Hoffmann-La Roche Ltd
5/Protocol BN40423, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Huntington's Disease.................................... 27
1.2
Background on RO7234292 .................................................. 28
1.3
Study Rationale and BenefitRisk Assessment..................... 30
2.
OBJECTIVES AND ENDPOINTS ............................................................... 31
2.1
Efficacy Objectives ................................................................ 31
2.1.1
Primary Efficacy Objective..................................................... 31
2.1.2
Secondary Efficacy Objective................................................ 31
2.1.3
Exploratory Efficacy Objective............................................... 32
2.2
Safety Objective .................................................................... 32
2.3
Pharmacokinetic Objectives................................................... 33
2.4
Immunogenicity Objectives ........ ........................................... 33
2.5
Biomarker Objectives............................................................. 33
2.5.1
Primary Biomarker Objective................................................. 33
2.5.2
Secondary Biomarker Objective ............................................ 33
2.5.3
Exploratory Biomarker Objective ........................................... 34
2.6
Health Status Utility Objective ............................................... 34
3.
STUDY DESIGN......................................................................................... 34
3.1
Description of the Study......................................................... 34
3.1.1
Overview of Study Design ..................................................... 34
3.1.1.1
Study Design Overview for Patients Enrolled 
prior to Implementation of Protocol Version 4 ...................... 39
3.1.2
Independent Data Monitoring Committee .............................. 42
3.2
End of Study and Length of Study......................................... 42
3.3
Rationale for Study Design.................................................... 42
3.3.1
Rationale for RO7234292 Dose and Schedule...................... 42
3.3.2
Rationale for Patient Population ............................................ 44
3.3.3
Rationale for Control Group................................................... 45

RO7234292F. Hoffmann-La Roche Ltd
6/Protocol BN40423, Version 4
3.3.4
Rationale for Biomarker Assessments................................... 45
3.3.4.1
Cerebrospinal Fluid Biomarkers ............................................ 45
3.3.4.2
Blood Biomarkers .................................................................. 45
3.3.4.3
Genetic Testing to Determine CAG Repeat 
Length.................................................................................... 46
3.3.4.4
Clinical Genotyping................................................................ 46
3.3.4.5
Magnetic Resonance Imaging ............................................... 46
4.
MATERIALS AND METHODS .................................................................... 47
4.1
Patients.................................................................................. 47
4.1.1
Inclusion Criteria.................................................................... 47
4.1.2
Exclusion Criteria................................................................... 49
4.2
Method of Treatment Assignment and Blinding..................... 51
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 52
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 52
4.3.1.1
RO7234292 ........................................................................... 52
4.3.1.2
Placebo.................................................................................. 53
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 53
4.3.2.1
RO7234292 and Placebo ...................................................... 53
4.3.3
Investigational Medicinal Product Accountability ................... 53
4.3.4
Continued Access to RO7234292 ......................................... 54
4.4
Concomitant Therapy ............................................................ 55
4.4.1
Permitted Therapy................................................................. 55
4.4.2
Prohibited Therapy ................................................................ 55
4.5
Study Assessments ............................................................... 56
4.5.1
Informed Consent Forms and Screening Log........................ 56
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 57
4.5.3
Physical and Neurologic Examinations.................................. 57
4.5.4
Vital Signs.............................................................................. 58
4.5.5
Collection of Cerebrospinal Fluid (Lumbar 
Puncture Procedure) ............................................................. 58

RO7234292F. Hoffmann-La Roche Ltd
7/Protocol BN40423, Version 4
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 59
4.5.7
Magnetic Resonance Imaging ............................................... 61
4.5.8
Electrocardiograms................................................................ 61
4.5.9
Patient-Reported, Clinician-Reported, Study 
Observer-Reported, and Performance Outcomes ................. 62
4.5.9.1
Composite Unified Huntington's Disease Rating 
Scale...................................................................................... 63
4.5.9.2
Total Functional Capacity Scale ............................................ 63
4.5.9.3
Total Motor Score.................................................................. 63
4.5.9.4
Symbol Digit Modalities Test ................................................. 63
4.5.9.5
Stroop Word Reading Test .................................................... 63
4.5.9.6
UHDRS Functional Assessment............................................ 64
4.5.9.7
Independence Scale.............................................................. 64
4.5.9.8
HD Daily Activities Scale ....................................................... 64
4.5.9.9
Clinical Global ImpressionSeverity and Change 
Scales.................................................................................... 64
4.5.9.10
Patient Global ImpressionSeverity and Change 
Scales.................................................................................... 64
4.5.9.11
Companion-Reported Global 
ImpressionSeverity and Change Scales .............................. 65
4.5.9.12
Montreal Cognitive Assessment ............................................ 65
4.5.9.13
Work Productivity and Activity Impairment............................. 65
4.5.9.14
Apathy Evaluation Scale........................................................ 66
4.5.9.15
Neuro-Qol Cognition Function Short Form, 
Version 2 ............................................................................... 66
4.5.9.16
HD Speaking Difficulty Item ................................................... 66
4.5.9.17
Symptoms of Major Depressive Disorder Scale .................... 66
4.5.9.18
HD Companion-Reported Irritability and Angry 
Outbursts Scale..................................................................... 66
4.5.9.19
EuroQol 5-Dimension, 5-Level Questionnaire ....................... 67
4.5.9.20
Health Utilities Index Mark 2 and Mark 3 ............................... 67
4.5.9.21
Columbia-Suicide Severity Rating Scale ............................... 67
4.5.9.22
Optional Exit Interviews ......................................................... 68
4.5.9.23
Roche HD Mobile Application:  Remote Testing 
(Smartphone and Wrist-Worn Wearable)............................... 68

RO7234292F. Hoffmann-La Roche Ltd
8/Protocol BN40423, Version 4
4.5.9.24
Roche HD Mobile Application:  In-Clinic 
Assessments ......................................................................... 69
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 69
4.5.10.1
Overview of the Research Biosample Repository.................. 69
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 70
4.5.10.3
Sample Collection.................................................................. 70
4.5.10.4
Confidentiality........................................................................ 71
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 71
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 72
4.5.10.7
Monitoring and Oversight....................................................... 72
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 72
4.6.1
Study Treatment Discontinuation........................................... 73
4.6.2
Patient Discontinuation from Study........................................ 73
4.6.3
Study Discontinuation............................................................ 74
4.6.4
Site Discontinuation............................................................... 74
5.
ASSESSMENT OF SAFETY....................................................................... 74
5.1
Safety Plan ............................................................................ 74
5.1.1
Known Risks Associated with Lumbar Puncture.................... 74
5.1.1.1
PostLumbar Puncture Syndrome......................................... 75
5.1.1.2
Spinal Hematoma.................................................................. 76
5.1.1.3
Meningitis .............................................................................. 76
5.1.2
Potential Risks Associated with RO7234292......................... 76
5.1.2.1
Neurologic Changes............................................................... 76
5.1.2.2
Elevations in CSF WBCs and Protein ................................... 77
5.1.2.3
Thrombocytopenia................................................................. 77
5.1.2.4
Kidney Effects........................................................................ 77
5.1.2.5
Liver Effects........................................................................... 78
5.1.2.6
Hydrocephalus....................................................................... 78
5.1.2.7
Neuropsychiatric Changes..................................................... 78

RO7234292F. Hoffmann-La Roche Ltd
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5.1.2.8
Potential Risk due to Reduction of Target Protein 
HTT........................................................................................ 79
5.1.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 80
5.1.3.1
Dose Modifications ................................................................ 80
5.1.3.2
Treatment Interruption ........................................................... 80
5.1.3.3
Management Guidelines........................................................ 80
5.2
Safety Parameters and Definitions ........................................ 82
5.2.1
Adverse Events ..................................................................... 83
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 83
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 84
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 84
5.3.1
Adverse Event Reporting Period ........................................... 84
5.3.2
Eliciting Adverse Event Information....................................... 85
5.3.3
Assessment of Severity of Adverse Events ........................... 85
5.3.4
Assessment of Causality of Adverse Events ......................... 86
5.3.5
Procedures for Recording Adverse Events............................ 86
5.3.5.1
Injection Reactions ................................................................ 86
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 87
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 87
5.3.5.4
Persistent or Recurrent Adverse Events................................ 87
5.3.5.5
Abnormal Laboratory Values ................................................. 88
5.3.5.6
Abnormal Vital Sign Values ................................................... 89
5.3.5.7
Abnormal Liver Function Tests.............................................. 89
5.3.5.8
Deaths ................................................................................... 89
5.3.5.9
Preexisting Medical Conditions.............................................. 90
5.3.5.10
Lack of Efficacy or Worsening of Huntington's 
Disease.................................................................................. 90
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 90
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error ............................................... 91

RO7234292F. Hoffmann-La Roche Ltd
10/Protocol BN40423, Version 4
5.3.5.13
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 92
5.3.5.14
Safety Biomarker Data........................................................... 92
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 93
5.4.1
Emergency Medical Contacts................................................ 93
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 94
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 94
5.4.2.2
Events That Occur after Study Drug Initiation........................ 94
5.4.3
Reporting Requirements for Pregnancies.............................. 94
5.4.3.1
Pregnancies in Female Patients............................................ 94
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 95
5.4.3.3
Abortions ............................................................................... 95
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 95
5.5
Follow-Up of Patients after Adverse Events .......................... 96
5.5.1
Investigator Follow-Up........................................................... 96
5.5.2
Sponsor Follow-Up ................................................................ 96
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 96
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 96
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 97
6.1
Analysis Populations ............................................................. 97
6.2
Determination of Sample Size ............................................... 98
6.3
Testing Strategy and Multiplicity Adjustment..................... 99
6.4
Summaries of Conduct of Study.......................................... 100
6.5
Summaries of Demographic and Baseline 
Characteristics..................................................................... 100
6.6
Efficacy Analyses ................................................................ 100
6.6.1
Estimands............................................................................ 100
6.6.2
Primary Efficacy Analysis .................................................... 102
6.6.3
Secondary Efficacy Analyses .............................................. 102
6.6.4
Subgroup Analyses ............................................................. 103

RO7234292F. Hoffmann-La Roche Ltd
11/Protocol BN40423, Version 4
6.6.5
Exploratory Efficacy Analysis............................................... 103
6.6.6
Historical Controls ............................................................... 103
6.7
Safety Analyses................................................................... 104
6.8
Pharmacokinetic Analyses................................................... 104
6.9
Immunogenicity Analyses.................................................... 105
6.10
Biomarker Analyses............................................................. 105
6.11
Health Status Utility Analysis............................................... 106
6.12
Optional Interim Analyses.................................................... 106
7.
DATA COLLECTION AND MANAGEMENT ............................................. 106
7.1
Data Quality Assurance....................................................... 106
7.2
Electronic Case Report Forms............................................. 107
7.3
Electronic Patient-, Clinician-, and 
Observer-Reported Outcome Data...................................... 107
7.4
Electronic Data Obtained by the Roche HD 
Digital Monitoring Platform................................................... 107
7.5
Source Data Documentation................................................ 108
7.6
Use of Computerized Systems ............................................ 108
7.7
Retention of Records........................................................... 109
8.
ETHICAL CONSIDERATIONS.................................................................. 109
8.1
Compliance with Laws and Regulations .............................. 109
8.2
Informed Consent................................................................ 109
8.3
Institutional Review Board or Ethics Committee.................. 111
8.4
Confidentiality...................................................................... 111
8.5
Financial Disclosure ............................................................ 112
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION ................................................................................... 112
9.1
Study Documentation .......................................................... 112
9.2
Protocol Deviations.............................................................. 112
9.3
Site Inspections ................................................................... 113
9.4
Administrative Structure....................................................... 113
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 113
9.6
Protocol Amendments ......................................................... 114

RO7234292F. Hoffmann-La Roche Ltd
12/Protocol BN40423, Version 4
10. REFERENCES ......................................................................................... 115
LIST OF TABLES
Table 1
Treatment Regimens after Implementation of Protocol 
Version 4 .................................................................................... 35
Table 2
Treatment Regimens prior to Implementation of Protocol 
Version 4 .................................................................................... 39
Table 3
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 81
Table 4
Adverse Event Severity Grading Scale ....................................... 85
Table 5
Causal Attribution Guidance ....................................................... 86
LIST OF FIGURES
Figure 1
Study Schema for Patients Enrolled after Implementation of 
Protocol Version 4 ...................................................................... 37
Figure 2
Dosing Schema for Patients Enrolled after Implementation 
of Protocol Version 4 .................................................................. 38
Figure 3
Study Schema for Patients Enrolled prior to Implementation 
of Protocol Version 4 .................................................................. 40
Figure 4
Dosing Schema for Patients Enrolled prior to 
Implementation of Protocol Version 4 ........................................ 41
LIST OF APPENDICES
Appendix 1
Schedule of Activities for Patients Enrolled after 
Implementation of Protocol Version 4 ...................................... 119
Appendix 2
Clinician-Reported Outcomes for Patients Enrolled after 
Implementation of Protocol Version 4 ...................................... 127
Appendix 3
Patient-Reported, Observer-Reported, and Performance 
Outcomes and Roche HD Mobile Application for Patients 
Enrolled after Implementation of Protocol Version 4................... 128
Appendix 4
Clinical Assessments Order and Duration for Patients 
Enrolled after Implementation of Protocol Version 4................ 131
Appendix 5
Grading Scale for Adverse Events Relating to Laboratory 
Abnormalities for All Patients................................................... 135

RO7234292F. Hoffmann-La Roche Ltd
13/Protocol BN40423, Version 4
Appendix 6
Roche HD Mobile Application for Patients Enrolled after 
Implementation of Protocol Version 4:  Active Test.................. 138
Appendix 7
Diagnostic Confidence Level for All Patients ........................... 142
Appendix 8
Guidance for Neurological Examination for All Patients ......... 143
Appendix 9
Schedule of Activities for Patients Enrolled before 
Implementation of Protocol Version 4 ...................................... 144
Appendix 10
Clinician-Reported Outcomes for Patients Enrolled before
Implementation of Protocol Version 4 ...................................... 151
Appendix 11
Patient-Reported, Observer-Reported, and Performance 
Outcomes and Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4.............. 152
Appendix 12
Clinical Assessments Order and Duration for Patients 
Enrolled before Implementation of Protocol Version 4.............. 155
Appendix 13
Roche HD Mobile Application for Patients Enrolled before
Implementation of Protocol Version 4:  Active Test ................. 159

RO7234292F. Hoffmann-La Roche Ltd
14/Protocol BN40423, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PHASE III CLINICAL 
STUDY TO EVALUATE THE EFFICACY AND 
SAFETY OF INTRATHECALLY ADMINISTERED 
RO7234292 (RG6042) IN PATIENTS WITH 
MANIFEST HUNTINGTON'S DISEASE
PROTOCOL NUMBER:
BN40423
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002987-14
IND NUMBER:
137873
TEST PRODUCT:
RO7234292 
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.

RO7234292F. Hoffmann-La Roche Ltd
15/Protocol BN40423, Version 4
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PHASE III CLINICAL STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF INTRATHECALLY ADMINISTERED 
RO7234292 (RG6042) IN PATIENTS WITH MANIFEST 
HUNTINGTON'S DISEASE
PROTOCOL NUMBER:
BN40423
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-002987-14
IND NUMBER:
137873
TEST PRODUCT:
RO7234292
PHASE:
Phase III
INDICATION:
Huntington's disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, pharmacokinetic (PK), and biomarker effects of 
RO7234292 compared with placebo in patients with manifest Huntington's disease (HD).  
Specific objectives and corresponding endpoints for the study are outlined below.
Efficacy Objectives
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of RO7234292 compared 
with placebo on the basis of the following endpoint:

Change from baseline in the composite Unified Huntington's Disease Rating Scale
(cUHDRS) score at Week 101
Note:  The primary efficacy endpoint for the U.S. Food and Drug Administration (FDA) 
will be change from baseline in the Total Functional Capacity (TFC) score at Week 101 
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of RO7234292 
compared with placebo on the basis of the following endpoints:  

Change from baseline in scores for the following individual scales at Week 101:
-
TFC
-
Total Motor Score (TMS)
-
Symbol Digit Modalities Test (SDMT)
-
Stroop Word Reading Test (SWR)
Note:  For the U.S. FDA, the first secondary endpoint will be change from baseline in
the cUHDRS score at Week 101 instead of TFC, as TFC will be the primary endpoint.

Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S) score at
Week 101

RO7234292F. Hoffmann-La Roche Ltd
16/Protocol BN40423, Version 4

Proportion of patients with a decrease from baseline of 1 point on the TFC at Week 101

Proportion of patients with a decline from baseline of 1.2 points on the cUHDRS at Week
101

Proportion of patients with an unchanged or improved score on the Clinical Global
Impression, Change Scale (CGI-C) score from baseline at Week 101
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoints:  

Change from baseline in the Apathy Evaluation Scale (AES) score at Week 101

Change from baseline in the Symptoms of Major Depressive Disorder Scale (SMDDS)
score at Week 101

Change from baseline in the Huntington's Disease Daily Activities Scale (HD-DAS) score at
Week 93

Change from baseline in the Patient Global Impression, Severity Scale (PGI-S) score at
Week 101

Change from baseline in the Quality of Life in Neurological Disorders (Neuro-Qol) Cognition
Function Short Form at Week 101

Change from baseline in the Huntington's Disease Speaking Difficulty Item Scale (HD-SDI)
score at Week 101

Change from baseline in the Huntington's Disease Companion-Reported Irritability and
Angry Outbursts Scale (HD-CIAOS) score at Week 101

Change from baseline in the in-clinic patient-reported EuroQol 5-Dimension Questionnaire
(5-level version; EQ-5D-5L) index-score and visual analogue scale (VAS) at Week 101

Change from baseline in the sensor-based measures collected by the Roche HD mobile
application (app; smartphone and wrist-worn wearable) at Week 101
Safety Objective
The safety objective for this study is to evaluate the safety and tolerability of RO7234292 
compared with placebo on the basis of the following endpoints: 

Incidence and severity of adverse events, with severity determined according to the
Adverse Event Severity Grading Scale

Change from baseline in Montreal Cognitive Assessment (MoCA)

Change from baseline in vital signs

Change from baseline in ECG parameters

Change from baseline in clinical laboratory results

Proportion of patients with suicidal ideation or behavior, as assessed by Columbia-Suicide
Severity Rating Scale (C-SSRS) score at each visit, including detailed focus on any
individual cases identified as having severe ideation or behavior during the study conduct
Pharmacokinetic Objectives
The PK objective for this study is to characterize the RO7234292 PK profile in plasma and 
trough CSF on the basis of the following endpoints:

Concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints
The exploratory pharmacokinetic/pharmacodynamic (PK/PD) objective for this study is to 
evaluate potential relationships between drug exposure and the efficacy and safety of 
RO7234292 on the basis of the following endpoints:

Relationship between plasma profiles and/or trough CSF concentrations of PK parameters
for RO7234292 and efficacy endpoints

RO7234292F. Hoffmann-La Roche Ltd
17/Protocol BN40423, Version 4

Relationship between plasma profiles and/or trough CSF concentrations of PK parameters
for RO7234292 and safety endpoints
Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response to RO7234292
on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the prevalence
of ADAs at baseline

Titer and antibody subtype, determined if ADAs are identified
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objectives
Primary Biomarker Objective
The primary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoint:

Change from baseline in CSF mHTT protein level at Week 101
Secondary Biomarker Objective
The secondary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoints:

Change from baseline in whole and regional brain volumes (caudate, whole brain, and
ventricular), as determined by structural magnetic resonance imaging (MRI), at Week 101

Change from baseline in CSF neurofilament light chain (NfL) protein level at Week 101
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are predictive of 
response to RO7234292 (i.e., predictive biomarkers), are early surrogates of efficacy, are 
associated with progression to a more severe disease state (i.e., prognostic biomarkers), are 
associated with acquired resistance to RO7234292, are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring or investigation 
(i.e., safety biomarkers), can provide evidence of RO7234292 activity (i.e., PD biomarkers), or 
can increase the knowledge and understanding of disease biology and drug safety, on the basis 
of the following endpoints:

Relationship between biomarkers in blood, plasma, and CSF and efficacy, safety, PK,
immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers (e.g., putamen, cortical grey matter, cortical
white matter volumes, resting state functional MRI signal) and efficacy, safety, PK,
immunogenicity, or other biomarker endpoints
Health Status Utility Objective
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with RO7234292 on the basis of the following endpoint:

Change from baseline in patient- and companion-reported EQ-5D-5L Index and VAS scores
at specified timepoints

Change from baseline in companion self-reported and proxy-reported Health Utilities Index
Mark 2 (HUI2) and Mark 3 (HUI3) scores at specified timepoints

Change from baseline in patient- and companion-reported Work Productivity and Activity
Impairment (WPAI) scores at specified timepoints

RO7234292F. Hoffmann-La Roche Ltd
18/Protocol BN40423, Version 4
Study Design
Description of Study
Study BN40423 is a Phase III, randomized, placebo-controlled, double-blind, multicenter clinical 
study to evaluate the efficacy, safety, PK, and biomarker effects of intrathecally administered 
RO7234292 in patients with manifest HD. 
Prospective patients will undergo screening assessments during a 4-week screening period.  A 
maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for 
patients who fail the initial screening.
Upon completion of the screening period, eligible patients will be randomly allocated in a 
1:1:1 ratio to receive RO7234292 every 8 weeks (Q8W; RO7234292 Q8W arm), RO7234292 
every 16 weeks (Q16W; RO7234292 Q16W arm), or placebo Q8W (placebo arm) by IT 
injection.  To maintain the study blind and integrity, patients in the RO7234292 Q16W arm will 
also receive placebo (i.e., alternating doses of active drug and placebo).
During scheduled clinic visits, patients will undergo safety and tolerability evaluations that 
include neurologic examinations, vital signs, ECGs, clinical laboratory tests, MoCA, C-SSRS, 
neuroimaging assessments (neurologic safety sequences), and a review of any adverse events 
including related concomitant medications, as detailed in the schedule of activities.  
If there is the occurrence of a failed IT bolus dosing procedure due to inadequate 
establishment of access to the IT space, a second dosing attempt may occur up to 7 days after 
the originally scheduled dosing visit.  At this additional visit, safety and tolerability 
evaluations will be performed as described in the schedule of activities.
A telephone safety follow-up call will be conducted for the months in which no clinic visits 
are scheduled to check for any change in patient status (i.e., adverse events, concomitant 
medications) since the patient’s last visit.  Where deemed appropriate, an unscheduled clinic 
visit should be arranged for safety follow-up; no dosing will occur at these unscheduled visits. 
During the telephone follow-up call, patients will be reminded of their next follow-up visit.  
Patients who complete the treatment period will return to the clinic for an end-of-treatment visit 
at Week 101.  Patients will then be given the option on an individual basis of receiving 
RO7234292 in an OLE study (BN40955) upon completion of Study BN40423, provided they 
meet eligibility criteria and the data from the ongoing RO7234292 program support continued 
development.  Approval of the OLE study must also be granted by the relevant competent 
authority and Ethics Committee (EC)/Investigational Review Board (IRB).  
All patients enrolled in Study BN40423 who choose to discontinue study treatment prematurely, 
but do not withdraw consent for continued participation in the study, will return to the clinic for 
study visits at Weeks 53 and 69 (if not already completed) for collection of at least the data for 
the primary and secondary endpoints.  If the early treatment termination visit falls within 30 
days of either scheduled visits at Week 53 or Week 69, then only the early treatment 
termination visit will be considered.  The early treatment termination visit should be performed 
28 days (3 days) after the last dose.  Patients will also attend the scheduled end-of-treatment 
visit at Week 101. 
An independent Data Monitoring Committee (iDMC) and independent Data Coordinating Center 
(iDCC) will be employed to monitor and evaluate patient safety throughout the study as well as 
to evaluate evidence of early efficacy.  
Study Design Overview for Patients Enrolled prior to Implementation of Protocol Version 4
All patients enrolled in Study BN40423 prior to implementation of the Version 4 protocol 
amendment will be prematurely discontinued by the Sponsor from this study and will be 
offered treatment in the OLE Study BN40955, once approval has been granted by the relevant 
competent authority and ECs/IRBs.  Patients will continue to receive treatment in 
Study BN40423 until the OLE study has been approved at their study site.  Patients who 
discontinue treatment or study prior to Sponsor discontinuation will not be eligible for the 
OLE Study BN40955. 
Patients who choose to enroll in the OLE will complete an end-of-treatment visit in 
Study BN40423, which can also serve as the inclusion visit for Study BN40955.  All patients 
who are prematurely discontinued by the Sponsor who choose not to consent to Study 
BN40955 will additionally undergo a 5-month postdose safety follow-up visit. 

RO7234292F. Hoffmann-La Roche Ltd
19/Protocol BN40423, Version 4
Number of Patients
Approximately 660 patients with HD will be enrolled in this global study from the 
implementation of Protocol Version 4 and onwards.  This is in addition to patients who 
enrolled prior to Version 4, who will be discontinued from this study and offered participation 
in OLE Study BN40955.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at baseline prior to randomization and study drug dosing):

Signed Informed Consent Form

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form and at the time
of first dose administration

Manifest HD diagnosis, defined as a diagnostic confidence level (DCL) score of 4

Independence Scale (IS) score 70

Genetically confirmed disease by direct DNA testing with a CAP score 400 (Zhang et al.
2011), calculated as follows:
CAP Age (CAG repeat length 33.66)

Ability to read the words "red," "blue," and "green" in native language

Ability to walk unassisted without a cane or walker and move about without a wheelchair on
a daily basis as determined at screening and baseline visit
-
Long-distance (e.g., 50 meters) use of wheelchairs for convenience or transfer is
permitted.

Body mass index 1632 kg/m2; total body weight 40 kg

Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no severe chorea or
other condition that precludes MRI scans or renders scanning intolerable for the patient, no
MRI-incompatible intrauterine devices, metallic dental braces, or other metal implants)

Ability to tolerate blood draws and lumbar punctures

Estimated glomerular filtration rate (eGFR) 60 mL/min (Cockcroft-Gault formula)

Ability and willingness, in the investigator's judgment, to comply with all aspects of the
protocol including completion of interviews and questionnaires for the duration of the study

Ability and willingness, in the investigator's judgment, to carry a smartphone, wear a digital
monitoring device, and complete smartphone-based tasks

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to screening
and at the time of enrollment

Signed study companion consent for participation, if a study companion is available, who
fulfills all of the following criteria:
-
Age 18 years
-
Reliable and competent, in the investigator's judgment
-
Sufficiently knowledgeable of the patient's condition to complete study companion
assessments of the patient, and likely to remain sufficiently knowledgeable throughout
the study, in the investigator's judgment
-
Able to comment on study participant's symptoms and functioning experience
Note:  Companions must have no cognitive, behavioral or motor change, in the
opinion of the investigator, that would question the validity of the acquired observer-
reported data.
All effort should be made to retain the study companion; however, should this not be
possible, a study companion can be replaced and new consent obtained.

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
For women of childbearing potential:  agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive measures, as defined below:
Women must remain abstinent or use two methods of contraception, including at least 
one method with a failure rate of 1% per year, during the treatment period and for 5 
months after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.  A vasectomized man must undergo a medical assessment 
that confirms the success of the surgery before he can be considered surgically sterile.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 5 months after 
the final dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that
required hospital visit and/or change in level of care within 12 months prior to screening
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
investigator.  If suicidal ideation is present, a risk assessment should be done by an 
appropriately qualified mental health professional to assess whether it is safe for the 
patient to participate in the study.  Mild passive suicidal ideation (i.e., occasional 
thoughts that life is not worth living or is hard) without history of attempts or 
hospitalization over the past 12 months is generally acceptable for study participation, 
but final decision on participation should be made carefully and in consultation with an 
appropriately qualified mental health professional. 

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, or vital sign abnormality or
claustrophobia at screening that, in the investigator's judgment, precludes the patient's safe
participation in and completion of the study

History known to the investigator or presence of an abnormal ECG that is clinically
significant in the investigator's opinion, including complete left bundle branch block, second-
or third-degree atrioventricular heart block, or evidence of prior myocardial infarction

Clinical diagnosis of chronic migraines

Pregnant or breastfeeding, or intending to become pregnant during the study or within
5 months after the final dose of study drug

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End of Study 
The end of this study is defined as the date when the last patient, last visit occurs.  The end of 
the study is expected to occur approximately 117 weeks (29 months) after the last patient is 
enrolled.   
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years.  
Investigational Medicinal Products 
The investigational medicinal products (IMPs) for this study are RO7234292 and RO7234292 
placebo.  
Test Product (Investigational Drug) 
RO7234292 will be supplied by the Sponsor as sterile, preservative-free liquid in a 20-mL 
single-use vial containing 10 mL of 6.0 mg/mL RO7234292 drug product for IT injection.  For a 
120-mg dose (20-mL dosing volume), two vials containing 10 mL of 6.0 mg/mL RO7234292 will
be pooled by drawing them up into the same injection syringe containing 20 mL of study drug.
For information on the formulation, preparation, and handling of RO7234292, refer to the 
pharmacy manual. 
Placebo 
RO7234292 placebo will be supplied by the Sponsor as a sterile, preservative-free liquid in a 
20-mL single-use vial containing 10 mL RO7234292 placebo drug product for IT injection.  The
liquid is no different in color than the active drug.
For a 20 mL dosing volume, two vials containing 10 mL of RO7234292 placebo will have to be 
pooled by drawing them up into the same injection syringe containing 20 mL of placebo drug 
product. 
For information on the formulation, preparation, and handling of RO7234292 placebo, refer to 
the pharmacy manual. 
Statistical Methods 
Primary Analysis 
The primary efficacy endpoint is the change from baseline in cUHDRS score at Week 101.  This 
is defined as the attribute "variable" of the primary estimand. 
Note:  The primary efficacy endpoint for the U.S. FDA will be change from baseline in the TFC 
score at Week 101.  TFC will be analyzed the same way as the cUHDRS. 
The primary efficacy analysis for this study will compare each active treatment arm, RO7234292 
Q8W and RO7234292 Q16W, against the placebo arm.  To account for the multiple 
comparison, an appropriate procedure will be used to maintain the overall two-sided type I error 
at 5% (details will be given in the SAP).  
The analysis of the primary endpoint will be performed by means of analysis of covariance 
(ANCOVA).  The model will include the corresponding endpoint baseline score, CAG repeat 
length, baseline CAP score, and treatment as covariates; the final list of covariates will be 
defined in the SAP.  On the basis of this analysis, least squares mean for the treatment 
differences at Week 101 and corresponding 95% CIs will be derived.   
The robustness of the primary method of estimation described above may be explored by 
alternative sensitivity estimators based on varying assumptions underlying the multiple 
imputation strategy. These sensitivity analyses will be described in the SAP. 
Determination of Sample Size   
The planned sample size is adequate to capture meaningful clinical decline on both the TFC 
and cUHDRS and was estimated on the basis of data available from non-interventional studies 
(TRACK-HD, COHORT, ENROLL-HD) and a randomized placebo-controlled study (2CARE).  
Based on these data, using the anticipated trial population, a meta-analysis for the change from 
baseline at 24 months in TFC score suggested a natural decline of 1.36 points and a 
corresponding pooled standard deviation of 1.78.  A conservative treatment discontinuation 
rate at Week 101 for patients receiving placebo or active is assumed to be 20% and 15%, 

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respectively.  Using these assumptions, the simulation described in the protocol was 
performed to estimate the sample size.   
It was estimated that 220 patients per arm will provide approximately 80% power, at a two-sided 
  0.05 level, to detect a 40% slowing of clinical decline for RO7234292 as compared with 
placebo at 101 weeks.  This treatment effect translates into an expected average decline of 
~0.82 points at 101 weeks for the RO7234292 arms.  The minimal detectable difference with 
these assumptions is ~0.38 points.   
Optional Interim Analyses 
The Sponsor may choose to conduct one or more interim analyses for efficacy.  Below are the 
specifications in place to ensure the study continues to meet the highest standards of integrity 
when an optional interim analysis is executed. 
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis will be 
conducted by an iDCC and reviewed by the iDMC.  Interactions between the iDMC and Sponsor 
will be carried out as specified in the iDMC Charter. 
The decision to conduct an interim analysis, along with the rationale, specification of the 
endpoint (e.g., clinical and/or biomarker endpoint), number of patients, and statistical details for 
each analysis, will be introduced via a future protocol amendment, which will be submitted to 
relevant health authorities at least 2 months prior to the conduct of the interim analysis.  The 
iDMC Charter will document potential recommendations the iDMC can make to the Sponsor as 
a result of an interim analysis, and the iDMC Charter will be made available to relevant health 
authorities.  
If there is a potential for the study to be stopped for positive efficacy as a result of an interim 
analysis of efficacy data, the type I error rate will be controlled to ensure statistical validity is 
maintained.  Additional criteria for recommending that the study be stopped for positive efficacy 
will be added to a future protocol amendment.   

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HRQoL
health-related quality of life
HTT
huntingtin (gene)
HTT
huntingtin (protein)
HUI
Health Utilities Index
HUI2
HUI Mark 2
HUI3
HUI Mark 3
ICE
intercurrent event
ICH
International Council for Harmonisation
iDCC
independent Data Coordinating Center
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IS
Independence Scale
IT
intrathecal
ITT
intent-to-treat (population)
IxRS 
interactive voice or web-based response system 
mHTT
mutant huntingtin (protein)
MoCA
Montreal Cognitive Assessment
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology 
Criteria for Adverse Events
Neuro-Qol
Quality of Life in Neurological Disorders
NfL
neurofilament light chain (protein)
NRS
numeric rating scale
NSDR
nonstudy drugrelated (reasons)
ObsRO
observer-reported outcome
OLE
open-label extension
PD
pharmacodynamic
PerfO
performance outcome
PGI-C
Patient Global ImpressionChange
PGI-S
Patient Global ImpressionSeverity
PK
pharmacokinetic
PRO
patient-reported outcome
Q4W
every 4 weeks
Q8W
every 8 weeks
Q16W
every 16 weeks

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QTc
corrected QT interval
RBR
Research Biosample Repository
SAP
Statistical Analysis Plan
SDMT
Symbol Digit Modalities Test
SDR
study drugrelated (reasons)
SMDDS
Symptoms of Major Depressive Disorder Scale
SWR
Stroop Word Reading
TFC
Total Functional Capacity Scale
TMS
Total Motor Score
UHDRS
Unified Huntington's Disease Rating Scale
VAS
visual analogue scale
WES
whole exome sequencing
WGS
whole genome sequencing
WPAI
Work Productivity and Activity Impairment
wtHTT
wild-type huntingtin (protein)

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1.
BACKGROUND
1.1
BACKGROUND ON HUNTINGTON'S DISEASE
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused 
by expansion of CAG repeats in exon 1 of the Huntingtin HTT gene on chromosome 4, 
which encodes for a mutant huntingtin (mHTT) protein.  Based upon nonclinical and 
clinical evidence, mHTT is considered the primary driver of HD pathophysiology 
(Wild and Tabrizi 2017).  Individuals who carry at least 40 CAG repeats inevitably 
experience progressive motor, cognitive, and functional decline usually in adult life, with 
a mean age of motor onset of 45 years.  The average illness course postmotor onset is 
approximately 1020 years, with pneumonia, heart failure, or other complications
frequently cited as the cause of death (Sorensen and Fenger 1992).  Individuals with 
end-stage disease have complete physical disability and profound body wasting.  
The estimated prevalence of HD in North America, northwestern Europe, and Australia 
ranges from 5.96 to 13.17 cases per 100,000 (Baig et al. 2016).  Although genetic 
testing can be used to identify individuals who will develop the disease, the diagnosis of 
HD is clinical through neurologic examination of the motor system.  The clinical 
diagnosis of HD is made when the patient exhibits "unequivocal presence of an 
otherwise unexplained extrapyramidal movement disorder" (e.g., chorea, dystonia, 
bradykinesia, rigidity) or "motor onset" (Huntington Study Group 1996;
Hogarth et al. 2005).  Motor onset is typically confirmed through use of the 15-item motor 
examination of the Unified Huntington's Disease Rating Scale (UHDRS).  After 
completion of the examination, a certified motor rater assigns a diagnostic confidence 
level (DCL) score.  Scores range from 0 to 4, with 0 representing no impairment and 
4 representing unequivocal motor signs of HD (99% confidence).  Among the 
considerable clinical phenotypic heterogeneity of the disease, motor onset is one of the 
more robust and consistently-agreed-upon disease features.  Behavioral features, 
including emotional disorders and personality changes, do not have a uniform 
presentation, are episodic in nature, and do not usually progress steadily over time 
(Ross et al. 2014).  
Individuals with HD can be categorized as having either premanifest disease (diagnosed 
prior to motor onset) or manifest disease (diagnosed on the basis of motor onset).  The 
premanifest disease period can be subdivided into presymptomatic and prodromal
periods.  During the presymptomatic period, from birth to young adulthood, individuals 
are not clinically distinguishable from controls.  During the prodromal period, which can 
last many years before threshold clinical motor diagnosis, subtle motor changes and 
variable cognitive and behavioral changes appear but are not sufficient to make the 
clinical diagnosis of HD. 
The manifest disease period can be subdivided into five stages based on functional 
capacity (Ross et al. 2014).  Stage 1 represents the highest level of capacity and is 
characterized by mild or no incapacity in terms of independence in daily activities.  

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Stage 5 represents severe disability and dependence on full-time care (Shoulson and 
Fahn 1979).  The five clinical stages are defined by the score on the UHDRS Total 
Functional Capacity (TFC) Scale, with Stage 1 corresponding to TFC scores of 1113, 
Stage 2 to scores of 710, Stage 3 to scores of 36, Stage 4 to scores of 12, and 
Stage 5 to a score of 0 (Shoulson et al. 1979).  
Currently approved treatments aim to reduce the burden of symptoms, maximize 
function, and improve the patient's quality of life (Nance et al. 2011).  Tetrabenazine and 
deutetrabenazine target abnormal involuntary movements (i.e., chorea) associated with 
HD, and these symptomatic therapies have a challenging benefitrisk profile.  These 
drugs have been linked to many significant adverse events, including parkinsonism, 
akathisia, sedation, and depression and suicidal thoughts.  They are contraindicated in 
patients who are actively suicidal and in patients with untreated or inadequately treated 
depression.  Additionally, they may prolong the corrected QT interval (QTc), and caution 
is advised when used in combination with other drugs or medical conditions that 
potentially prolong the QTc.
Other medications are utilized in HD to address particular symptoms, such as 
antidepressants (for depression, agitation, irritability), anticonvulsants (for irritability, 
impulsive behavior), anxiolytics (for anxiety), cognitive-enhancing agents (for cognitive 
disturbances), and neuroleptics (for chorea) (Paulson and Albin 2011).  
To date, there are no approved treatments able to slow or stop the clinical progression
of HD.  
1.2
BACKGROUND ON RO7234292
Neuropathological abnormalities in HD appear to be the consequence of a toxic 
gain of function of the mHTT protein (Wexler et al. 1987; Walker 2007; 
Moumné et al. 2013).  Therefore, a therapy that reduces synthesis of the toxic mHTT
protein should directly target the primary disease mechanism.  As the genetic origin of 
HD is localized to just one gene, inhibiting the expression of this HTT gene is a 
promising therapeutic option (Stanek et al. 2013).
RO7234292 (RG6042) was originally developed by Ionis Pharmaceuticals, Inc. and was 
formerly known as ISIS443139 and IONIS-HTTRx.  This antisense oligonucleotide (ASO)
is being developed to reduce the synthesis of all forms of the HTT protein by targeting 
the HTT mRNA from both the wild-type and the mutant alleles and directing its catalytic 
degradation through the action of ribonuclease H1, an endogenous enzyme present in 
most mammalian cells (Crooke and Bennett 1996; Cerritelli and Crouch 2009), including 
cells of interest in the CNS (e.g., neurons and neuroglia).  Reduction of the HTT gene 
mRNA, which in turn limits translation of the wild-type and mutant huntingtin protein,
could potentially inhibit all downstream toxic effects and lead to a sustained reversal in 
HD symptoms.

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Pharmacology data support selective targeting of HTT mRNA transcripts from both 
alleles as a potentially safe and effective mechanism for the treatment of HD.  Using 
ASOs targeting human HTT mRNA in rodents and non-human primates, significant 
reduction of mutant HTT mRNA transcripts, wild-type HTT mRNA transcripts, and mHTT
protein has been achieved throughout most brain regions (Kordasiewicz et al. 2012).  
Furthermore, transient delivery of these ASOs in transgenic mouse models of HD
delayed disease progression and mediated a sustained reversal of disease phenotype 
that persisted longer than HTT mRNA knockdown (Kordasiewicz et al. 2012; Stanek et 
al. 2013).  
Nonclinical proof-of-concept studies with ASOs targeting mutant HTT have been 
conducted in three models of HD, including YAC128 mice expressing the full-length 
mutant human HTT transgene with a 128 CAG repeat expansion, bacterial artificial 
chromosome (BAC)HD mice expressing the full-length mutant human HTT genomic 
sequence with 97 CAG/CAA repeats, and R6/2 mice expressing exon 1 of the mutant 
human HTT gene with 110135 CAG repeats.  These studies demonstrate that ASOs 
targeting human HTT mRNA improve motor function and protect against human HTT
transgene expression in YAC128 mice; improve motor function, hypoactivity, and stress 
response in BACHD mice; and preserve striatal volume and increase survival in R6/2 
mice.
The pharmacokinetics and toxicity of intrathecal (IT) administration of RO7234292, an 
ASO that targets human HTT mRNA, were assessed in cynomolgus monkeys for 
13 weeks (biweekly for the first month and then monthly thereafter) at dose levels up to 
50 mg/dose (5 bolus administrations, for a total dose of 250 mg) and chronically for 
9 months, up to 35 mg/dose (10 bolus monthly administrations for a total dose of 
350 mg).  The drug was safe and well tolerated in these studies.
In a first-in-human, Phase I/IIa double-blind, placebo-controlled, dose-escalation study 
(Clinicaltrials.gov Identifier NCT02519036) (ISIS 443139-CS1) four doses of RO7234292 
(ranging from 10 mg to 120 mg) were well tolerated and achieved significant 
dose-dependent lowering of cerebrospinal fluid (CSF) mHTT protein when administered 
intrathecally every 4 weeks (Q4W; monthly) to 46 patients with early manifest HD.  
Exploratory analyses identified a relationship between lowering of mHTT protein and 
improvement in some clinical measures.  Taken together, these data support further 
clinical testing to demonstrate definitive clinical benefit of mHTT protein reduction in the 
CNS. The data from this study also supported the initiation of Study ISIS 443139-CS2 
(Study BN40697; Clinicaltrials.gov Identifier NCT03342053), a Phase II open-label 
extension (OLE) study for patients who participated in Study ISIS 443139-CS1.  
Nine-month clinical data from the ongoing, 15-month, Phase II OLE 
Study BN40697including CSF mHTT protein, exploratory fluid biomarkers, and 
safety/tolerability dataare available for reporting.  All individuals in Study BN40967 
have reached the 9-month timepoint of the planned 15-month study, and several 

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individuals have now received RO7234292 for over 1 year on both regimens.  
Study BN40697 will be continued until its anticipated completion by December 2019.    
Preliminary data show that a 120 mg every-8-week (Q8W; every 2 months) dosing 
regimen of RO7234292 achieves 47% median CSF mHTT lowering at trough 
(i.e., sample taken immediately before the next dose) and the 120 mg Q4W dosing 
regimen achieves 66% median lowering at trough.  Both results exceed the 20%40% 
target for CSF mHTT lowering at trough and steady state based upon efficacy data from 
nonclinical models, and exceed the result of approximately 40% median lowering 
observed in the completed Phase I/IIa study. 
Further details on nonclinical and clinical studies can be found in the RO7234292
Investigator's Brochure.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Presently, there are no therapies available to stop or slow the clinical progression of HD, 
which is relentless until patients experience premature death.  The ASO RO7234292 is 
designed to target the cause of HD and offers the potential to meet this unmet medical 
need.  
To date, nonclinical and clinical data support further investigation of RO7234292 in 
patients with manifest HD.  Building on the completed Phase I/IIa study and the ongoing 
Phase II OLE study, this Phase III, double-blind, placebo-controlled study (BN40423) will 
collect longer-term clinical efficacy and safety data to definitively evaluate the benefit 
and potential risks of RO7234292 when administered by IT bolus injection Q8W or every 
16 weeks (Q16W; every 4 months) over a 25-month (2-year) period to patients with 
manifest HD.  
Review of safety and tolerability 9-month data for RO7234292 from the Phase II OLE 
suggests that, relative to the Q4W treatment regimen, the Q8W treatment regimen may 
be more suitable for chronic IT dosing, as evidenced by improved adherence to the less 
frequent regimen.  This is supported by observations of fewer overall adverse events, 
decreased proportion of patients with moderate adverse events, and fewer adverse events 
considered possibly related to study drug in the Q8W regimen compared to the Q4W 
regimen (for details see the RO7234292 Investigator’s Brochure).
There have been no acute safety concerns meriting a change to the ongoing Phase II 
OLE study protocol (BN40697).  However, given the 9-month CSF mHTT results, 
which suggest a longer than anticipated duration of effect of RO7234292 on CSF 
mHTT lowering, it is not necessary to use a Q4W paradigm to test the dose rationale.   
As a result, the results from OLE Study BN40697 justify a change in Study BN40423 
to explore less frequent dosing regimens by continuing the Q8W RO7234292 and 
placebo arms, and replacing the Q4W arm with a Q16W arm.

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The existing dose rationale tests a more frequent dosing regimen (i.e., 120 mg Q8W), 
which from present data is anticipated to maintain trough CSF mHTT reduction of at 
least ~40%, and a less frequent regimen (i.e., 120 mg Q16W), which is still anticipated 
to lower mHTT acutely, but will allow greater recovery of HTT levels between doses.  
From present data, trough CSF mHTT reduction of ~20% is maintained in a 120-mg 
Q16W paradigm.  
The known potential risks associated with RO7234292 and additional risks related to 
lumbar punctures are elaborated, along with mitigation measures, in Section 5.1. Taking 
into account the measures to minimize risk to patients participating in this study, the 
potential risks identified for IT administration of RO7234292 are justified by the 
anticipated benefits that may be afforded to patients with HD.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, pharmacokinetic (PK), and biomarker effects
of RO7234292 compared with placebo in patients with manifest HD.  Specific objectives 
and corresponding endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoint:

Change from baseline in the composite Unified Huntington's Disease Rating Scale
(cUHDRS) score at Week 101
Note:  The primary efficacy endpoint for the U.S. Food and Drug Administration 
(FDA) will be change from baseline in the TFC score at Week 101.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of RO7234292 
compared with placebo on the basis of the following endpoints:  

Change from baseline in scores for the following individual scales at Week 101:
-
TFC
-
Total Motor Score (TMS)
-
Symbol Digit Modalities Test (SDMT)
-
Stroop Word Reading (SWR) Test
Note:  For the U.S. FDA, the first secondary endpoint will be change from
baseline in the cUHDRS score at Week 101 instead of TFC, as TFC will be the
primary endpoint.

Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S)
score at Week 101

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
Proportion of patients with a decrease from baseline of 1 point on the TFC at 
Week 101

Proportion of patients with a decline from baseline of 1.2 points on the cUHDRS at 
Week 101

Proportion of patients with an unchanged or improved score on the Clinical Global 
Impression, Change Scale (CGI-C) score from baseline at Week 101
2.1.3
Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292
compared with placebo on the basis of the following endpoints:  

Change from baseline in the Apathy Evaluation Scale (AES) score at Week 101

Change from baseline in the Symptoms of Major Depressive Disorder Scale 
(SMDDS) score at Week 101

Change from baseline in the Huntington's Disease Daily Activities Scale (HD-DAS) 
score at Week 93

Change from baseline in the Patient Global Impression, Severity Scale (PGI-S) 
score at Week 101

Change from baseline in the Quality of Life in Neurological Disorders (Neuro-Qol) 
Cognition Function Short Form at Week 101

Change from baseline in the Huntington's Disease Speaking Difficulty Item Scale 
(HD-SDI) score at Week 101

Change from baseline in the Huntington's Disease Companion-Reported Irritability 
and Angry Outbursts Scale (HD-CIAOS) score at Week 101

Change from baseline in the in-clinic patient-reported EuroQol 5-Dimension 
Questionnaire (5-level version; EQ-5D-5L) index-score and visual analogue scale 
(VAS) at Week 101

Change from baseline in the sensor-based measures collected by the Roche HD 
mobile application (app; smartphone and wrist-worn wearable) at Week 101
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of RO7234292 
compared with placebo on the basis of the following endpoints: 

Incidence and severity of adverse events, with severity determined according to the 
Adverse Event Severity Grading Scale (see Table 4)

Change from baseline in Montreal Cognitive Assessment (MoCA)

Change from baseline in vital signs 

Change from baseline in ECG parameters

Change from baseline in clinical laboratory results

Proportion of patients with suicidal ideation or behavior, as assessed by 
Columbia-Suicide Severity Rating Scale (C-SSRS) score at each visit, including 

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detailed focus on any individual cases identified as having severe ideation or 
behavior during the study conduct
2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the RO7234292 PK profile in plasma 
and trough CSF on the basis of the following endpoints:

Concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints
The exploratory pharmacokinetic/pharmacodynamic (PK/PD) objective for this study is to 
evaluate potential relationships between drug exposure and the efficacy and safety of 
RO7234292 on the basis of the following endpoints:

Relationship between plasma profiles and/or trough CSF concentrations of
PK parameters for RO7234292 and efficacy endpoints

Relationship between plasma profiles and/or trough CSF concentrations of PK
parameters for RO7234292 and safety endpoints
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objective for this study is to evaluate the immune response to 
RO7234292 on the basis of the following endpoints:

Incidence of anti-drug antibodies (ADAs) at specified timepoints relative to the
prevalence of ADAs at baseline

Titer and antibody subtype, determined if ADAs are identified
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following endpoint:

Relationship between ADA status and efficacy, safety, or PK endpoints
2.5
BIOMARKER OBJECTIVES
2.5.1
Primary Biomarker Objective
The primary biomarker objective for this study is to evaluate the effects of RO7234292 
compared with placebo on the basis of the following endpoint:

Change from baseline in CSF mHTT protein level at Week 101
2.5.2
Secondary Biomarker Objective
The secondary biomarker objective for this study is to evaluate the effects of 
RO7234292 compared with placebo on the basis of the following endpoints:

Change from baseline in whole and regional brain volumes (caudate, whole brain,
and ventricular), as determined by structural magnetic resonance imaging (MRI), at
Week 101

Change from baseline in CSF neurofilament light chain (NfL) protein level at
Week 101

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2.5.3
Exploratory Biomarker Objective
The exploratory biomarker objective for this study is to identify biomarkers that are 
predictive of response to RO7234292 (i.e., predictive biomarkers), are early surrogates 
of efficacy, are associated with progression to a more severe disease state 
(i.e., prognostic biomarkers), are associated with acquired resistance to RO7234292, are 
associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of RO7234292 activity (i.e., PD biomarkers), or can increase the knowledge and 
understanding of disease biology and drug safety, on the basis of the following 
endpoints:

Relationship between biomarkers in blood, plasma, and CSF (listed in Section 4.5.6)
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers (e.g., putamen, cortical grey matter, 
cortical white matter volumes, resting state functional MRI signal) (see Section 4.5.7) 
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints
2.6
HEALTH STATUS UTILITY OBJECTIVE
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with RO7234292 on the basis of the following endpoint:

Change from baseline in patient- and companion-reported EQ-5D-5L Index and 
VAS scores at specified timepoints 

Change from baseline in companion self-reported and proxy-reported Health Utilities 
Index Mark 2 (HUI2) and Mark 3 (HUI3) scores at specified timepoints

Change from baseline in patient- and companion-reported Work Productivity and 
Activity Impairment (WPAI) scores at specified timepoints 
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
Study BN40423 is a Phase III, randomized, placebo-controlled, double-blind, multicenter
clinical study to evaluate the efficacy, safety, PK, and biomarker effects of intrathecally 
administered RO7234292 in patients with manifest HD. 
Prospective patients will undergo screening assessments during a 4-week screening 
period.  A maximum of one re-screening will be allowed within 8 weeks of the initial 
screening failure for patients who fail the initial screening (see Section 4.5.1). 
Upon completion of the screening period, eligible patients will be randomly allocated in a 
1:1:1 ratio to receive RO7234292 Q8W (RO7234292 Q8W arm), RO7234292 Q16W
(RO7234292 Q16W arm), or placebo Q8W (placebo arm) by IT injection, as described 

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in Table 1.  To maintain the study blind and integrity, patients in the RO7234292 Q16W
arm will also receive placebo (i.e., alternating doses of active drug and placebo).
Table 1
Treatment Regimens after Implementation of Protocol Version 4
Arm
Treatment Regimen
RO7234292 Q8W arm
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
RO7234292:  120 mg Q8W from Week 13 to Week 93 (11 doses)
RO7234292 Q16W arm
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
RO7234292:  120 mg Q16W from Week 21 to Week 85 (5 doses)
Placebo:  Q16W from Week 13 to Week 93 (6 doses)
Placebo arm
Placebo:  at Days 1 and 29 (2 doses) and Q8W from Week 13 to 
Week 93 (11 doses)
Q8W every 8 weeks; Q16W every 16 weeks.
During scheduled clinic visits, patients will undergo safety and tolerability evaluations
that include neurologic examinations, vital signs, ECGs, clinical laboratory tests, MoCA, 
C-SSRS, neuroimaging assessments (neurologic safety sequences), and a review of
any adverse events including related concomitant medications, as detailed in Appendix 1.
If there is the occurrence of a failed IT bolus dosing procedure due to inadequate 
establishment of access to the IT space, a second dosing attempt may occur up to 7 days 
after the originally scheduled dosing visit.  At this additional visit, safety and 
tolerability evaluations will be performed as described in Appendix 1.
A telephone safety follow-up call will be conducted for the months in which no clinic 
visits are scheduled to check for any change in patient status (i.e., adverse events, 
concomitant medications) since the patient’s last visit.  Where deemed appropriate, an 
unscheduled clinic visit should be arranged for safety follow-up; no dosing will occur at 
these unscheduled visits.  During the telephone follow-up call, patients will be 
reminded of their next follow-up visit.
Patients who complete the treatment period will return to the clinic for an 
end-of-treatment visit at Week 101.  Patients will then be given the option on an 
individual basis of receiving RO7234292 in an OLE study (BN40955) upon completion of 
Study BN40423, provided they meet eligibility criteria and the data from the ongoing 
RO7234292 program support continued development. Approval of the OLE study must 
also be granted by the relevant competent authority and Ethics Committee
(EC)/Investigational Review Board (IRB).  
All patients enrolled in Study BN40423 who choose to discontinue study treatment 
prematurely, but do not withdraw consent for continued participation in the study, will
return to the clinic for study visits at Weeks 53 and 69 (if not already completed) for 

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collection of at least the data for the primary and secondary endpoints (see 
Sections 2.1.1, 2.1.2, and 2.2).  If the early treatment termination visit falls within 30 
days of either scheduled visits at Week 53 or Week 69, then only the early treatment 
termination visit will be considered.  The early treatment termination visit should be 
performed 28 days (7 days) after the last dose.  Patients will also attend the scheduled 
end-of-treatment visit at Week 101.  
An independent Data Monitoring Committee (iDMC) and independent Data Coordinating 
Center (iDCC) will be employed to monitor and evaluate patient safety throughout the 
study as well as to evaluate evidence of early efficacy (see Section 3.1.2).  
The Sponsor may choose to conduct one or more interim analyses during the study 
(further details are given in Section 6.12).
Figure 1 and Figure 2 present the study schema and overview of the dosing schedule 
respectively, for patients enrolled in Study BN40423 after implementation of Protocol 
Version 4.  A schedule of activities is provided in Appendix 1.

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Figure 2
Dosing Schema for Patients Enrolled after Implementation of Protocol Version 4
EoT end of treatment; Q8W every 8 weeks; Q16W every 16 weeks.
Notes:  Red, solid arrows indicate study drug administration, while black, dotted arrows indicate placebo administration.  Patients in the 
RO7234292 Q8W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by active study drug Q8W. Patients 
in the RO7234292 Q16W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by alternating Q8W doses 
of placebo and active study drug.

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3.1.1.1
Study Design Overview for Patients Enrolled prior to 
Implementation of Protocol Version 4
All patients enrolled in Study BN40423 prior to implementation of the Version 4 
protocol amendment will be prematurely discontinued by the Sponsor from this study 
and will be offered treatment in the OLE Study BN40955, once approval has been 
granted by the relevant competent authority and ECs/IRBs.  Patients will continue to 
receive treatment in Study BN40423 until the OLE study has been approved at their 
study site.  Patients who discontinue treatment or study prior to Sponsor 
discontinuation will not be eligible for the OLE Study BN40955. 
Patients who choose to enroll in the OLE will complete an end-of-treatment visit in 
Study BN40423, which can also serve as the inclusion visit for Study BN40955.  All 
patients who are prematurely discontinued by the Sponsor who choose not to consent to 
Study BN40955 will additionally undergo a 5-month postdose safety follow-up visit. 
Table 2 presents the treatment regimen for all patients before implementation of the 
Version 4 protocol.
Table 2
Treatment Regimens prior to Implementation of Protocol 
Version 4
Arm
Treatment Regimen
RO7234292 Q4W arm
RO7234292:  120 mg Q4W from Week 1 to Week 97 (25 doses)
RO7234292 Q8W arm
RO7234292 loading dose:  120 mg at Days 1 and 29 (2 doses)
Placebo:  Q8W from Week 9 to Week 97 (12 doses)
RO7234292:  120 mg Q8W from Week 13 to Week 93 (11 doses)
Placebo arm
Placebo:  Q4W from Week 1 to Week 97 (25 doses)
Q4W every 4 weeks; Q8W every 8 weeks.
Figure 3 and Figure 4 present study schema and overviews of the dosing schedule, 
respectively.  A schedule of activities is provided in Appendix 9, with additional 
assessments described in Appendix 10, Appendix 11, Appendix 12, and Appendix 13.

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Figure 4
Dosing Schema for Patients Enrolled prior to Implementation of Protocol Version 4
EoT end of treatment; Q4W every 4 weeks; Q8W every 8 weeks.
Notes:  Red, solid arrows indicate study drug administration, while black, dotted arrows indicate placebo administration.  Patients in the 
RO7234292 Q8W arm will receive a loading dose of RO7234292 on Days 1 and 29 (loading period), followed by alternating doses of placebo and 
active study drug. 

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3.1.2
Independent Data Monitoring Committee 
The incidence and nature of adverse events, serious adverse events, adverse events of 
special interest, and abnormalities from neuroimaging assessments; vital signs; ECG
assessments; laboratory parameters; and any other relevant safety information will be 
reviewed on a regular basis by an iDMC in an unblinded fashion.  This information may 
also include MRI data and exploratory CSF biomarkers, for example NfL and Tau.
These reviews will occur approximately every 6 months or at the discretion of the iDMC. 
The iDMC will also undertake evaluation of any interim analysis. Specific operational 
details, such as the committee's composition, frequency and timing of meetings, and 
members' roles and responsibilities, will be detailed in an iDMC Charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs.  The 
end of the study is expected to occur approximately 117 weeks (29 months) after the last 
patient is enrolled.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4.5 years. 
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for RO7234292 Dose and Schedule
The magnitude and duration of mHTT protein lowering that is required for clinical 
efficacy is unknown.  Specifically, it is unknown whether acute mHTT protein lowering 
alone with full recovery of protein levels between dosing will be sufficient for clinical 
efficacy, or whether more sustained suppression of protein levels will be required for 
clinical efficacy.  Data from transgenic animal models suggest that brain tissue lowering 
of mHTT protein in the range of 30%60% is associated with beneficial effects on the 
disease phenotype, which corresponds to a trough CSF lowering range of 20%40%
based on a non-human primate PK/PD model.  
Because of this uncertainty, two active dosing regimens and a placebo arm will be used 
in this study:  RO7234292 Q8W (RO7234292 Q8W arm), RO7234292 Q16W
(RO7234292 Q16W arm), and placebo Q8W (placebo arm) by IT injection.  To maintain 
the study blind and integrity, patients in the RO7234292 Q16W arm will also receive 
placebo (i.e., alternating doses of active drug and placebo).
The 120-mg dose has been chosen for the Q8W dosing group based on the following:

In the chronic toxicology study in cynomolgus monkeys, the no-observed-adverse-
effect level was determined to be at least 35 mg/dose (the highest dose tested).  
Conservatively correcting for differences in CSF volume between cynomolgus 

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monkeys (15 mL) and humans (150 mL) with a scaling factor of 10, the human 
equivalent dose corresponds to 350 mg, representing a 3-fold safety margin to the 
proposed 120-mg clinical dose.  

Both the 90-mg and 120-mg RO7234292 Q4W groups in the Phase I/IIa study 
(ISIS 443139-CS1) resulted in a median CSF mHTT protein reduction of 
approximately 40%, with individual cases reaching approximately 60% reduction at 
trough, well above the described preclinical threshold for efficacy.  The 120-mg dose 
group exhibited a more consistent decline compared with the 90-mg dose group. 

In the same Phase I/IIa study, 120 mg of RO7234292 administered intrathecally 
Q4W for four doses was safe and well tolerated compared with placebo.  See 
additional details in the RO7234292 Investigator's Brochure. 

In approximately 70% of patients (23 of 34 patients) assigned to receive 
RO7234292 in the Phase I/IIa study, CSF mHTT protein was declining at the last 
trough measurement (either Day 113 or 141), suggesting sustained reduction of 
CSF mHTT protein up to 2 months postdose (last timepoint assessed). 

In the 120-mg RO7234292 group in the Phase I/IIa study, CSF mHTT protein levels 
were reduced by at least 35% in all five cases for which a Day 141 sample was 
collected (i.e., 8 weeks after the last dose), in line with the observed Q8W OLE 
data. 

Data from the ongoing Phase II OLE Study BN40697 (ISIS 443139-CS2) showed 
that 120-mg doses administered in Q4W and Q8W regimens achieved 66% and 47% 
median reductions of CSF mHTT from baseline at trough, respectively, after 9 
months.  Both results exceed the 20%40% target for CSF mHTT lowering at 
trough and steady state based upon efficacy data from nonclinical models, and 
exceed the result of approximately 40% median lowering observed in the completed 
Phase I/IIa study.  The observed effects on CSF mHTT lowering in the OLE after 
administration of three or four doses of 120 mg were also approximately 40%, 
consistent with results from the Phase I/IIa study (ISIS 443139-CS1).

Review of safety and tolerability data for RO7234292 from the Phase II OLE 
suggest that relative to the Q4W treatment regimen, the Q8W treatment regimen 
may be more suitable for chronic IT dosing.  This is supported by observations of 
fewer overall adverse events, decreased proportion of patients with moderate 
adverse events, and fewer adverse events considered possibly related to study drug 
in the Q8W regimen compared to the Q4W regimen (for details see the RO7234292 
Investigator’s Brochure).
The 120-mg dose has been chosen for the Q16W dosing group based on the following: 

The nonclinical PK/PD model predicted the observed Q8W 9-month reductions (for 
details see the RO7234292 Investigator’s Brochure).  From this same model, a 
Q16W regimen is predicted to result in median CSF HTT trough lowering of 20%, 
within the range of the 20%40% target for CSF mHTT lowering at trough and 
steady state. 

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
Acute lowering in this same model in the 120-mg Q16W regimen is 20% CSF 
mHTT reduction, above observed threshold for efficacy based upon nonclinical 
models. 

Maintenance of trough lowering is not a necessary feature of this less frequent arm 
to test the primary hypothesis.   The hypothesis of this 120-mg Q16W arm (acute 
lowering, followed by more full recovery of target protein) is supported by 
nonclinical evidence that transient ASO-mediated lowering of HTT protein is 
associated with sustained phenotypic benefit in the BACHD model (Kordasiewicz 
et al. 2012).  Efficacy in this model is sustained for 6 months even after a complete 
recovery of target mRNA and protein. 

Testing the less frequent regimen is of high interest to mitigate potential unknown 
long-term complications associated with a more frequent IT dosing of 120 mg Q8W.  
This approach could also mitigate the theoretical risks of suppression of wild-type 
HTT and will provide a more patient-friendly long-term dosing regimen.
To date, RO7234292 has only been administered intrathecally in clinical trials.  IT bolus 
administration has been shown to overcome the challenges faced by ASOs, as they are 
unable to cross the blood-brain barrier and achieve adequate brain and spinal cord 
concentrations when administered systemically (Schoch and Miller 2017).  Therefore, 
the IT drug delivery method will be used in this trial, as presently no alternatives exist.  
A 25-month (2-year) study treatment length has been chosen because the 
signal-to-noise characteristics of the primary endpoint cUHDRS (TFC for U.S. FDA)as 
investigated in prospective observational cohort studies and in placebo groups of prior 
clinical trialssuggest that this length is optimal for trial efficacy.  A treatment duration of 
25 months will also enable demonstration of sustained, durable benefit on slowing
clinical progression as presumed to be achievable with RO7234292 (which is proposed 
to be administered as a chronic treatment to slow clinical progression).  Studies with a 
shorter treatment duration, such as 18 months, would require a dramatically larger 
sample size (i.e., 50%) under the 30% slowing of clinical progression assumption. This 
would result in a potential risk of signal dilution due to inherent variability of a larger 
number of sites and clinical raters, resulting in a potential increased risk of type II error.  
In summary, a 120-mg Q8W dosing regimen and the less frequent dosing regimen of 
120 mg Q16W have been selected for this Phase III study to maximize CSF mHTT 
protein lowering acutely and to test the hypothesis of clinical efficacy, as a function of 
more versus less frequent dosing, while mitigating theoretical risks of long-term IT 
dosing of 120 mg and of non-allele specific lowering of HTT.  The 25-month duration is 
also considered appropriate for providing evidence of the benefitrisk profile of
RO7234292 and longer-term tolerability of IT administration.
3.3.2
Rationale for Patient Population
Patients with manifest HD (DCL score of 4 [i.e., motor abnormalities 99% likely to be 
due to HD]) who are ambulatory without assistance, verbal, and possess a CAGAge 

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Product (CAP) score of 400 (Zhang et al. 2011; see Section 4.1.1) and an 
Independence Scale (IS) score of 70 will be included in this study.  This patient 
population represents manifest disease where disability might be more plausibly 
reversed or slowed in response to a therapeutic intervention compared with patients with 
more advanced disease (Penney et al. 1990).  This definition also corresponds to the 
patients most commonly recruited at present for clinical trials aiming to slow clinical 
progression.  Such cohorts are known to have a longitudinal decline in clinical measures 
(Paulsen et al. 2014) over a timeframe appropriate for clinical trials.
3.3.3
Rationale for Control Group
Patients will be randomly allocated to receive active treatment (RO7234292 Q8W or 
Q16W) or placebo in this double-blind study because there are no disease-modifying 
standard-of-care treatments for patients with HD.  The placebo arm will be compared 
with the RO7234292 treatment arms to enable a robust assessment of the primary 
endpoint and the benefit-risk profile.  As each patient completes the study or is 
prematurely discontinued by the Sponsor as a consequence of the changes to the study 
through Protocol Version 4, they will be given the option of receiving RO7234292 in an 
OLE study (BN40955), provided they meet eligibility criteria and the data from the 
ongoing RO7234292 program support continued development.  Approval of 
Study BN40955 must also be granted by the relevant competent authority and EC/IRB.  
3.3.4
Rationale for Biomarker Assessments
3.3.4.1
Cerebrospinal Fluid Biomarkers 
Measurement of protein levels in the CSF offers the potential to monitor molecular 
changes that take place in the CNS.  A toxic gain-of-function mechanism of mHTT
protein is widely considered to be the primary driver of disease pathophysiology in HD 
(Wild and Tabrizi 2017).  mHTT protein in human CSF is associated with disease stage 
and severity and with biomarkers of neuronal damage, including CSF NfL and CSF tau 
levels (Wild et al. 2015).  NfL levels in CSF predict progressive MRI measures of brain 
atrophy, as well as progressive clinical decline in patients (Wild and Tabrizi 2017).  
Longitudinal analysis of mHTT, NfL, and other biomarkers related to HD, 
neurodegeneration, and inflammation in CSF may extend the current understanding of 
HD pathophysiology and progression and provide further data on how these putatively 
prognostic and potentially predictive biomarkers will respond to disease-modifying 
treatment.
3.3.4.2
Blood Biomarkers
NfL levels in blood correlate with NfL levels in CSF and could serve as prognostic blood 
biomarkers of disease onset and progression in HD (Wild and Tabrizi 2017;
Johnson et al. 2018).  Longitudinal analysis of NfL and other biomarkers related to HD, 
neurodegeneration, and inflammation in blood may facilitate understanding of HD 
pathophysiology and progression.

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3.3.4.3
Genetic Testing to Determine CAG Repeat Length
HD is caused by mutation in exon 1 of the HTT gene located on chromosome 4,
resulting in a polyglutamine (CAG) expansion in the huntingtin protein.  Above 35 CAG 
repeats, the age of HD onset is inversely correlated with the length of the expansion 
(Duyao et al. 1993).  CAG repeat length will be determined by direct DNA testing
performed centrally.  
3.3.4.4
Clinical Genotyping
Although CAG repeat length is inversely correlated to age of onset in HD, it only 
accounts for approximately 50% of the variance.  Identification of other genetic modifiers
of disease severity and disease progression in HD could provide important insights, as 
has been recently shown in the Genetic Modifiers of Huntington's Disease Consortium 
(2015), where relatively common single nucleotide polymorphisms in the HD population
were found to be associated with either an accelerated or delayed age of motor onset.  
A blood sample will be collected to detect individual single nucleotide polymorphisms to 
explore, for example, their influence on progression rates, age of onset, disease severity, 
or response to treatment.  
3.3.4.5
Magnetic Resonance Imaging
MRI is a non-invasive method to assess structure and function of the human brain and 
can provide insights into pathophysiological mechanisms of neurologic and 
neuropsychiatric disease. Several MRI techniques have shown sensitivity to detect 
abnormal structure and function within brains of individuals suffering from HD.  Structural 
MRI will be used to assess brain volume, diffusion-weighted MRI will be used to examine 
structural brain connectivity, and resting-state functional MRI will be employed to identify 
functional connectivity. All of the measures will be assessed at the whole-brain and
regional levels. The acquisition parameters of each sequence, structure, and length of 
each MRI session and image processing algorithms will be outlined in a separate MRI 
manual.
Structural Magnetic Resonance Imaging
Numerous structural MRI studies have demonstrated wide-spread brain atrophy,
including whole-brain, caudate, and ventricular changes in patients with premanifest and 
manifest HD (Douaud et al. 2006; Harrington et al. 2016).  Brain volume correlates with 
cognitive function (Peinemann et al. 2005).  Further, whole-brain, caudate, and 
ventricular volumes can predict and track progressive clinical decline in patients with HD 
and can also be associated with molecular biomarkers of neurodegeneration, 
such as NfL (Tabrizi et al. 2012). 
Diffusion Magnetic Resonance Imaging
Widespread changes in basal gangliacortical structural connectivity have also been 
observed in patients with HD (Novak et al. 2015), including associations between 
striatum-sensorimotor cortex connections and UHDRS motor scale and TMS

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(Bohanna et al. 2011), suggesting that the clinical phenotype in manifest HD may be a 
result of altered structural connectivity.
Resting-State Functional Magnetic Resonance Imaging
Resting-state functional MRI studies have generated evidence for functional connectivity 
alterations and their correlation to several clinical and cognitive measures in patients 
with HD (Werner et al. 2014; Dogan et al. 2015; Liu et al. 2016; Espinoza et al. 2018), 
implying that disrupted functional integrity of distinct brain networks may underlie clinical 
progression in HD.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 660 patients with HD will be enrolled in this global study from the 
implementation of Protocol Version 4 and onwards.  This is in addition to patients who 
enrolled prior to Version 4, who will be discontinued from this study and offered 
participation in OLE Study BN40955.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at baseline prior to randomization and study drug dosing):

Signed Informed Consent Form

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form and at 
the time of first dose administration

Manifest HD diagnosis, defined as a DCL score of 4 (see Appendix 7)

Independence Scale (IS) score 70 

Genetically confirmed disease by direct DNA testing with a CAP score 400 (Zhang 
et al. 2011), calculated as follows:
CAPAge(CAG repeat length 33.66)

Ability to read the words "red," "blue," and "green" in native language

Ability to walk unassisted without a cane or walker and move about without a 
wheelchair on a daily basis as determined at screening and baseline visit
-
Long-distance (e.g., 50 meters) use of wheelchairs for convenience or
transfer is permitted.

Body mass index 1632 kg/m2; total body weight 40 kg

Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no severe chorea 
or other condition that precludes MRI scans or renders scanning intolerable for the 
patient, no MRI-incompatible intrauterine devices, metallic dental braces, or other 
metal implants)

Ability to tolerate blood draws and lumbar punctures

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
Estimated glomerular filtration rate (eGFR) 60 mL/min (Cockcroft-Gault formula)

Ability and willingness, in the investigator's judgment, to comply with all aspects of 
the protocol including completion of interviews and questionnaires for the duration of 
the study 

Ability and willingness, in the investigator's judgment, to carry a smartphone, wear a 
digital monitoring device, and complete smartphone-based tasks

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to 
screening and at the time of enrollment

Signed study companion consent for participation, if a study companion is available,
who fulfills all of the following criteria:
-
Age 18 years
-
Reliable and competent, in the investigator's judgment
-
Sufficiently knowledgeable of the patient's condition to complete study 
companion assessments of the patient, and likely to remain sufficiently 
knowledgeable throughout the study, in the investigator's judgment
-
Able to comment on study participant's symptoms and functioning experience, 
as required per Appendix 1
Note:  Companions must have no cognitive, behavioral or motor change, in the 
opinion of the investigator, that would question the validity of the acquired 
observer-reported data.
All effort should be made to retain the study companion; however, should this 
not be possible, a study companion can be replaced and new consent obtained.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, as defined below:
Women must remain abstinent or use two methods of contraception, including 
at least one method with a failure rate of 1% per year, during the treatment 
period and for 5 months after the final dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices.  A vasectomized man must undergo a medical 
assessment that confirms the success of the surgery before he can be considered 
surgically sterile. 
Hormonal contraceptive methods must be supplemented by a barrier method.

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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
5 months after the final dose of study drug to avoid exposing the embryo.  Men 
must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal 
ideation) that required hospital visit and/or change in level of care within 12 months 
prior to screening
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
investigator.  If suicidal ideation is present, a risk assessment should be done 
by an appropriately qualified mental health professional to assess whether it is 
safe for the patient to participate in the study.  Mild passive suicidal ideation 
(i.e., occasional thoughts that life is not worth living or is hard) without history of 
attempts or hospitalization over the past 12 months is generally acceptable for 
study participation, but final decision on participation should be made carefully 
and in consultation with an appropriately qualified mental health professional. 

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, or vital sign 
abnormality or claustrophobia at screening that, in the investigator's judgment,
precludes the patient's safe participation in and completion of the study

History known to the investigator or presence of an abnormal ECG that is clinically 
significant in the investigator's opinion, including complete left bundle branch block, 
second- or third-degree atrioventricular heart block, or evidence of prior myocardial 
infarction

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
Clinical diagnosis of chronic migraines

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 5 months after the final dose of study drug
Women of childbearing potential must have a negative serum pregnancy test 
result at baseline and a confirmatory urine pregnancy test prior to initiation of 
study drug.  

Presence of an implanted shunt for the drainage of CSF or an implanted CNS 
catheter

Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg)
at screening

Known HIV infection

Current or previous use of an antisense oligonucleotide (including small interfering 
RNA)

Current or previous use of anti-psychotics prescribed for a primary independent 
psychotic disorder (i.e., schizophrenia, schizoaffective disorder, bipolar disorder 
type I, severe with psychotic features), cholinesterase inhibitors, memantine, 
amantadine, or riluzole within 12 weeks from initiation of study treatment

Current use of antipsychotics for motor symptoms or mood stabilization 
(i.e., irritability or aggressive behavior) and/or tetrabenazine, valbenazine, or 
deutetrabenazine at a dose that has not been stable for at least 12 weeks prior to 
screening or is anticipated to change between screening and treatment initiation

Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose that 
has not been stable for at least 6 weeks prior to screening or is anticipated to 
change during the study

Current use of an antidepressant or benzodiazepine at a dose that has not been 
stable for at least 12 weeks prior to screening or is anticipated to change between 
screening and treatment initiation

Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives 
prior to screening, whichever is longer

Antiplatelet or anticoagulant therapy within 14 days prior to screening or anticipated 
use during the study, including, but not limited to, aspirin (unless 81 mg/day), 
clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban

History of bleeding diathesis or coagulopathy

Platelet count less than the lower limit of normal  
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as 
the investigator confirms there is no evidence of current bleeding diathesis or 
coagulopathy.  

History of gene therapy, cell transplantation, or any experimental brain surgery

Concurrent or planned participation in any interventional clinical study, including 
explicit pharmacological and non-pharmacological interventions

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Observational studies (e.g., ENROLL-HD prospective study) are acceptable. 

Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse
or psychological or physiological dependency within 12 months prior to screening, 
as per the investigator's judgment
Abuse is defined as a maladaptive pattern of use that leads to failure to fulfill 
major work or social obligations or use in situations where it leads to physical 
danger or legal problems, and may be the focus of clinical attention.  

Poor peripheral venous access

Scoliosis or spinal deformity or surgery making IT injection not feasible in an 
outpatient setting and potentially interfering with distribution of RO7234292 up 
the neuraxis

An infection requiring oral or IV antibiotics within 14 days prior to screening

Antiretroviral medications, including antiretroviral medication taken as prophylaxis

Malignancy within 5 years prior to screening, except basal or squamous cell
carcinoma of the skin or carcinoma in situ of the cervix that has been successfully 
treated

Preexisting structural brain lesion (e.g., tumor, arterio-venous malformation) as 
assessed by a centrally read MRI scan during the screening period
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
All patients who were enrolled prior to implementation of Protocol Version 4 and have 
not already discontinued for another reason will be prematurely discontinued and 
offered treatment in OLE Study BN40955.  The treatment assignments of these patients 
will remain blinded until at least after the entire cohort has been discontinued from 
Study BN40423.  Patients will receive either the Q8W regimen or Q16W regimen in 
Study BN40955.  These patients will not be included in the primary analysis for Study 
BN40423.
Patients enrolled after implementation of Protocol Version 4 will be randomly allocated 
to receive 120 mg of RO7234292 Q8W, 120 mg of RO7234292 Q16W, or placebo Q8W.  
An independent interactive voice or web-based response system (IxRS) provider will 
conduct randomization and hold the treatment assignment code.
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during the clinical trial. These roles include the unblinding group, clinical 
supply chain managers, sample handling staff, operational assay group personnel, IxRS 
service provider, iDMC members, and iDCC members.
While PK and ADA samples must be collected from patients assigned to the placebo 
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 

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these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratories responsible for performing study drug PK and ADA assays will 
be unblinded to patient treatment assignment in order to identify appropriate samples for 
analysis.  PK samples from patients assigned to the placebo arm will not be analyzed for 
study drug PK concentration except by request (e.g., to evaluate a possible error in 
dosing).  Baseline ADA samples will be analyzed for all patients.  Post-baseline ADA 
samples from patients assigned to the placebo arm will not be analyzed for ADAs except 
by request.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment.  The investigator, patient, 
and Sponsor personnel will remain blinded to treatment assignment, with the exception 
of the Drug Safety representative and personnel who must have access to patient 
treatment assignments to fulfill their roles (as defined above).
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are RO7234292 and 
RO7234292 placebo. 
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
RO7234292
RO7234292 will be supplied by the Sponsor as sterile, preservative-free liquid in a 
20-mL single-use vial containing 10 mL of 6.0 mg/mL RO7234292 drug product for
IT injection. For a 120-mg dose (20-mL dosing volume), two vials containing 10 mL of
6.0 mg/mL RO7234292 will be pooled by drawing them up into the same injection
syringe containing 20 mL of study drug.

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For information on the formulation, preparation, and handling of RO7234292, refer to the 
pharmacy manual.
4.3.1.2
Placebo
RO7234292 placebo will be supplied by the Sponsor as a sterile, preservative-free liquid 
in a 20-mL single-use vial containing 10 mL RO7234292 placebo drug product for IT 
injection.  The liquid is no different in color than the active drug.
For a 20 mL dosing volume, two vials containing 10 mL of RO7234292 placebo will have 
to be pooled by drawing them up into the same injection syringe containing 20 mL of 
placebo drug product.
For information on the formulation, preparation, and handling of RO7234292 placebo, 
refer to the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of accidental overdose or medication error, along
with any associated adverse events, should be reported as described in Section 5.3.5.12
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.2.1
RO7234292 and Placebo
Each dose of RO7234292 (120 mg) and placebo will be administered as a single 
IT bolus injection of 20 mL by a qualified physician experienced in performing lumbar 
punctures.  In exceptional circumstances, study staff who are licensed physician 
assistants or nurse practitioners with extensive experience of performing lumbar 
punctures and administrating IMP for ASOs intrathecally may be acceptable with 
Sponsor approval.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO7234292 or placebo) will be provided 
by the Sponsor.  The study site will acknowledge receipt of IMPs supplied by the 
Sponsor, using the IxRS to confirm the shipment condition and content.  Any damaged 
shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 

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documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to RO7234292
The Sponsor will offer continued access to Roche IMP (RO7234292) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (RO7234292) after completing the study if 
all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (RO7234292) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for HD

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HD

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive RO7234292 as part of an OLE study (BN40955), as 
described in Section 3.1.

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4.4
CONCOMITANT THERAPY
Concomitant HD therapy should constitute the optimal supportive care for the individual 
according to the investigator's own best clinical judgment.  Concomitant therapy consists 
of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from screening to the end-of-treatment visit for patients 
who enter OLE Study BN40955 or the safety follow-up visit for patients who do not enroll 
in the OLE study.  All such medications should be reported to the investigator and 
recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Contraceptive agents

Supplements (e.g., coenzyme Q10, vitamins, creatine) if the dose has been stable 
for at least 6 weeks prior to screening and the dose is not anticipated to change 
during the study

Antipsychotics only if prescribed for motor symptoms or for mood stabilization (i.e., 
irritability or aggressiveness) and/or tetrabenazine/deutetrabenazine/valbenazine if 
the dose has been stable for at least 12 weeks prior to screening and the dose is 
not anticipated to change between screening and the start of study treatment 
If clinically indicated, dose changes or medication stopping or starting can occur 
as per investigator judgment during the course of the study.

Antidepressant or benzodiazepine if the dose has been stable for at least 12 weeks 
prior to screening and the dose is not anticipated to change between screening and 
the start of study treatment 
If clinically indicated, dose changes or medication stopping or starting can occur 
as per investigator judgment during the course of the study.

Anti-epileptics if given for mood stabilization, pain, restless legs, or insomnia

Aspirin at doses 81 mg/day

Local anesthesia for the lumbar puncture procedure, depending on institutional 
guidelines  
Sedation may not be used for lumbar puncture.
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited:

Experimental agents or marketed HD agents at experimental doses that are being 
tested for the treatment of HD, including, but not limited to, cholinesterase inhibitors, 
memantine, amantadine, and riluzole  

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
Antiplatelet or anticoagulant therapy, including, but not limited to, aspirin (unless
81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and
apixaban

Sedation for lumbar puncture or IT bolus procedures in the study
Depending on institutional guidelines, local anesthesia is permissible for the 
lumbar puncture procedure

Use of anti-anxiety medication is discouraged during scheduled MRI scans in the
study. Anti-anxiety medication used to prevent movement disorder to allow
successful MRI scan is not permitted in this study, as movement disorder too
severe to scan under drug-free conditions is an overall study exclusionary criterion.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for patients and study companions (if available) will be maintained at the 
study site, regardless of whether the patient is subsequently enrolled.  If a patient's 
capacity to consent is in question, the investigator should consult an appropriately 
qualified colleague who will independently assess capacity.  This additional assessment 
should also be documented.  If the patient’s capacity is confirmed, the investigator may 
proceed with signing of the Informed Consent Form.
All screening evaluations must be completed and reviewed to confirm that patients meet 
eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
A maximum of one re-screening will be allowed within 8 weeks of the initial screening 
failure for patients who fail the initial screening (e.g., as a consequence of abnormal 
laboratory values or general medical status not meeting inclusion or exclusion criteria).  
If re-screening is required, CAG repeat length testing does not need to be repeated 
(historical values will not be accepted) and the screening MRI and viral serology from the 
initial screening, including from other Roche studies, may be acceptable as part of the 
re-screening assessments if performed within 12 weeks of the baseline visit.

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4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, HD history (including 
past hospitalizations [i.e., number, duration, and reason]) over the last 2 years, 
reproductive status, smoking history, and use of alcohol and drugs of abuse will be 
recorded at baseline.  Alcohol and/or drug abuse is defined as a maladaptive pattern of 
use that leads to failure to fulfill major work or social obligations or use in situations 
where it leads to physical danger or legal problems, and may be the focus of clinical 
attention.  Daily use of any drug (i.e., cannabinoid, opioid, stimulant, hallucinogen, 
designer) or daily alcohol use that meets criteria for either abuse or psychological or 
physiological dependence is not permitted and is exclusionary.  Occasional use that 
does not meet the criteria for abuse is permissible in this study.  
In addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the patient from 
screening to the end-of-treatment visit for patients who enter OLE Study BN40955 or the 
safety follow-up visit for patients who do not enroll in the OLE study will be recorded.  At 
the time of each study drug administration and telephone safety follow-up calls, an
interval medical history should be obtained and any changes in medications and any 
physician visits for HD or general medical care should be recorded.
Demographic data will include age, sex, self-reported race/ethnicity, and education level 
based on the International Standard Classification of Education scale.  Demographic
data and social status data (e.g., relationship to patient and employment status) will also 
be collected for the study companion. Race/ethnicity is recorded because of the 
potential contribution of this variable to differences in observed pharmacokinetics, 
pharmacodynamics, toxicity, and/or response to treatment. 
A unique HD identification number (HDID) will be collected from patients who already 
have an HDID.  For patients without an HDID, the number will be created via a web 
portal (see Section 8.4).
4.5.3
Physical and Neurologic Examinations
A complete physical examination, performed at screening and other specified visits (see 
Appendix 1), should include an evaluation of the head, eyes, ears, nose, and throat, and 
the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems (including fundoscopy); genitourinary examinations may be 
performed if clinically indicated.  The physical examinations should be conducted in the 
same manner on each occasion to ensure comparability to previous examinations.  
Height will be measured at baseline only.
A neurologic examination, performed at screening and at every clinical visit, should 
include assessment of mental status, level of consciousness, cranial nerve function, 
motor function, sensory function, reflexes, gait, and coordination (see Appendix 8).  The

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neurologic examination should be conducted in the same manner on each occasion to 
ensure comparability to previous examinations.  Neurologic examinations should be 
performed before and after treatment on each dosing day.  Weight should also be 
measured at each visit.
Any abnormality identified at baseline (Week 1) should be recorded on the General 
Medical History and Baseline Conditions eCRF.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
(i.e., beyond expected variation or normal age-related change) should be recorded as 
adverse events on the Adverse Event eCRF.  
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse, temperature, and 
systolic and diastolic blood pressure while the patient is in a seated position after resting 
for approximately 5 minutes.  All data should be recorded on the appropriate eCRF.
4.5.5
Collection of Cerebrospinal Fluid (Lumbar Puncture Procedure)
Within 72 hours prior to performing each scheduled lumbar puncture, local laboratory 
analysis of coagulation factors (INR and/or PT, aPTT) and platelets must be conducted 
and the results reviewed.  The lumbar puncture should be performed at approximately 
the same time at each visit (ideally in the morning between 8:00 a.m. and 12:00 noon or 
in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal 
variation of CSF parameters.  CSF fluid (20 mL) is to be collected for analyses using a 
lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a 
minimum of 5 mL should be collected over a maximum of 60 minutes, once CSF flow has 
been established.  The operator must confirm CSF flow is present prior to injecting drug.  
A 24G atraumatic needle, as specified in the LP procedure and CSF collection 
guidelines manual, should be used to minimize risk of postlumbar puncture syndrome.  
Depending on institutional guidelines, local anesthesia should be used for the procedure.  
Sedation may not be used.  Spinal ultrasound may be used for the lumbar puncture 
procedure if deemed necessary, but ultrasound is not required.  Ultrasound guidance 
may be used if attempts at lumbar puncture without imaging are unsuccessful, if it is 
local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound 
with each lumbar puncture.  For details on the lumbar puncture and IT bolus dosing 
procedure, please refer to the LP procedure and CSF collection guidelines manual and 
instructional video.
Administration will occur via a lumbar puncture using a needle inserted into the 
L3/L4 space, although placement at a different level (either in the space above or the 
space below) is allowed if patient anatomy or clinical judgment dictates.  The left lateral 
position is mandatory in the first instance for the procedure, unless patient-specific 
factors require use of the upright, sitting position.  Whichever position is used, once 
access is established to the IT space, the entire IT bolus procedure should be completed 

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in the same position, to limit the risk of the needle losing position while the spinal 
needle is inserted.
Patients will be discouraged from resting supine after the lumbar puncture procedure 
and will be encouraged to mobilize immediately by walking around at a minimum and, 
if feasible, walking briskly for approximately 30 minutes.  Patients should not perform 
any activity that is associated with a change in the ambient air pressure for at least 
72 hours postdose (e.g., air travel, scuba diving, or hot air balloons).
Lumbar punctures will be performed as specified in the schedule of activities (see 
Appendix 1), with the last CSF sample obtained at the Week 101 end-of-treatment visit.  
No study drug will be administered at that visit.
4.5.6
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Coagulation:  INR and/or PT, aPTT, and platelet count

Urine pregnancy test
Urine pregnancy tests will be performed for women of childbearing potential at 
specified visits.  If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test (analyzed at a central laboratory).

CSF for safety:  cell count (including RBCs and WBCs), glucose, and protein

CSF sample for differential cell counts (absolute or percentage), where feasible
The following samples will be sent to a central laboratory:

Hematology:  WBC count, RBC count, platelet count, hemoglobin, hematocrit, and
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes)

Serum chemistry panel:  bicarbonate or total carbon dioxide (if considered standard
of care for the region), sodium, potassium, chloride, glucose, BUN or urea,
creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP,
ALT, AST, uric acid, gamma-glutamyl transferase, and CPK

Thyroid panel:  thyroid-stimulating hormone and free thyroxine (also known as T4)
levels

Viral serology:  HBsAg and HCV antibody

Serum pregnancy test
Serum pregnancy tests will be performed for women of childbearing potential at 
screening.  At subsequent visits, it will be performed to confirm a positive urine 
pregnancy test (if applicable).

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
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)
and microscopic examination for all abnormal dipstick results (sediment, RBCs,
WBCs, casts, crystals, epithelial cells, bacteria)

CSF and blood (plasma) samples for PK analyses and metabolite identification

Blood (plasma) samples for immunogenicity analyses

Blood sample for determination of CAG repeat length in HTT for patient eligibility

CSF samples for analysis of mHTT and NfL levels to evaluate the effects of
RO7234292 compared with placebo (primary and secondary biomarker endpoints)

Blood, plasma, and CSF samples for exploratory research on biomarkers and
biomarker assay development
Exploratory biomarker research may include, but will not be limited to, total HTT protein, 
tau, and other proteins related to HD, neurodegeneration, and inflammation.  Research 
may involve extraction of DNA and analysis of mutations, single nucleotide 
polymorphisms, and other genetic variations.  Research will not be aimed at
distinguishing germline mutations from somatic mutations.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Blood, plasma, and CSF samples collected for biomarker research and biomarker
assay development will be destroyed no later than 10 years after the final Clinical
Study Report has been completed.

Blood (plasma) and CSF samples collected for PK or immunogenicity analysis may
be needed for additional immunogenicity characterization and for PK or
immunogenicity assay development and validation; therefore, these samples will be
destroyed no later than 5 years after the final Clinical Study Report has been
completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 

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patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Magnetic Resonance Imaging
Structural MRI will be used to assess brain volume, diffusion-weighted MRI will be used 
to examine structural brain connectivity, and resting-state functional MRI will be 
employed to identify functional connectivity. All of the measures will be assessed at the 
whole-brain and regional levels.  All scans are mandatory unless a site does not have 
the capability to perform a resting-state functional MRI or diffusion-weighted 
MRI. For these cases, the Medical Monitor should be consulted; approval to continue 
without these scans would be required.
The MRI should be performed using a 3-Tesla (3T) magnet.  The acquisition parameters 
of each sequence, structure, and length of each MRI session, as well as image 
processing algorithms, will be outlined in a separate MRI manual.  MRI scans will be 
managed by a central laboratory to monitor and ensure the integrity and quality of the 
acquired data.  The screening MRI will be evaluated by the central laboratory to 
determine patient eligibility.  Local neuroradiologists will still be responsible for assessing 
MRI-related ongoing safety monitoring. During central review, the Sponsor and/or site 
staff will be notified of any unexpected findings requiring clinical follow-up.  
MRI should take place as early as possible within the screening window but may take 
place at any time during screening.  The MRI safety and efficacy screening scan will 
need to pass the central laboratory image QC and the results must be available before 
the patient can be enrolled in the study.  
After patient enrollment at specified timepoints, the MRI must be scheduled to occur 
before the lumbar puncture (see Appendix 1).  The MRI scan should be performed 
714 days prior to the lumbar puncture to allow time for re-scanning if the quality of 
the initial MRI is inadequate.
4.5.8
Electrocardiograms
Triplicate ECG recording will be obtained at specified timepoints, within approximately 
5 minutes of each other, as outlined in the schedule of activities (see Appendix 1), and 
may be obtained at unscheduled timepoints as clinically indicated.
The ECG recordings must be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recording 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other invasive procedures scheduled at 
that same time (e.g., blood draws) and should not be obtained within 30 minutes after 
any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 

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during the pre-ECG resting period and during ECG recording. All data should be 
recorded on the appropriate eCRF.
The ECG recordings may be electronically transferred to a central vendor.  The
investigator must review, sign, and date all ECG tracings.  Paper copies of ECG tracings 
will be kept as part of the patient's permanent study file at the site.  
4.5.9
Patient-Reported, Clinician-Reported, Study 
Observer-Reported, and Performance Outcomes
Patient-reported outcome (PRO), clinician-reported outcome (ClinRO), 
observer-reported outcome (ObsRO), and performance outcome (PerfO) data will be
collected in the clinic to document the change from baseline over time.  Additionally, 
PRO, ObsRO, and PerfO data will be collected remotely.  The instruments, translated 
into the local language as appropriate, will be completed in their entirety at specified 
timepoints during the study.  To ensure instrument validity and that data standards meet 
health authority requirements, instruments will be self-administered or administered by a 
trained rater (as appropriate).  In-clinic data should be collected prior to the performance 
of the lumbar puncture procedure.
Patients, clinicians, and study companions (if participating) will use an electronic device 
to capture outcome data during clinic visits, and scoring of ClinRO and PerfO measures 
will be supervised during acquisition and entry into a tablet to ensure instructions are 
given and appropriately followed.  Paper must not be used to capture clinical outcome 
data, unless it is for performance outcome measures (e.g., SDMT and MoCA). 
Performance measure outcomes must be completed in ink and not pencil.
Patients will use a smartphone and wrist-worn wearable to capture outcome data 
remotely and at specified visits (see Section 4.5.9.22).  Study companions will use an 
electronic device to capture data remotely and at specified visits.  The electronic devices
and/or instructions for completing the questionnaires electronically will be provided to 
patients and study companions by site staff.  Study companion device data will be 
transmitted to a centralized database maintained by the electronic device vendor.  The 
patient device data will be transmitted to a centralized database maintained by the 
Sponsor.  The data will be available for access by appropriate study personnel.  If the 
device is lost, a replacement will be sent.  All devices are encrypted and password 
protected.  See Appendix 1 for the schedule of activities, and Appendix 3 and 
Appendix 4 for a summary of timing and duration of each PRO, ClinRO, ObsRO, and 
PerfO assessment. Appendix 5 shows the order and approximate timing of 
assessments at each clinic visit. Appendix 9 through Appendix 13 show relevant 
information for patients who enrolled in Study BN40423 before implementation of 
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4.5.9.1
Composite Unified Huntington's Disease Rating Scale
The cUHDRS is a composite motor, cognitive, and global functional clinical outcome 
measure in patients with HD comprised of an equally weighted sum of Z scores of the 
TFC, the TMS, the SDMT, and the SWR scores from the UHDRS (Huntington Study 
Group 1996). It is a multidomain measure of clinical decline that tracks underlying 
progressive brain changes and is related to changes in daily functional ability 
(Schobel et al. 2017).  
4.5.9.2
Total Functional Capacity Scale 
The TFC is a validated measure of global patient function in HD.   The TFC represents 
the investigator's assessment of the patient's capacity to perform a range of activities of 
basic daily living, including working, chores, managing finances, eating, dressing, and 
bathing.  The 5-item assessment is based on a brief interview with the patient and the 
study companion (if available).  The TFC score ranges from 0 to 13, with a higher score 
representing better functioning.  A 1-point change in TFC score is a clinically meaningful 
change in patient function (e.g., a 1-point decline may indicate the loss of ability to work 
in a normal capacity) (Huntington Study Group 1996).  The TFC takes approximately 
10 minutes to administer and will be completed at clinic visits.  
4.5.9.3
Total Motor Score
The TMS is a holistic measure of motor function in HD that is linked to both functional 
capacity based on the TFC score, independence, and driving status 
(Beglinger et al. 2012; Schobel et al. 2017).  
The TMS score is the sum of the individual motor ratings obtained from administration of 
the 31-item motor assessment portion of the UHDRS by the investigator.  The score 
ranges from 0 to 124, with a higher score representing more severe impairment.  The 
TMS takes approximately 15 minutes to administer and will be completed at clinic visits.
4.5.9.4
Symbol Digit Modalities Test
The SDMT is used to assess attention, visuoperceptual processing, working memory, 
and psychomotor speed. It has been shown to have strong reliability and validity 
(Smith 1982).  The patient pairs abstract symbols with specific numbers according to a 
translation key.  The test measures the number of items correctly paired (maximum 
of 110 correct pairs) in 90 seconds.  The SDMT will be administered at clinic visits and 
can be completed in less than 5 minutes.  It will also be administered at specified 
timepoints indicated in Appendix 6 on the Roche HD mobile app (via electronic SDMT).
4.5.9.5
Stroop Word Reading Test 
The SWR Test is a measure of attention, processing, and psychomotor speed and 
depends upon quick verbal motor output.  Patients are presented with a page of color 
names (i.e., "BLUE," "RED," or "GREEN") printed in black ink and are asked to read 
aloud as many words as possible within a given amount of time (in 45 seconds).  The 
number of words read correctly is counted, with a higher score indicating better cognitive 

performance.  It will also be administered at specified timepoints indicated in 
Appendix 6 on the Roche HD mobile app (via electronic SWR).    
4.5.9.6 
UHDRS Functional Assessment
The UHDRS Functional Assessment is a checklist of 25 common daily tasks.  The 
investigator indicates if the patient can perform the task by giving a score of 1 to all "yes" 
replies.  The checklist is then summed, and scores can range from 0 (inability to do any 
task) to 25 (ability to do all tasks on the checklist).  The UHDRS FA can be completed in 
15 minutes.  
4.5.9.7 
Independence Scale
A patient's IS score is a measure of disease progression in functional disability and will 
be completed to evaluate a patient's degree of independence at screening and at 
specified timepoints.  It is a subscale of the UHDRS. The scale consists of 19 discrete 
levels ranging from 10 to 100 (by 5), in which a score of 100 indicates no special care is 
needed and a score of 10 indicates the patients is fed by tube and requires total bed 
care. 
4.5.9.8 
HD Daily Activities Scale
The HD-DAS assesses patients' daily function.  Following a semi-structured interview 
with the patient and/or study companion, the patient's ability level to perform daily tasks 
such as eating or using a telephone will be recorded.  Each item is scored on a 4-point 
Likert-type scale, where 0 indicates no impact and 3 indicates severe impact.
4.5.9.9 
Clinical Global ImpressionSeverity and Change Scales
The CGI-S is a single-item measure of current global severity and is completed by the 
clinician at specified clinic visits.  The CGI-S is assessed using an 11-point numeric 
rating scale (NRS), where higher scores indicate greater severity.  The CGI-S can be 
completed in approximately 2 minutes.
The CGI-C is a single-item measure of change in global status (since starting the study) 
and is completed by the clinician at specified postbaseline visits.  The CGI-C has seven 
response options:  "very much worse," "much worse," "minimally worse," "no change," 
"minimally improved," "much improved," and "very much improved."  The CGI-C can be 
completed in approximately 2 minutes.  To assess the relevance of this change, a 
follow-up question with dichotomous response options ("yes" or "no") asks if the change 
has had a meaningful impact on the patient’s well-being.
4.5.9.10 
Patient Global ImpressionSeverity and Change Scales
The PGI-S is a single-item measure of current global severity and is completed by the 
patient at specified clinic visits.  The PGI-S can be completed in approximately 2 minutes.  
The PGI-S is assessed using an 11-point NRS, where higher scores indicate greater 
severity.  
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The PGI-C is a single-item measure of change in global status (since starting the study) 
and is completed by the patient at specified post-baseline visits.  The PGI-C has seven 
response options:  "very much worse," "much worse," "minimally worse," "no change," 
"minimally improved," "much improved," and "very much improved." To assess the 
relevance of this change, a follow-up question with dichotomous response options ("yes" 
or "no") asks if the change has had a meaningful impact on the patient's well-being.  The 
PGI-C can be completed in approximately 2 minutes.
4.5.9.11
Companion-Reported Global ImpressionSeverity and Change 
Scales
The Companion-Reported Global ImpressionSeverity (CrGI-S) is a single-item measure 
of current global severity and is completed by the companion (about the patient) at 
specified clinic visits.  The CrGI-S can be completed in approximately 2 minutes.  The 
CrGI-S is assessed using an 11-point NRS, where higher scores indicate greater 
severity.  
The Companion-Reported Global ImpressionChange (CrGI-C) is a single-item measure 
of change in global status (since starting the study) and is completed by the companion 
(about the patient) at specified post-baseline visits.  The CrGI-C has seven response 
options:  "very much worse," "much worse," "minimally worse," "no change," "minimally 
improved," "much improved," and "very much improved." To assess the relevance of this 
change, a follow-up question with dichotomous response options ("yes" or "no") asks if 
the change has had a meaningful impact on the patient's well-being.  The CrGI-C can be 
completed in approximately 2 minutes.  
4.5.9.12
Montreal Cognitive Assessment
The MoCA is a patient-completed assessment used to detect cognitive impairment.  It 
contains a series of basic assessments, including attention and visuospatial tasks.  The 
total score ranges from 030, where lower scores indicate greater impairment.  It will be 
used in this study to characterize patients at screening and longitudinally to assess 
cognitive status at regular intervals throughout the study.  It takes approximately 
10 minutes to administer.
4.5.9.13
Work Productivity and Activity Impairment
The WPAI contains 6 items assessing the impact of disease on employment status 
(yes/no), hours missed due to disease, hours missed due to other reasons, hours 
worked, and impact on productivity and on daily activities (both using an 11-point NRS, 
where higher scores indicate greater impact).  The WPAI takes approximately 5 minutes 
to complete.  The WPAI will be completed by the patient (about him/herself) and by the 
study companion (if available, about him/herself).  It will be completed at specified 
timepoints remotely by the patient on the Roche HD mobile app and by the study 
companion (if available) on an electronic device.

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4.5.9.14
Apathy Evaluation Scale 
The AES is an 18-item assessment of apathy, including overt behavior, cognitive 
aspects of motivation, and emotional responsivity.  Each item is scored on a 4-point 
Likert scale, from 1 ("Not at all") to 4 ("A lot").  A total score is created by summing the 
18 items (scores range from 18 to 72; 3 items are reverse scored), with higher scores 
indicating greater apathy.  The AES takes approximately 10 minutes to complete and will 
be completed by the patient and study companion (if available) at specified clinic visits.
4.5.9.15
Neuro-Qol Cognition Function Short Form, Version 2
The Neuro-Qol Cognition Function Short Form contains 8 items (including "trouble 
concentrating" and difficulty "learning new tasks or instructions"), each assessed using a 
5-point Likert scale, where lower scores indicate greater difficulty (4 items) or greater
frequency (4 items).  The raw sum score is converted to a T-score distribution
(mean50, standard deviation10).  The Neuro-Qol Cognition Function Short Form
takes approximately 5 minutes to complete and will be completed by the patient at
specified clinic visits.
4.5.9.16
HD Speaking Difficulty Item
The HD-SDI includes a single question assessing difficulty speaking over the past 
7 days. It is assessed using a 5-point Likert scale, where higher scores indicate a 
greater frequency of difficulty.  The HD-SDI can be completed in less than 1 minute and 
will be completed at specified timepoints remotely by the patient on the Roche HD 
mobile app.
4.5.9.17
Symptoms of Major Depressive Disorder Scale 
The SMDDS is a newly developed, valid, and reliable self-report assessment of 
depression (McCarrier et al. 2016).  It contains 16 items, measuring concepts such as 
sadness, irritability, worry, and sleep disturbance.  Each item is assessed on a 5-point 
Likert scale, from "Not at all" to "Extremely" (9 items) and from "Never" to "Always" 
(7 items).  Item scores from 15 of the items (the least severe of the two eating items is 
not included) are summed to create a 060 score, where higher scores indicate more 
severe depressive symptomatology.  The SMDDS takes approximately 10 minutes to 
complete and will be completed by the patient at specified clinic visits.
The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.9.18
HD Companion-Reported Irritability and Angry Outbursts Scale 
The HD-CIAOS is a study companion-reported assessment of the patient's irritability and 
angry outbursts over the past 7 days and will be completed at specified timepoints 
remotely by the companion (if available) on an electronic device.  It consists of three 
items: frequency of irritable behavior (6-point Likert scale: "Not at all" to "Always"), 
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(4-point Likert scale "Mild" to "Very severe").  The HD-CIAOS takes about 2 minutes to 
complete.
4.5.9.19
EuroQol 5-Dimension, 5-Level Questionnaire
The EQ-5D-5L is a validated self-report health status questionnaire used to calculate a 
health status utility score for use in health economic analyses (EuroQol Group 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There are two components to 
the EQ-5D-5L:  a 5-item health state profile that assesses mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, as well as a VAS that measures 
health state.  Published weighting systems allow for creation of a single composite score 
of the patient's health status (Index score) from the 5-item scores (i.e., does not include 
the VAS).  The EQ-5D-5L takes approximately 5 minutes to complete.  The Index score 
will be used in this study for informing pharmacoeconomic evaluations. The VAS score 
will be used to assess health-related quality of life (HRQoL). The EQ-5D-5L will be 
completed both by the patient (about him/herself) and by the study companion
(if available, about him/herself) at baseline and at specified post-baseline clinic visits on 
an electronic device.  In addition, it will be completed remotely at specified timepoints by 
the patient on the Roche HD mobile app and by the study companion on an electronic 
device.
4.5.9.20
Health Utilities Index Mark 2 and Mark 3
The HUIis a multi-attribute system of health status (Feeny et al. 1995).  The HUI2 and 
HUI3 questionnaire (commonly referred to as HUI2/3) contains 15 items with Likert-type 
response options.  From these items, two scores can be produced:  HUI2 (7 items) and 
HUI3 (8 items).  Both scores are health utility indexes, where 0death, and 1perfect 
health.
The HUI2/3 will be completed by the companion, both about him/herself and as a proxy 
report of the patient’s HRQoL.  The HUI2/3 will be completed at specified timepoints at 
clinic visits and remotely on an electronic device.
4.5.9.21
Columbia-Suicide Severity Rating Scale
The C-SSRS is a structured tool to assess suicidal ideation and behavior.  
Four constructs are measured:  severity of ideation, intensity of ideation, behavior, and 
lethality of actual suicide attempts.  Binary (yes/no) data are collected for 10 categories, 
and composite endpoints based on the categories are followed over time to monitor 
patient safety (Posner et al. 2011).  It maps to the Columbia-Classification Algorithm for 
Suicide Assessment and meets the criteria listed in the U.S. FDA draft guidance for 
assessment of suicidality in clinical trials (FDA 2012).  The C-SSRS will be used to 
assess eligibility for the study (full version at baseline, requiring approximately 20 
minutes to administer) and to monitor the patients throughout the study at clinic visits 
(follow-up version, requiring approximately 5 minutes to administer, assuming absence 
of suicidal ideation and no change in clinical status from previous administration).

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The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.9.22
Optional Exit Interviews
Optional exit interviews will be conducted with a subset of patients (up to 60 patients) at 
select sites within approximately 1 week after the end-of-treatment visit.  The 
semi-structured interviews will be conducted by an external vendor and can be 
conducted by telephone.  The interviews will enable patients to provide details about 
changes they observe in their symptoms, as well as any impacts on daily life.
Interviews will be transcribed verbatim, and themes emerging from these transcripts will 
be interpreted in relation to changes in patients' clinical outcome assessment scores. All 
participants in this optional study interview will be asked which arm they thought they 
were assigned to (120 mg Q8W, 120 mg Q16W, or placebo).  Of note, patients, staff,
and the Sponsor will remain blind to patient treatment assignment during the study, as 
outlined in Section 4.2.
Additional consent for this optional portion of the study will be included in the relevant 
Informed Consent Form.
4.5.9.23
Roche HD Mobile Application:  Remote Testing (Smartphone 
and Wrist-Worn Wearable)
Smartphones and wrist-worn wearables have high-quality sensors that enable the 
remote, non-invasive, frequent, and precise measurement of motor and non-motor 
symptoms (Maetzler et al. 2013; Andrzejewski et al. 2016; Adams et al. 2017; Lipsmeier 
et al. 2018).  Each patient will receive a preconfigured smartphone and wrist-worn 
wearable with installed software for the Roche HD mobile app assessments.  The 
devices and software will monitor motor symptoms, non-motor symptoms, and activities 
associated with routine daily living throughout the course of the study.  Additional details 
are available in the Roche HD mobile app (Smartphone) manual.
Patients will be provided with devices and trained on their use during screening.  
Patients will also have in-clinic assessments of the digital platform that are supervised 
as indicated in Appendix 6.  Outside of the clinic, patients will be instructed to conduct
an "active test" every day at approximately the same time (ideally in the morning, after 
breakfast).  The active test consists of a short, preconfigured schedule of tasks that 
assess motor symptoms (upper and lower body movements, upper limb dexterity, voice) 
and non-motor symptoms (processing speed, voice).  Testing will usually last 
approximately 5 minutes in total on a typical day of testing.  Not all tests are daily.  
Additional information on the tasks and schedule is specified in Appendix 6.  
For "passive monitoring," patients will be instructed to carry the smartphone in a manner 
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wrist-worn wearable throughout the day as they go about their daily routines.  
Companions (where available) will receive their own independent electronic device at 
screening, which is different from the patient smartphone.  
Patients will be encouraged to adhere to the daily schedule of tasks as much as possible; 
however, patients will not be excluded from the study for poor adherence, nor will 
missing a daily test be considered a protocol deviation. 
Device sensor data will be recorded continuously, throughout the active tests and 
passive monitoring.  Sound will only be recorded during selected active test tasks.  Data 
will be encrypted and uploaded to secure servers when the smartphone is connected 
to Wi-Fi.  Patients will be asked to charge the devices overnight.  If patients have a Wi-Fi 
network at home, they will be encouraged to connect their smartphone to enable data 
transfer.  If no Wi-Fi network is available, the sensor data will be transferred during clinic 
visits or after the devices have been returned.
Roche HD mobile app "baseline" data will consist of all data collected prior to and 
including the baseline visit (up to 28 days).  Baseline data will be collected for at least 
the 7 days up to and including Day 1. 
4.5.9.24
Roche HD Mobile Application:  In-Clinic Assessments
Patients will be instructed to bring the smartphone and wearable to every clinic visit to 
check adherence and technical status of the devices.  At specified clinic visits, patients 
will be asked to conduct the "active test" tasks under the supervision of trained site staff, 
as shown in Appendix 6.  
The smartphone and wearable must be returned to the clinic in cases where the patient 
does not meet eligibility criteria, at the end of the study, or upon early termination from 
the study.  At the time of study completion or early termination, patients will be asked to 
complete a pen-and-paper satisfaction survey about their experience using the 
smartphone and wrist-worn wearable.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of 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.

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Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
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 Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10)
will not be applicable at that site.
4.5.10.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7234292, the HTT 
protein, HD or other diseases, or drug safety:

Blood and serum samples collected at baseline and at Weeks 37, 69, and 101

Leftover blood, plasma, and CSF samples and any derivatives thereof (e.g., proteins, 
peptides)
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researchers' understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.
Data generated from RBR samples 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 and characterization of important biomarkers and 
pathways to support future drug development.

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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.

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4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining 
samples will be destroyed or will no longer be linked to the patient.  However, if RBR 
samples have been tested prior to withdrawal of consent, results from those tests will
remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her RBR samples during the study, the investigator must inform the 
Medical Monitor in writing of the patient's wishes through use of the appropriate RBR 
Subject Withdrawal Form and must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  
If a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.10.7
Monitoring and Oversight
RBR samples 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.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
Due to the Sponsor’s decision to discontinue the 120-mg Q4W dosing regimen and 
replace this with a 120-mg Q16W dosing regimen in Protocol Version 4, all patients 
who enrolled prior to implementation of Protocol Version 4 will be prematurely 
discontinued from the study by the Sponsor and will complete their end-of-treatment 
visit prior to entry into Study BN40955. 
An excessive rate of withdrawals (either study treatment discontinuation or withdrawal 
from the study) can render the study results non-interpretable.  Therefore, all efforts 
should be taken to motivate patients to comply with all study-specific procedures and to 
be followed until the end of the 101-week, placebo-controlled treatment period. 

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Investigators should explore all possible options to contact patients for visits, especially 
end-of-treatment visits.  The site must document all attempts to try to contact the patient 
in the patient's medical records and source documents.
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Loss of capacity to consent, if legal guardian consent is not possible
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be
replaced.
All patients who discontinue study treatment prematurely but do not withdraw consent for 
continued participation in the study will return to the clinic for study visits at Weeks 53 
and 69 (if not already completed) for collection of at least the data for the primary and 
secondary endpoints (see Sections 2.1.1, 2.1.2, and 2.2).  If the early treatment
termination visit falls within 30 days of either scheduled visits at Week 53 or Week 69, 
then only early treatment termination will be considered.  Patients will also attend the 
scheduled end-of-treatment visit at Week 101 window.  
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be
replaced.

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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
RO7234292 is not approved and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with RO7234292 in completed and 
ongoing studies.  The known safety risks for the lumbar puncture procedure and 
RO7234292 are outlined below in Sections 5.1.1 and 5.1.2, respectively.  Please refer to 
the RO7234292 Investigator's Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study, 
including the eligibility criteria.  Patients will undergo safety monitoring during the study, 
including assessment of the incidence and severity of adverse events.  Guidelines for 
managing adverse events, including criteria for treatment interruption or discontinuation, 
are provided below.
5.1.1
Known Risks Associated with Lumbar Puncture
Postlumbar puncture syndrome, spinal hematoma, and meningitis (see 
Sections 5.1.1.1 through 5.1.1.3) are potential risks associated with lumbar puncture. 
In the completed Phase I/IIa study, the most commonly reported adverse events across 
all treatment groups (RO7234292, n34; placebo, n12) were procedural pain (54% of 
patients) and postlumbar puncture syndrome (37% of patients).

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In the ongoing Phase II OLE Study BN40967 (9-month data), potential postlumbar 
puncture adverse events (including procedural pain, postlumbar puncture syndrome, 
post-procedural discomfort, headache, and migraine) occurring within 72 hours of drug 
administration were summarized per cohort.  For the Q4W cohort (n23), 28 events 
were reported in 13 (56%) of patients; for the Q8W cohort (n23), 27 events were 
reported in 12 (52.2%) patients. 
Many of the complications associated with lumbar puncture can be avoided by the 
mandatory use of a 24G atraumatic needle with a stylet, adherence to procedural 
guidelines (see lumbar puncture manual and instructional video), and careful 
assessment of the patient, including neurologic examination with fundoscopy both prior
to and postlumbar puncture procedure.  Lumbar puncture should be avoided when a 
contraindication is present.
CSF leakage is more likely with larger bore needles.  To minimize this risk, a 
24G atraumatic needle will be used.  Training for use of the 24G atraumatic needle in 
this study will be provided prior to initiation of lumbar puncture, as will a review of 
extension tubing use and the need to gently aspirate CSF for timely collection.  If 
headache with characteristics of low-pressure syndrome is present after the procedure
and persists despite standard-of-care treatment, a blood patch should be considered.  
Formation of a subarachnoid epidermal cyst (i.e., when a skin plug is introduced into the 
arachnoid space) can be avoided by use of a needle with stylet, which is mandatory.  
Rarely, brain herniation can occur in the setting of lumbar puncture and increased 
intracranial pressure.  
There are specific contraindications to performing lumbar puncture.  These include 
unstable cardiorespiratory status, where positioning patient for lumbar puncture may not 
be tolerated, signs of cerebral herniation or incipient cerebral herniation, signs of 
increased intracranial pressure, or focal neurological findings on examination.  In those 
patients, lumbar puncture (and IT treatment administration) should not be performed and 
appropriate diagnostic work-up should be initiated.  On a case-by-case basis and 
following discussion with the Medical Monitor, such patients may be able to resume 
treatment.  Previous lumbar surgery is an exclusion criterion for this study.   
In the setting of HD, for the purposes of lumbar puncture and IT bolus injection of
RO7234292, moderate to severe truncal chorea may also be prohibitive.  
5.1.1.1
PostLumbar Puncture Syndrome
RO7234292 will be delivered directly to the CNS by IT lumbar puncture injection.  
Postlumbar puncture syndrome (e.g., headaches, nausea, vomiting, infection, 
hemorrhage, nerve irritation pain) can occur with IT administration.  Experience to date 
with postlumbar puncture syndrome, as reported in the completed Phase I/IIa study, 
includes headache, which occurred after 10% of procedures and was transient and mild 
in the vast majority of patients.  In the ongoing Phase II OLE Study BN40967 (9-month 

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data), 4 events of post lumbar puncture syndrome were reported in the Q4W cohort 
(17.4%) and 3 in the Q8W cohort (13.0%).  All these events were rated as mild and 
resolved without treatment with the exception of 1 event in the Q4W cohort that 
required treatment (mild and resolved). 
Patients should walk postlumbar procedure, to assist drug distribution (see 
Section 4.3.2.1); however, if a patient develops a headache after the lumbar puncture 
with characteristic features, which makes walking intolerable, the patient should be 
encouraged to first sit down and if the headache persists then lie in a comfortable 
position, which is most likely in the supine position owing to the postural nature of the 
symptoms.  Supportive treatment may include rehydration, consumption of caffeinated 
drinks, simple analgesics, opioids, and antiemetics.  If these conservative measures fail, 
more specific measures may be indicated.
5.1.1.2
Spinal Hematoma
Postlumbar puncture spinal hematoma is a very rare but important potential risk that 
can present as persistent back pain, radicular pain, new sensory or motor symptoms, 
sphincter disturbance, or meningism.  Prompt MRI scanning should be performed if 
suspicion of spinal hematoma arises.  Patients with susceptibility to bleeding, patients 
with coagulopathy, and patients receiving anticoagulant therapy are at an increased risk 
of spinal hematoma and will be excluded from the study (see Section 4.1.2).  
Management of spinal hematomas should include consultation with neurosurgical 
colleagues.
5.1.1.3
Meningitis
Meningitis is a rare potential risk of lumbar puncture.  Patients may present with 
headache, meningism, photophobia, neck stiffness, and pyrexia.  Guidelines for 
management of patients with suspected meningitis are provided in Table 3. 
5.1.2
Potential Risks Associated with RO7234292
The potential risks identified below have been considered in relation to clinical data 
available as of 30 January 2019, including the completed Phase I/IIa study and ongoing 
Phase II OLE study (9-month datacut).  
5.1.2.1
Neurologic Changes
In cynomolgus monkeys, acute, transient deficits in lower spinal reflexes (patellar 
reflex in particular) were typically observed 2 to 8 hours following dosing, in the 13-
week and the chronic toxicity studies.  The transient changes in patellar reflex were 
observed in all treatment groups, including controls, with a slightly higher incidence in 
the high-dose groups.  These findings were fully reversible within 24 hours following 
dosing.  No other treatment-related changes in general sensory and motor function 
parameters nor changes in the cerebral reflexes were observed.

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In the Phase I/IIa MAD study (ISIS 443139-CS1), no adverse trends in neurological 
examinations were detected and only a few drug-related neurological adverse events 
were observed in 2 patients.  See the RO7234292 Investigator’s Brochure for more 
information.
Following LP administration and post-LP mobilization, neurologic examinations should 
be conducted.  In addition, patients should be observed in clinic for any complications 
or complaints post-LP and intrathecal bolus injection of RO7234292.
5.1.2.2
Elevations in CSF WBCs and Protein
Mild elevations in CSF WBCs have been observed during the Phase I/IIa, 
dose-escalation study (Study ISIS 443139-CS1) and its respective OLE study 
(Study ISIS 443139-CS2 [Study BN40697]) at various timepoints that are sometimes 
associated with changes in CSF protein without signs of inflammation.  The majority of 
patients have counts under 10 WBCs, with several patients with higher elevations
observed to date in the OLE study.  Patients with CSF WBC elevations have generally 
been asymptomatic.  One case with elevations in CSF WBCs and CSF protein 
presented with ankle hyporeflexia after the seventh dose of 120 mg monthly with 
enhancement of the cauda equina noted on MRI of the spine, with no other clinical 
sequelae noted.  
The CSF WBC elevations were also observed in the chronic non-human primate study 
with slight increases over time.  Increases were mild, and there was no apparent dose 
dependency.
5.1.2.3
Thrombocytopenia
Reductions in platelet count have been observed after systemic administration of some 
2'-MOE chimeric ASOs to clinical trial subjects.  However, no clinically significant 
reductions in platelet counts have been observed in clinical studies for RO7234292 to 
date.  In one 13-week and one 9-month IT toxicity studies of RO7234292 in the 
cynomolgus monkey, there were no effects on hematology or coagulation parameters.
No clinically significant reduction in platelet counts was observed in the completed 
RO7234292 Phase I/IIa study. In the ongoing phase II OLE study (BN40697), no 
events of thrombocytopenia have been reported to date (9-month data).
Platelet counts will be monitored at each study visit prior to lumbar puncture.  See 
Table 3 for patient stopping and treatment discontinuation rules.
5.1.2.4
Kidney Effects
Reductions in renal function have been observed after administration of some 2'-MOE 
containing chimeric ASOs to clinical trial subjects.  In the 13-week and 9-month toxicity 
studies of RO7234292 in cynomolgus monkeys, there were no test articlerelated 
histologic findings in the visceral organs or effects on clinical chemistries.

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No clinically significant reduction in kidney function was observed in the completed 
RO7234292 Phase l/IIa study. In the ongoing Phase II OLE study (BN40697), one case 
of moderate proteinuria considered related to the study drug has been reported in the 
Q4W cohort (resolved without any intervention); no other clinically significant kidney 
abnormality has been observed.
Kidney function will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased renal function are provided in Table 3.
5.1.2.5
Liver Effects
Elevations in liver enzymes have been observed after administration of some 2'-MOE 
chimeric ASOs to clinical trial subjects. However, no clinically significant elevation in liver 
enzymes was observed in the clinical studies for RO7234292 to date.
In the 13-week and 9-month toxicity studies of RO7234292 in cynomolgus monkeys, 
there were no drugrelated histologic findings in the visceral organs, including the liver, 
or effects on clinical chemistry test levels. No clinically significant elevations in liver 
enzymes were observed in the completed RO7234292 Phase I/IIa study. In the ongoing 
Phase II OLE study (BN40697), liver enzyme adverse events were reported in 
2 patients in the Q4W cohort (one moderate event of gamma-glutamyltransferase 
increase, ongoing, and one mild hepatic enzyme increase which resolved without any 
intervention and were considered not related to RO7234292 by the investigator).  No 
other clinically significant hepatic abnormality has been observed.
Liver enzymes will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased liver function are provided in Table 3.
5.1.2.6
Hydrocephalus
Hydrocephalus is included as a warning in the labelling of one marketed 
IT-administered 2'-MOE chimeric ASO.  No hydrocephalus was observed in the 
completed RO7234292 Phase I/IIa MAD study (ISIS 443139-CS2) and the ongoing 
Phase II OLE study (BN40697) to date.
5.1.2.7
Neuropsychiatric Changes
RO7234292 is directly administered to the CNS, with limited clinical experience.
Nonclinical studies in animals did not show any adverse effects on the CNS.  Though a 
single case of completed suicide has occurred in the ongoing Phase II OLE study 
(BN40697), when weighing all available details of the case, the investigator has 
concluded that this event was not related to RO7234292.  Patients should be closely 
monitored for signs and symptoms of neuropsychiatric changes in addition to routine 
monitoring with the Columbia-Suicide Severity Rating Scale (C-SSRS) and the 
Montreal Cognitive Assessment battery.

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5.1.2.8
Potential Risk due to Reduction of Target Protein HTT
By specifically targeting mRNA from both HTT alleles, RO7234292 lowers levels of both 
mHTT protein and normal wild-type huntingtin (wtHTT) protein in all patients, regardless 
of genetic variations.  The ASO modality provides partial, transient, reversible, and 
titratable HTT lowering.  Partial HTT lowering is safe and well tolerated in normal rodents 
and non-human primates, as shown in multiple studies using ASOs and non-reversible 
approaches. Furthermore, no safety signals of concern emerged during the recent 
Phase I/IIa study of RO7234292 in adults with HD (see RO7234292 Investigator's 
Brochure), in which partial lowering was achieved.
Transgenic mice expressing human mHTT develop progressive HD-like phenotypes that 
recapitulate many aspects of HD in humans.  ASO-mediated mHTT lowering provides 
therapeutic benefits and often restores normal functioning in transgenic and fully 
humanized animal models of HD, with generally similar results regardless of whether 
wtHTT is also lowered. Moreover, no detrimental effects of partial wtHTT lowering in 
animal models have been reported in multiple studies using ASOs and non-reversible 
approaches.
Still, the current understanding of the diverse cellular functions of HTT suggests potential 
theoretical risks associated with reducing total HTT levels in people with HD. More than 
two decades of research findings implicate HTT in a wide array of cellular functions, 
including microtubule-based transport, F-actin-based trafficking, Rab-based trafficking, 
brain-derived neurotrophic factor transport, ciliogenesis, transcription, chromatin 
modification, post-transcriptional gene-expression regulation, neurogenesis, 
synaptogenesis, synaptic plasticity, signaling pathways, cell stress responses, cell 
survival, selective macro-autophagy and DNA damage repair, as detailed in a recent 
review article (Liu and Zeitlin 2017).
Although functional HTT (mutant or wild-type) is essential for embryogenesis, 
near-complete genetic ablation of HTT has little or no reported neurological effect in 
normal adult animals. However, complete ablation of wtHTT protein expression 
throughout life results in a worsening motor phenotype and, in male transgenic mice, 
age-dependent emergence of brain atrophy and decreased testicular size (Van 
Raamsdonk et al. 2005).  In contrast, decreases in mHTT protein expression ameliorate 
disease, and increases in mHTT protein exacerbate disease in animal models of HD, 
regardless of concomitant changes in wtHTT protein levels.
No clinically significant new neurologic events were observed in the completed 
Phase l/IIa study.  As a precaution, a full neurologic examination will be conducted at 
each study visit (on dosing days before and after dosing), and additional monitoring of 
cognition will be conducted throughout the study using the MoCA.

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5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Dose Modifications
No dose modifications are permitted in this study, whether by varying the amount of 
study drug volume injected or the frequency of procedure per protocol (i.e., all 
participants will receive 20 mL of study drug per injection on a Q8W basis).
5.1.3.2
Treatment Interruption
Study drug may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  If study drug has been withheld for 60 days
because of signs of persistent drug-induced toxicity or if the scheduled dose has been 
missed, the investigator should consult the Medical Monitor to determine if 
discontinuation from study drug is warranted.  Study drug may be suspended for 
reasons other than toxicity (e.g., surgical procedures) with Medical Monitor approval.  
The investigator and the Medical Monitor will determine the acceptable length of 
treatment interruption.
5.1.3.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 3.  
Additional guidelines are provided in the subsections below.
Initial clinical laboratory tests with results meeting criteria for withholding study drug must 
be repeated on new specimens as soon as possible, and results must be available prior 
to administering the next dose of study drug. In general, patients who do not reach the 
stopping rule may continue dosing; however, the investigator and Sponsor should confer 
as to whether additional close monitoring of the patient is indicated.

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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events
Event
Action to Be Taken
Elevations in CSF WBC 
count or proteins or 
suspected meningitis, 
radiculitis, arachnoiditis, or 
other acute neurologic 
symptoms

Withhold study drug if diagnosis of meningitis, radiculitis,
arachnoiditis, or acute neurologic symptoms is suspected and 
initiate appropriate diagnostic work-up as indicated. 

Clinical signs and symptoms (e.g., headache, stiff neck, fever) 
plus confirmatory WBC count are required for diagnosis of 
suspected meningitis, and clinical signs and symptoms are 
required for diagnosis of radiculitis, arachnoiditis, or acute 
neurologic symptoms.  Isolated low-level (e.g., 550 WBC 
count) elevations in CSF WBC count without clinical symptoms 
does not meet criteria for diagnosis of suspected meningitis.  

The Medical Monitor should be consulted in all cases where 
WBC count CSF elevations above 10 are present, or a change 
from baseline in CSF proteins greater than twice baseline or 
where there is uncertainty to discuss next steps of patient 
management in the study.

If diagnosis of suspected meningitis, radiculitis, arachnoiditis, or 
other acute neurologic symptoms is refuted, the study drug may 
be resumed after consultation with the Medical Monitor.

In the event meningitis, radiculitis, arachnoiditis, or acute
neurologic symptom diagnosis is confirmed, standard-of-care 
therapies should be instituted as indicated.
Thrombocytopenia

If platelet count is 100,000/mm3:
o
Monitor platelet count weekly

If platelet count is 75,000/mm3 and 50,000/mm3 in the 
absence of major bleeding or clinically relevant non-major 
bleeding:
o
Withhold study drug until the platelet count has recovered 
to 100,000/mm3.  
o
The suitability of the patient for continued dosing and 
frequency of monitoring should be discussed with the 
Medical Monitor. 

If platelet count is 50,000/mm3:
o
Permanently discontinue study drug. 
o
Monitor platelet counts daily until two successive values 
show improvement.  Then monitor every 23 days until 
platelet count is stable, and at least weekly until platelet 
count returns to normal.
o
Treatment per standard of care should be considered for 
patients whose platelet count is 25,000/mm3.

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Table 3
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Decreased renal function

Withhold study drug in the event of a persistent (2 weeks) 
decrease in eGFR or CrCl or increase in creatinine, as defined
below:
o
eGFR (using Cockcroft-Gault) or CrCl 60 mL/min
o
Creatinine level increase of 2.0 above baseline

Study drug may be resumed when follow-up test results show
that the patient no longer meets the dose interruption criteria.
Elevated liver enzymes

ALT or AST is 3ULN:
o
Monitor weekly until ALT and AST return to 1.2ULN.
o
Further investigation into the liver enzyme elevations may
include hepatitis serologies and other diagnostic tests at
the discretion of the investigator in consultation with the
Medical Monitor.

Withhold study drug in the event of liver enzymes that meet the
following criteria without an alternative explanation (as
discussed with the Medical Monitor):
o
ALT or AST 5ULN
o
ALT or AST 3ULN, combined with total
bilirubin 2ULN or INR 1.5
o
ALT or AST 3ULN coinciding with new appearance of
fatigue, nausea, vomiting, right upper quadrant pain or
tenderness, fever, rash, and/or concomitant eosinophilia.
o
Discontinue study drug permanently if levels do not return
to baseline after 30 days.
CrClcreatinine clearance; CSF cerebrospinal fluid; eGFRestimated glomerular filtration rate; 
ULNupper limit of normal.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.

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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding),
symptom, or disease temporally associated with the use of a medicinal product,
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and
5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is
associated with symptoms or leads to a change in study treatment or concomitant
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those
that occur prior to assignment of study treatment (e.g., screening invasive
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event
results in substantial disruption of the patient's ability to conduct normal life
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the
patient or may require medical/surgical intervention to prevent one of the outcomes
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see

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Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 

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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 5 months after the 
final dose of study drug or until the patient receives his or her first dose in the OLE study 
(BN40955), at which time reporting will occur per the new study requirements.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale indicated in Table 4 will be used for assessing 
adverse event severity.  Laboratory values determined as an adverse event should be 
graded as per Appendix 5, which is based on the NCI CTCAE (v5.0).
Table 4
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 Section 5.2.2).

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5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 

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rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of IT bolus-related reaction or anaphylactic reaction.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult,
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 

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Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).

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5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2 ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). This 
includes death attributed to progression of HD.

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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed solely to progression of HD, "Huntington's disease progression" 
should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Huntington's Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  

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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

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
RO7234292 or placebo, adverse events associated with special situations should be 
recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

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In addition, all special situations associated with RO7234292 or placebo, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF 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 two
entries on the Adverse Event eCRF, one entry to report the accidental overdose and 
one entry to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.3.5.13
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived by the Sponsor from PRO, ObsRO, or digital 
wearable device (HD mobile app) data, and safety analyses will not be performed using 
PRO or ObsRO or digital wearable device data.  Sites are not expected to review the 
PRO or ObsRO or digital wearable device data for adverse events.
5.3.5.14
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.

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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor:
, M.D., Ph.D.
Telephone No.:
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 

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5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 5 months after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 5 months after the final 
dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 

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Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
5 months after the final dose of study drug after the final dose of study drug.  A paper 
Clinical Trial Pregnancy Reporting Form should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  An 
investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 

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Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
greater than 5 months after the final dose of study drug), if the event is believed to be 
related to prior study drug treatment.  These events should be reported through use of 
the Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.

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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

RO7234292 Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
All patients enrolled prior to Version 4 of the protocol will not be included for any 
efficacy analysis.  The safety data collected for these patients up to and including the 
end of treatment visit in Protocol BN40423 will be analyzed separately.  
The primary efficacy analysis will be conducted at the end of the study (see Section 3.2).  
Treatment assignments will be unblinded to the Sponsor at the end of the study after the 
data have been cleaned and verified and the database has been locked.
Details of the planned statistical analyses mentioned below will be fully specified in a 
separate Statistical Analysis Plan (SAP), which will be finalized prior to the locking and 
unblinding of the study database.
Unless otherwise specified, all the p-values considered in Section 6 are two-sided.
6.1
ANALYSIS POPULATIONS
The intent-to-treat (ITT) population will consist of all patients enrolled after 
implementation of Protocol Version 4 who received any study treatment. Randomized 
patients who receive incorrect therapy from that intended will be summarized in the 
group according to their planned randomized treatment.  The ITT population will be the 
primary population for all analyses of primary and secondary efficacy variables.
The safety population for the trial will consist of all patients who enroll after 
implementation of Version 4 of the protocol and also receive any study treatment.  The 
safety population will be the primary population for all safety analyses.  For the 
purpose of all safety analyses, it will be assessed whether patients received a treatment 
different from the one they were randomized to at any time during the course of the 
study.  In case the number and duration of such “treatment switches” warrants it, the 
safety population may be redefined by reallocating individual patients to the treatment 
actually received, as opposed to which treatment they were randomized to.
The PK population will include all randomized patients who received at least one dose, 
and had sufficient sampling to permit PK evaluation.

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2.
Generate change from baseline values in TFC at Week 49 and Week 101 for
N placebo patients according to the following bivariate normal distribution:
where y_wk49 and y_wk101 is the change from baseline in TFC, respectively, at 
Week 49 and Week 101, is the assumed true change at those two timepoints, 
and ∑is the variance-covariance matrix.  Subsequently:

set to missing both values at Week 49 and Week 101 for 10% of the
N placebo patients

set to missing only the value at Week 101 for additional 10% of the
N placebo patients
Given how missing data will be imputed, it is not relevant to differentiate 
missing data into SDR versus NSDR reasons for placebo patients.
3.
Apply multiple imputations and derive 20 complete datasets.  Missing data on
placebo patients were imputed from the placebo arm.  Missing data on active
patients, depending on if due to NSDR or SDR reasons, were imputed
respectively from the active or the placebo arm.
4.
Use a t-test to compare active versus placebo at Week 101 for each completed
dataset and pool the result (Rubin 1987) to derive an estimate of the treatment
effect, including a p-value.
Across the 500,000 simulations, the power achieved, with the N patients per arm was 
calculated by dividing the number of times the p-value (in above Step 4) was below 5% 
by 500,000.  The above procedure was repeated by only changing the N until the 
calculated power was close to 80%.
It was estimated that 220 patients per arm will provide approximately 80% power, at a 
two-sided 0.05 level, to detect a 40% slowing of clinical decline for RO7234292 as 
compared with placebo at 101 weeks.  This treatment effect translates into an expected 
average decline of ~0.82 points at 101 weeks for the RO7234292 arms.  The minimal 
detectable difference with these assumptions is ~0.38 points.  
6.3
TESTING STRATEGY AND MULTIPLICITY ADJUSTMENT 
A hierarchical approach will be used for multiple adjustments that accounts for 
comparisons of two active dosing regimens (RO7234292 Q8W and RO7234292 Q16W) 
versus placebo, as well as multiple endpoints (the primary and secondary endpoints).  

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The primary endpoint will be tested for RO7234292 Q8W against placebo at alpha level 
5% and, if significant, then RO7234292 Q16W against placebo. 
Secondary endpoints will be tested for each active treatment versus placebo.  Within 
each testing chain (RO7234292 Q8W and RO7234292 Q16W), the endpoint will be 
tested only if the preceding endpoint is significant at the divided alpha level.  Details of
the order for secondary endpoints and the split of alpha will be detailed in the SAP. 
6.4
SUMMARIES OF CONDUCT OF STUDY
The numbers of patients who enroll in the study, discontinue from the study, and
complete the study will be summarized overall and by treatment arm.  Reasons for 
premature study withdrawal will be listed and summarized.  Enrollment and major 
protocol deviations will be listed and evaluated for their potential effects on the 
interpretation of study results.
6.5
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, CAG repeat length, CAP, 
HD stage, education) will be summarized using means, standard deviations, medians, 
and ranges for continuous variables and proportions for categorical variables, as 
appropriate.  Summaries will be presented overall and by treatment group.
6.6
EFFICACY ANALYSES
To ensure the treatment groups under comparison are concurrent and that treatment 
regimens are comparable across the entire dosing period of the 25-month study, for all 
efficacy analyses, patients enrolled prior to implementation of Protocol Version 4 will 
not be included and will be offered the option to enroll into Study BN40955 before 
reaching the primary endpoint assessment in the current study.    
6.6.1
Estimands
Following the very recent estimand framework outlined in the ICH-E9 draft addendum
(FDA 2017), the attributes of the estimand for the primary endpoint are defined as 
follows:

Population: ITT population (see Section 6.1)

Variable:  Change from baseline in cUHDRS score at Week 101  
–
Note: cUHDRS scale will be replaced by TFC scale for the FDA.

Intercurrent events (ICEs): 
–
Treatment discontinued for study drugrelated reasons (e.g., treatment-related 
adverse event or lack of efficacy):
After treatment discontinuation, the actual off-treatment values will be 
used in the analysis. 

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–
Treatment discontinued for NSDR reasons (e.g., lost to follow-up):
After treatment discontinuation, imputed hypothetical values as if patients 
had continued receiving study drug will be used in the analysis. In this 
instance, any data collected after treatment discontinuation will not be 
included in the analysis. 

Population level summary:  Difference in mean change from baseline at Week 101
between each active arm and the placebo arm
The primary estimand is a combination of a treatment-policy strategy and a hypothetical 
strategy (FDA 2017) to account for the different assumptions for each type of ICE. 
The Sponsor will emphasize to investigators the importance of collecting data for the 
primary endpoint through Week 101, even if patients discontinue study drug but do not 
withdraw study consent, as well as the importance of providing detailed reasons for 
treatment discontinuation. The primary estimator, described by the statistical model in 
Section 6.6.2, will be applied on the dataset produced after multiple imputation of any 
missing value.  In principle,

missing data as well as off-treatment data from patients who discontinued
treatment for NSDR reasons will be imputed from patients with available data
from the same treatment arm collected while on treatment

missing data from patients who discontinued treatment for SDR reasons will be
imputed from:
-
patients with available data from the placebo arm collected either while on
treatment or off treatment and
-
patients with available data from the same treatment arm collected while off
treatment
Multiple imputation of missing data values will be performed as follows:
1.
Imputation step:  Missing data values will be imputed "m" times leading to "m"
complete datasets.
2.
Analysis step:  Each of the resulting "m" datasets will be analyzed using the
statistical model described in Section 6.6.2, which will provide an estimate of
treatment difference.
3.
Pooling step:  The results from the "m" datasets will be combined (Rubin 1987)
leading to an overall estimate of the treatment effect and associated 95% confidence
intervals and p-values.
Full details of the algorithm for multiple imputation (e.g., which reference population to 
use for each missing data pattern, number of imputed datasets, method for imputation, 
etc.) will be provided in the SAP.
A supplementary estimand may be considered (and will be defined in the SAP). 

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6.6.2
Primary Efficacy Analysis
The primary efficacy endpoint is the change from baseline in cUHDRS score at 
Week 101.  This is defined as the attribute "variable" of the primary estimand in Section 
6.6.1.
Note: The primary efficacy endpoint for the U.S. FDA will be change from baseline in 
the TFC score at Week 101. TFC will be analyzed the same way as the cUHDRS.
The primary efficacy analysis for this study will compare each active treatment arm, 
RO7234292 Q8W and RO7234292 Q16W, against the placebo arm.  
To account for the multiple comparison, an appropriate procedure will be used to 
maintain the overall two-sided type I error at 5% (details will be given in the SAP). 
The analysis of the primary endpoint will be performed by means of analysis of 
covariance (ANCOVA).  The model will include the corresponding endpoint baseline 
score, CAG repeat length, baseline CAP score (defined in Section 4.1.1), and treatment 
as covariates.  On the basis of this analysis, least squares mean for the treatment 
differences at Week 101 and corresponding 95% CIs will be derived.  
The robustness of the primary method of estimation described above may be explored 
by alternative sensitivity estimators based on varying assumptions underlying the 
multiple imputation strategy. These sensitivity analyses will be described in the SAP.
6.6.3
Secondary Efficacy Analyses
The secondary efficacy endpoints are identified in Section 2.1.2.
Similar hypotheses as for the primary efficacy endpoint will be tested for the secondary 
continuous efficacy endpoints. 
Categorical endpoints, such as CGI-C and the proportion of progressors, will be 
analyzed by means of logistic regression and will include treatment (categorical), CAG 
repeat length, and CAP score as covariates.   
Methods for controlling type I error in the testing of the secondary endpoints will be 
described in the SAP. 

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6.6.4
Subgroup Analyses
The results of selected efficacy variables will be summarized within subgroups using 
descriptive statistics.  The following variables will be used to define subgroups:

Sex (male vs. female)

Age at baseline (45 vs. 45 years)

CAG repeat length (43 vs. 43)

Stage at baseline (I, II, III)
–
Stage III will be considered only if there are enough patients.
Additional exploratory analyses of efficacy results may be performed using an ANCOVA 
model, similar to the primary analysis, based on change from baseline for the variable of 
interest, with baseline score (not for analysis by baseline stage), CAP score, CAG repeat 
length (not for analysis by CAG repeat length), treatment, subgroup, and treatment-by-
subgroup interaction as covariates.
6.6.5
Exploratory Efficacy Analysis
The exploratory efficacy endpoints are identified in Section 2.1.3.
The exploratory endpoints will be summarized using tables, listings, and graphs, as 
appropriate.  Additional statistical modeling may be considered (e.g., ANCOVA, logistic 
regression).
6.6.6
Historical Controls
Should the treatment discontinuation rate in the placebo arm be significantly higher 
than expected, the Sponsor may consider the use of historical controls for efficacy 
analysis.  In this scenario, the use of historical controls will be deemed supportive 
analyses. 
Prior to database lock, the Sponsor may select historical controls from ENROLL-HD.  
These historical controls may be selected to match patients with regard to important 
baseline characteristics (e.g., gender, CAG, age, IS, International Standard 
Classification of Education).  The objective for use and exact algorithm for selecting 
historical controls will be specified in the SAP.  If implemented, the actual selection will 
be made before database lock and unblinding of treatment allocation and will be
documented and stored in the Sponsor's database.   
Whether the Sponsor will decide to use those the historical controls, the exact algorithm 
for borrowing and for deriving an overall treatment effect will be described in the SAP 
before unblinding.
Additionally, given that some of the patients who will be enrolled in this study may have 
been part of ENROLL-HD, the Sponsor may explore a within-patient comparison for the 

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rate of decline in cUHDRS or TFC score, before treatment with RO7234292 (prior to 
randomization, using ENROLL-HD registry data) and after treatment with RO7234292
(after randomization, using study data), for patients who were randomized to the active 
arm and had follow-up in ENROLL-HD of at least 1 year's duration prior to randomization 
into this study.
6.7
SAFETY ANALYSES
The safety population (see Section 6.1) will be the primary population for all analyses of 
safety data.  Incorrect treatment assignments (patients who received a treatment 
different than their planned randomized treatment) will be summarized and the impact on 
the safety assessment will be discussed.
For all safety analyses, patients enrolled prior to implementation of the Version 4 of the 
protocol will be summarized separately.
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms.  The 
adverse event severity grading scale indicated in Table 4 will be used for assessing 
adverse event severity.  Laboratory values determined as an adverse event should be 
graded as per Appendix 5, which is based on the NCI CTCAE (v5.0).
All safety data, including adverse events, laboratory tests, CSSR-S, MoCA, ECG, and 
vital signs will be reported in individual listings and summarized by treatment for each 
assessment time using descriptive statistics. For continuous variables, both the original 
value as well as the change from baseline will be reported. 
The incidence of adverse events will be summarized on the basis of body systems and 
dictionary preferred terms. The incidence of adverse events by severity and relationship 
to study drug or study procedure and incidence of marked abnormal laboratory test 
results will be provided. 
The iDMC will review safety data throughout the study. Analyses required for the iDMC 
data review will be performed as described in the iDMC Charter.
6.8
PHARMACOKINETIC ANALYSES
For all patients in the PK population (Section 6.1), CSF and plasma concentrations of 
RO7234292 will be presented descriptively, including arithmetic and geometric means, 
median, range, standard deviations, and coefficients of variation.  Nonlinear 
mixed-effects modeling will be used to analyze the concentrationtime data for
RO7234292 in CSF and plasma following IT administration. A covariate analysis will be 
conducted to evaluate the effect of covariates such as body weight, age, and sex on 
RO7234292 exposure.   
Population and individual estimates of primary PK parameters (e.g., clearance, 
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concentrationtime curve, average trough plasma concentration) will be computed and 
used to explore exposure-response relationship on primary and key secondary
endpoints, as well as safety measures.  The data from this study may be pooled with 
data from other studies conducted with RO7234292 to support the population PK/PD 
modeling.
Details of this mixed-effects modeling and exploration of exposure-response analysis 
and results will be described and reported in a document separate from the Clinical 
Study Report.
6.9
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) will be summarized by treatment group. For those who 
are ADA-positive, titers will be estimated as well as antibody subtype.  In addition, the 
numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized for patients on active treatment only. When determining 
post-baseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more post-baseline samples is at least is at least 4-fold 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or have missing 
data at baseline and all post-baseline samples are negative, or if they are ADA positive 
at baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.10
BIOMARKER ANALYSES
The biomarker endpoints are described in Section 2.5. 
A mixed-effects model repeat measurement model will be used to model the change in 
each primary and secondary biomarker endpoint, adjusting for the baseline endpoint, 
CAG repeat length, CAP score, treatment, visit, and treatment-by-visit interaction (the 
final list of covariates and details of the model will be specified in the SAP).

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6.11
HEALTH STATUS UTILITY ANALYSIS
The health status utility endpoints are described in Section 2.6.
The health status utility endpoints will be summarized using tables, listings, and graphs, 
as appropriate.  Additional statistical modeling may be considered.
6.12
OPTIONAL INTERIM ANALYSES 
The Sponsor may choose to conduct one or more interim analyses for efficacy.  Below 
are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an iDCC and reviewed by the iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC Charter.
The decision to conduct an interim analysis, along with the rationale, specification of the 
endpoint (e.g., clinical and/or biomarker endpoint), number of patients, and statistical 
details for each analysis, will be introduced via a future protocol amendment, which will 
be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.  The iDMC Charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of an interim analysis, and the iDMC Charter will be 
made available to relevant health authorities. 
If there is a potential for the study to be stopped for positive efficacy as a result of an 
interim analysis of efficacy data, the type I error rate will be controlled to ensure 
statistical validity is maintained.  Additional criteria for recommending that the study be 
stopped for positive efficacy will be added to a future protocol amendment.  
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data electronic data 
from clinic visits (see Section 7.3) and electronic data obtained from the Roche HD 
mobile app (see Section 7.4) will be sent directly to the Sponsor, using the Sponsor's 
standard procedures to handle and process the electronic transfer of these data.

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eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT-, CLINICIAN-, AND 
OBSERVER-REPORTED OUTCOME DATA
Electronic devices will be used to capture PRO, ClinRO, ObsRO, and PerfO data.  The 
devices are designed for entry of data in a way that is attributable, secure, and accurate, 
in compliance with U.S. FDA regulations for electronic records (21 CFR Part 11).  The 
data will be transmitted to a centralized database maintained by the electronic device 
vendor.
The electronic data will be available for view access only, via a secure vendor web portal. 
Only identified and trained users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will have view access only.  System backups for data stored 
by the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
ELECTRONIC DATA OBTAINED BY THE ROCHE HD DIGITAL 
MONITORING PLATFORM
During "active tests" and "passive monitoring," the smartphone and wrist-worn wearable 
record movement and location data.  Data on the technical status and connectivity of the 
devices is also recorded.  Patients can choose to pause location data recording.  

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No patient identifiable information is stored on the devices.  For selected "active test" 
tasks, touch and sound is also recorded.  Video is not recorded.
Roche HD mobile app (smartphone and wrist-worn wearable) sensor data are encrypted 
and uploaded to secure servers whenever the smartphone is connected to Wi-Fi. All 
sensor data will be managed by the Sponsor who will monitor and ensure the integrity 
and quality of the acquired data.  This includes, but is not limited, to the analysis of 
sensor data together with protocol-specified assessments and activities associated with 
routine daily living.  The data will not be analyzed for efficacy until study end, unless they 
are chosen to be a part of a pre-specified interim analysis along with other clinical and/or 
biomarker endpoints.
7.5
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.7.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.6
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 

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authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.7
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO, ClinRO, ObsRO (if applicable), and 
PerfO data (if applicable), Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms) will be provided to each site.  If applicable, it will be provided in a certified 
translation of the local language.  The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the "Consent Forms") before 

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IRB/EC submission.  The final IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient before his or her 
participation in the study.  If a study companion will participate, he/she must also sign 
and date a consent form prior to participation in the study.  The case history or clinical 
records for each patient shall document the informed consent process and that written 
informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.  If the patient 
should lose capacity to consent during the study (i.e., after enrollment), as judged by the 
investigator, a legally authorized representative may sign on behalf of the patient.
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.

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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 

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participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. Linking 
of data will be facilitated by the HDID number (see Section 4.5.2). The HDID is a unique 
coded identifier for persons participating in studies in HD.  This HDID will stay the same 
for a person throughout all trials.  The use of the unique identifier will assure that people 
are only enrolled once in large observational studies like Enroll-HD, REGISTRY, 
COHORT, PREDICT, and TRACK-HD and will also allow approved comparison and 
combination of data between studies.  The HDID is a 9-digit number created by a secure 
one-way algorithm, based on unchanging information (date of birth, birth name, place of 
birth and mother’s maiden name). The identifying data are used for the split second 
needed by the algorithm needed to generate the HDID and are never stored 
electronically on the web portal or in the study database. For patients without a 
pre-existing HDID number in the source notes, the investigator should store the original 
data and the newly generated HDID in the patient’s source documents and in the 
investigator file.  The HDID can be generated within the web portals of the observational 
studies or in the specially defined portal for the HDID generation under: 
https://hdid.enroll-hd.org. In addition, redacted clinical study reports and other summary 
reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 

RO7234292F. Hoffmann-La Roche Ltd
113/Protocol BN40423, Version 4
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 90 sites globally will participate to enroll approximately 660 patients after 
implementation of Version 4 of the protocol.  Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.6.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected.
An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details) and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials
Data at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 

RO7234292F. Hoffmann-La Roche Ltd
114/Protocol BN40423, Version 4
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

RO7234292F. Hoffmann-La Roche Ltd
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10.
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Baig SS, Strong M, Quarrell OW. The global prevalence of Huntington's disease: a 
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Harrington DL, Long JD, Durgerian S, et al. Cross-sectional and longitudinal multimodal 
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Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Hogarth P, Kayson E, Kieburtz K, et al. Interrater agreement in the assessment of motor 
manifestations of Huntington's disease. Mov Disord 2005;20:2937.
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Johnson EB, Byrne LM, Gregory S, et al. Neurofilament light protein in blood predicts 
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Liu W, Yang J, Chen K, et al. Resting-state fMRI reveals potential neural correlates of 
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Maetzler W, Domingos J, Srulijes K, et al. Quantitative wearable sensors for objective 
assessment of Parkinson's disease. Mov Disord 2013;28:162837.

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McCarrier KP, Deal LS, Abraham L, et al. Patient-centered research to support the 
development of the Symptoms of Major Depressive Disorder Scale (SMDDS): 
initial qualitative research. Patient 2016;9:11734.
Moumné L, Betuing S, Caboche J. Multiple aspects of gene dysregulation in 
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Nance M, Paulsen JS, Rosenblatt A, et al. A physician's guide to the management of 
Huntington's disease, 3rd edition. Huntington's Disease Society of America, 2011. 
Novak MJ, Seunarine KK, Gibbard CR, et al. Basal ganglia-cortical structural 
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Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington's disease with 
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Paulson HL, Albin RL. Huntington’s disease: clinical features and routes to therapy. In: 
Lo DC, Hughes RE, editors. Neurobiology of Huntington's disease: applications to 
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Peinemann A, Schuller S, Pohl C, et al. Executive dysfunction in early stages of 
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Schobel SA, Palermo G, Auinger P, et al. Motor, cognitive, and functional declines 
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Schoch KM, Miller TM. Antisense oligonucleotides: translation from mouse models to 
human neurodegenerative diseases. Neuron 2017;94:105670.
Shoulson I, Fahn S. Huntington disease: clinical care and evaluation. 
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Smith, A. Symbol Digit Modalities Test (SDMT). Manual (rev.). Los Angeles: Western 
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Sorensen SA, Fenger K. Causes of death in patients with Huntington's disease and in 
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Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of 
transcriptional dysregulation is correlated with behavioral benefits in the YAC128 
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Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in 
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Van Raamsdonk JM, Pearson J, Rogers DA, et al. Loss of wild-type huntingtin 
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Walker FO. Huntington's disease. Semin Neurol 2007;27:14350.
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Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in 
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Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease. Lancet 
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Appendix 1  
Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 
Screening a 
BL 
Treatment Period 
EoT b 
EoT 
for 
ETT 
Safety 
Follow-
Up 
Calls ee ETT b SFU 
Month 
1 
3 
5 
7 
9 
11 13 15 17 19 21 23 
25 
25 
 
29 
Week 
4 to 1 
1 
5 
13 21 29 37 45 53 61 69 77 85 93 
101 
101 
117 
Day (Window) 
28 to 2 
1 1 (
( 7) dd
( 7) 
( 7) 
Signed informed consent c 
x 
Review of inclusion and 
exclusion criteria  
x 
Demographic data 
x 
Medical history and baseline 
conditions d 
x 
xe 
Blood sample for CAG repeat 
length 
x 
Viral serology f 
x 
Thyroid panel g 
x 
Vital signs h
x 
xe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Complete physical examination i 
x 
xe 
 
x 
 
x 
 
x 
x 
x 
x 
Neurologic examination j 
x 
xe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG k
x
xe 
x 
x 
x 
x 
x 
x 
x 
Hematology l 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1:Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.) 
RO7234292F. Hoffmann-La Roche Ltd 
120/Protocol BN40423, Version 4 
 
Screening a 
BL 
Treatment Period 
EoT b 
EoT 
for 
ETT 
Safety 
Follow-
Up 
Calls ee ETT b SFU 
Month 
1 
3 
5 
7 
9 
11 13 15 17 19 21 23 
25 
25 
 
29 
Week 
4 to 1 
1 
5 
13 21 29 37 45 53 61 69 77 85 93 
101 
101 
117 
Day (Window) 
28 to 2 
1 1 (
( 7) dd
( 7) 
( 7) 
Chemistry m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test n
x 
xe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Local INR and/or PT, aPTT, 
platelet count x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Plasma sample for PK 
 
 
x
 
x 
x 
x p  
x 
x 
x 
x 
x 
Plasma sample for 
immunogenicity testing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Plasma sample for biomarkers 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood sample for clinical 
genotyping 
 
 
xe 
CSF sample for 
PK/safety/biomarkers 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xy 
x 
MRI q 
x 
x 
x 
x 
x 
x 
HD-DAS 
x 
x 
x 
x 
x 
x 
x 
Independence Scale 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MoCA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C-SSRS r
x 
xe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1:Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.) 
RO7234292F. Hoffmann-La Roche Ltd 
121/Protocol BN40423, Version 4 
 
Screening a 
BL 
Treatment Period 
EoT b 
EoT 
for 
ETT 
Safety 
Follow-
Up 
Calls ee ETT b SFU 
Month 
1 
3 
5 
7 
9 
11 13 15 17 19 21 23 
25 
25 
 
29 
Week 
4 to 1 
1 
5 
13 21 29 37 45 53 61 69 77 85 93 
101 
101 
117 
Day (Window) 
28 to 2 
1 1 (
( 7) dd
( 7) 
( 7) 
UHDRS FA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
TFC s 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
TMS s, cc 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
CGI-S 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CGI-C 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SDMT s 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
SWR s 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
AES 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SMDDS 
x 
x 
x 
x 
x 
x 
x 
x 
x 
NeuroQoL 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
EQ-5D-5L (in-clinic) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PGI-S 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PGI-C 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Roche HD mobile app in-clinic 
assessments 
x 
x 
x 
 
x 
x 
x 
x 
Roche HD mobile app remote 
data collection 
Continuous remote data collection t 
Optional exit interview u 
x 
x 

Appendix 1:Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.) 
RO7234292F. Hoffmann-La Roche Ltd 
122/Protocol BN40423, Version 4 
 
Screening a 
BL 
Treatment Period 
EoT b 
EoT 
for 
ETT 
Safety 
Follow-
Up 
Calls ee ETT b SFU 
Month 
1 
3 
5 
7 
9 
11 13 15 17 19 21 23 
25 
25 
 
29 
Week 
4 to 1 
1 
5 
13 21 29 37 45 53 61 69 77 85 93 
101 
101 
117 
Day (Window) 
28 to 2 
1 1 (
( 7) dd
( 7) 
( 7) 
CRQ: EQ-5D-5L, HUI-self, 
HUI-proxy, CrGI-S 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
CRQ: AES 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
CRQ: CrGI-C 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Remote data collection of CRQ 
(EQ-5D-5L, HUI-self, HUI-
proxy, HD-CIAOS, WPAI) 
Remote data collection (see Appendix 4) 
Blood sample for RBR DNA 
(optional) v 
 
x 
Blood sample for RBR RNA 
(optional) v 
x 
x 
x 
x 
x 
Serum sample for RBR
(optional) v 
 
 
x 
x 
x 
x 
x 
Change in medical information 
since previous visit w 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Lumbar puncture x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x y 
x y 
Study drug administration  
x 
x 
x z
x 
x z
x 
x z
x 
x z
x 
x z
x 
x z
Concomitant medications aa 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events bb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

Appendix 1:Schedule of Activities for Patients Enrolled after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
126/Protocol BN40423, Version 4
bb After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 5 months after the final dose of study drug.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment.  
cc The DCL will be assessed at screening only (i.e., without the full TMS assessment).  The TMS scale will be assessed (excluding the DCL) at all 
other timepoints.
dd Excluding MRIs, which have a visit window of 14 to 7 days.
ee Telephone safety follow-up calls will assess any changes to ongoing adverse events or occurrence of new adverse events and changes to 
concomitant medication.  Unscheduled visits can occur based on the outcome of this safety follow-up call.

Appendix 3:Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients Enrolled 
after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
129/Protocol BN40423, Version 4
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
HD-SDI
Huntington's 
Disease Speaking 
Difficulty Item 
1
Speech
1
PRO
Weekly
Roche HD 
mobile app
HD-CIAOS
Huntington's 
Disease Companion-
Reported Irritability 
and Angry Outbursts 
Scale
3
Irritability and angry 
outbursts
2
ObsRO
Weekly
Electronic 
device
HUI
Health Utilities Index
15
Health-related quality of 
life
10
ObsRO
Baseline, Weeks 5, 21, 37, 
53, 69, 85, and 101 and ETT
In-clinic
Weekly
Electronic 
device
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10
PerfO
Screening, baseline, 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT
In-clinic
Neuro-Qol 
Cog Func
Neuro-Qol Cognitive 
Function Short Form
8
Cognition
5
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 
In-clinic
PGI-C
Patient Global 
ImpressionChange
1
Overall change in 
patient status
2
PRO
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
PGI-S
Patient Global 
ImpressionSeverity
1
Overall severity of 
patient status
2
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 and 
ETT
In-clinic

Appendix 3:Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients Enrolled 
after Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
130/Protocol BN40423, Version 4
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
SDMT/
eSDMT
Symbol Digit 
Modalities Test
Max 
number in 
90 seconds
Cognitive
5
PerfO
SDMT at baseline and 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits 
In-clinic
eSDMT monthly + at clinic 
visits (screening, baseline, 
Weeks 5, 53,101, and ETT )
Roche HD 
mobile app 
(eSDMT)
SMDDS
Symptoms of Major 
Depressive 
Disorder Scale
16
Depression, anxiety, 
irritability, sleep
10
PRO
Baseline and Weeks 13, 29, 
45, 61, 77, 93, and 101 
In-clinic
SWR/eSWR
Stroop Word 
Reading Test
Max 
numbers in 
45 seconds
Cognitive
5
PerfO
SWR at baseline and 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
eSWR monthly + at clinic 
visits (screening, baseline, 
Weeks 5, 53, and 101 and 
ETT)
Roche HD 
mobile app 
(eSWR)
WPAI
Work Productivity 
and Activity 
Impairment
6
Work productivity
5
PROObsRO
Baseline and then monthly 
Roche HD
mobile app
and electronic 
device
appapplication; ETT early treatment termination; HD Huntington disease; ObsRO observer-reported outcome; PerfO performance outcome; 
PROpatient-reported outcome.

RO7234292F. Hoffmann-La Roche Ltd 
131/Protocol BN40423, Version 4
Appendix 4 Clinical Assessments Order and Duration for
Patients Enrolled after Implementation of Protocol Version 4
Table 1
Screening Visit Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Diagnostic Confidence Level
Huntington's Disease Daily Activities Scale
Independence Scale
MoCA
C-SSRS
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Roche HD mobile application
~20
Qualified 
study 
personnel
C-SSRColumbia-Suicide Severity Rating Scale; HDHuntington disease; MoCA Montreal
Cognitive Assessment.

Appendix 4: Clinical Assessments Order and Duration for Patients Enrolled after 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
132/Protocol BN40423, Version 4
Table 2
Baseline and Week 101 Clinical Assessments (for Primary 
Analysis)
Block
Assessments
Total 
Duration 
(minutes)
Site Staff Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic 
Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
(post-baseline visits only)
~60
Qualified study physician
Break (if needed)
~2030
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified study 
personnel
Break (if needed)
~10
3 a
Apathy Evaluation Scale (patient and 
companion)
Symptoms of Major Depressive Disorder 
Scale
~20
Qualified study 
personnel
Break (if needed)
~1020
4 a
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level 
Questionnaire (patient and companion)
Health Utilities Index (companion: self and 
proxy)
Patient/Companion-reported Global 
ImpressionSeverity
Patient/Companion-reported Global 
ImpressionChange (post-baseline visits 
only)
~20
Qualified study 
personnel
Break (if needed)
~1020
5 a
Roche HD mobile application
~20
Qualified study 
personnel
HDHuntington disease; MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in 
Neurological Disorders; UHDRSUnified Huntington's Disease Rating Scale.
a At the baseline visit and at week 101, Blocks 3, 4, and 5 can be completed on the same day 
after Blocks 1 and 2, or on the following day, but must be completed predose at the baseline 
visit.  

Appendix 4: Clinical Assessments Order and Duration for Patients Enrolled after 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
133/Protocol BN40423, Version 4
Table 3
Follow-Up Clinical Assessments at Weeks 5, 21, 37, 53, 69, 
and 85
Block
Assessments
Total 
Duration 
(minutes)
Site Staff 
Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified 
study 
personnel
Break (if needed)
~10
3
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level Questionnaire (patient
and companion)
Health Utilities Index (companion: self and proxy)
Patient/Companion-reported Global ImpressionSeverity
Patient/Companion-reported Global ImpressionChange 
~30
Qualified 
study 
personnel
4
Roche HD mobile application a
~20
Qualified 
study 
personnel
MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in Neurological Disorders; 
UHDRSUnified Huntington's Disease Rating Scale
a
These assessments will take place only at Weeks 5 and 53.

Appendix 4: Clinical Assessments Order and Duration for Patients Enrolled after 
Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
134/Protocol BN40423, Version 4
Table 4
Follow-Up Clinical Assessments at Weeks 13, 29, 45, 61, 77, 
and 93
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1 a
Apathy Evaluation Scale (patient and companion)
Symptoms of Major Depressive Disorder Scale
~20
Qualified 
study 
personnel
Break (if needed)
~10
2
Huntington's Disease-Daily Activities Scale
~25
Qualified 
study 
physician
a To be completed prior to safety assessments.

Appendix 5: Grading Scale for Adverse Events Relating to Laboratory Abnormalities for 
All Patients (cont.)
RO7234292F. Hoffmann-La Roche Ltd
136/Protocol BN40423, Version 4
LLNlower limit of normal; ULNupper limit of normal.

Appendix 5: Grading Scale for Adverse Events Relating to Laboratory Abnormalities for 
All Patients (cont.)
RO7234292F. Hoffmann-La Roche Ltd
137/Protocol BN40423, Version 4

Appendix 6 Roche HD Mobile Application for Patients Enrolled 
after Implementation of Protocol Version 4:  Active Test
The following tasks are part of the "active tests" conducted on the Roche Huntington's Disease 
(HD) mobile application by the patient. 
Daily Questions
Two daily single-item questions on mood and physical energy will be assessed, asking patients 
about their mood and physical health at the time they are performing the “Active” tests. The 
assessments aim to capture daily mood fluctuations and will be used as a control for the other 
motor and cognitive assessments. 
Cognitive Test (eSDMT)
The Cognitive Test asks participants to match symbols with numbers according to a key as 
quickly and accurately as possible. The key, symbols, numbers are all displayed on a 
smartphone screen. The test assesses visuo-motor integration, and measures visual attention 
and motor speed.  It is modelled on the pen and paper Symbol Digit Modalities Test (SDMT) 
(Smith, 1968). The SDMT has been shown to be sensitive to symptom changes in early HD 
patients (Tabrizi 2012) and is part of the Unified Huntington's Disease Rating Scale (UHDRS) 
assessment (Huntington’s Study Group, 1996).
Word Reading Test (eSWR)
The Word Reading Test asks participants to read aloud color words written in black font on a 
smartphone screen. Their voice will be recorded. The test assesses cognitive processing speed, 
and is modelled on the Stroop Word Reading (SWR) (Ridley 1935). The "Word Reading" part of 
the SWR Test has been shown to be sensitive to symptom changes in patients with early HD 
(Tabrizi 2012) and is part of the UHDRS assessment (Huntington’s Study Group 1996). 
Speeded Tapping Test
The Speeded Tapping Test asks participants to tap the smartphone screen as fast and regularly 
as possible, using the index finger of both the left and right hands. The test assesses 
bradykinesia. Performance will also be impacted by chorea and dystonia. It is modelled on 
tapping tests shown to be sensitive to symptom changes in early HD (Bechtel et al. 2010; Tabrizi 
et al. 2012). A similar finger tapping task is also included as part of the UHDRS assessment 
(Huntington’s Study Group 1996).
Draw a Shape Test
The Draw a Shape Test asks participants to trace a series of increasingly complex shapes on the 
smartphone screen. The shapes include lines, a square, a circle, an eight, and a spiral. This test 
is designed to assess visuomotor coordination and fine motor impairment in early HD patients. It 
is modelled on circle tracing tasks that have been shown to be sensitive to symptom changes in 
early HD (Say et al. 2011; Tabrizi et al. 2013). 
Chorea Test
The Chorea Test asks participants to hold the smartphone still in their hand with their arm 
outstretched, and wear the wrist-worn wearable. As a dual task, participants will also need to 
count backwards aloud. To ensure correct execution, voice will be recorded. The test is 
designed to assess chorea. It draws on other sensor-based approaches to measure chorea 
(Reilmann et al. 2010, 2011; Kegelmeyer et al. 2017). A chorea assessment is also part of the 
UHDRS (Huntington’s Study Group 1996). 
Balance Test
The Balance Test asks participants to stand still while wearing the smartphone and wrist-worn 
wearable. It is an assessment for patients’ static balance function. Sensor-based approaches for 
RO7234292F. Hoffmann-La Roche Ltd
138/Protocol BN40423, Version 4

Appendix 6: Roche HD Mobile Application for Patients Enrolled after Implementation of 
Protocol Version 4: Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
139/Protocol BN40423, Version 4
measuring static balance have been shown to be sensitive to differences in symptoms in early 
HD (Dalton et al. 2013). The test is also part of established scales like the Berg Balance Scale 
(Berg et al. 1992), which are used in HD (Busse et al. 2009; Rao et al. 2009). The test is 
anchored to the UHDRS assessments for maximal dystonia, maximal chorea, and tandem 
walking (Huntington Study Group 1996).
U-Turn Test
The U-Turn Test asks participants to walk and turn safely between two points that are at least
four steps apart, while wearing the smartphone and wrist-worn wearable. They need to make at
least five turns. The test is designed to assess gait and lower-body bradykinesia, which are also
assessed by the UHDRS. It is modelled on the Timed Up and Go Test, which has been clinically
validated for the HD population (Busse et al. 2009; Rao et al. 2009). The test is anchored to the
UHDRS gait, bradykinesia body, and tandem walking items (Huntington Study Group 1996).
Walk Test
The Walk Test asks participants walk as fast as is safely possible for 200 meters or 2 minutes 
every day. Ideally, the test is done in a straight path with no obstacles (e.g., in a park). 
Sensor-based approaches for measuring gait have been shown to be sensitive to differences in 
symptoms in early HD (Dalton et al. 2013). The test is anchored to the UHDRS gait, bradykinesia 
body, and tandem walking items (Huntington Study Group 1996).
Tasks are automatically scheduled as shown below in Figure 1 and take no more than 5 minutes 
per day.  If the patient does not complete the active test on a certain day, scheduled tasks that 
occur less frequently than every second day (i.e., EuroQol 5-Dimension, 5 Level Questionnaire, 
Work Productivity and Activity Impairment, Huntington's Disease Speaking Difficulty Item, 
2-Minute Walk Test) are rolled over to the next time the active test is completed.
References
Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest 
and symptomatic Huntington disease. Neurology 2010;75:215060.
Berg KO, Wood-Dauphinee SL, Williams JI, et al. Measuring balance in the elderly: validation of 
an instrument. Can J Public Health 1992;83(Suppl 2):S711.
Busse ME, Wiles CM, Rosser AE. Mobility and falls in people with Huntington's disease. J Neurol 
Neurosurg Psychiatry 2009;80:8890.
Dalton A, Khalil H, Busse M, et al. Analysis of gait and balance through a single triaxial 
accelerometer in presymptomatic and symptomatic Huntington’s disease. Gait Posture 
2013;37:4954.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.Kegelmeyer et al. 2017
Rao AK, Muratori L, Louis ED, et al. Clinical measurement of mobility and balance impairments in 
Huntington's disease: validity and responsiveness. Gait Posture 2009;29:4336.
Reilmann R, Bohlen S, Kirsten F, et al. Assessment of involuntary choreatic movements in 
Huntington's disease—toward objective and quantitative measures. Mov Disord 
2011;26:226773.

Appendix 6: Roche HD Mobile Application for Patients Enrolled after Implementation of 
Protocol Version 4: Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
140/Protocol BN40423, Version 4
Reilmann R, Bohlen S, Klopstock T, et al. Grasping premanifest Huntington's disease - shaping 
new endpoints for new trials. Mov Disord 2010;25:285862.
Say MJ, Jones R, Scahill R, et al. Visuomotor integration deficits precede clinical onset in 
Huntington's disease. Neuropsychologia 2011;49:26470.
Smith A. The symbol-digit modalites test: a neuropsychologic test of learning and other cerebral 
disorders. In: Helmuth J, editor. Learning disorders. Seattle: Special Child Publications; 
1968:83–91.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:64362.
Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and 
early Huntington's disease in the TRACK-HD study: analysis of 24 month observational 
data. The Lancet Neurology 2012;11.1:4253.
Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in 
premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-
month observational data. Lancet Neurol 2013;12:63749.

RO7234292F. Hoffmann-La Roche Ltd 
142/Protocol BN40423, Version 4
Appendix 7 Diagnostic Confidence Level for All Patients
The Diagnostic Confidence Level is calculated as shown below (from UHDRS 
Total Motor Score Scale, Item 17):
DIAGNOSIS CONFIDENCE LEVEL
To what degree are you confident that this person meets the operational 
definition of the unequivocal presence of an otherwise unexplained 
extrapyramidal movement disorder
(e. g., chorea, dystonia, bradykinesia, rigidity) in a subject at risk for HD?
0normal (no abnormalities)
1non-specific motor abnormalities (less than 50% confidence)
2motor abnormalities that may be signs of HD (50%89% confidence)
3motor abnormalities that are likely signs of HD (90%98% confidence)
4motor abnormalities that are unequivocal signs of HD (99% confidence)
Copyright 1999
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.

RO7234292F. Hoffmann-La Roche Ltd
143/Protocol BN40423, Version 4
Appendix 8
Guidance for Neurological Examination for 
All Patients
Perform the neurological examination in the same way every time at screening and at 
every clinic visit.  At dosing visits, perform examination predose and postdose after the 
participant has walked for 30 minutes postdrug injection.
Neurological Examination

Mental status (appearance, level of consciousness, behavior,
speech)

Cranial Nerves II (including Vision and Fundoscopy)XII

Motor examination (bulk, tone, and strength)

Coordination

Abnormal movements

Gait

Reflexes

Sensation (vibration, light touch, pin prick/temperature)
Note:  The neurological examination should be followed at the 
non-dosing clinic visits, end-of-treatment visit, and safety 
follow-up visit.

RO7234292F. Hoffmann-La Roche Ltd 
144/Protocol BN40423, Version 4
Appendix 9
Schedule of Activities for Patients Enrolled before Implementation of Protocol 
Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
Signed informed 
consent c
x
Review of inclusion and 
exclusion criteria 
x
Demographic data
x
Medical history and 
baseline conditions d
x
xe
Blood sample for CAG 
repeat length
x
Viral serology f
x
Thyroid panel g
x
Vital signs h
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical 
examination i
x
xe
x
x
x
x
x
x
Neurologic examination j
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
145/Protocol BN40423, Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
ECG k
x
xe
x
x
x
x
x
x
x
Hematology l
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistry m
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pregnancy test n
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Local INR, aPTT, PT
platelet count x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for PK
x
x
x
x p 
x
x
x
x
x
Plasma sample for 
immunogenicity testing
x
x
x
x
x
x
x
x
x
x
Plasma sample for 
biomarkers
x
x
x
x
x
x
x
x
x
x
Blood sample for clinical 
genotyping
xe
CSF sample for 
PK/safety/biomarkers
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xy
x
MRI q
x
x
x
x
x
x
HD-DAS
x
x
x
x
x
x
x
Independence Scale
x
x
x
x
x
x
x
x
x
x
x
MoCA
x
x
x
x
x
x
x
x
x
x
x

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
146/Protocol BN40423, Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
C-SSRS r
x
xe
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
UHDRS FA
x
x
x
x
x
x
x
x
x
x
TFC s
x
x
x
x
x
x
x
x
x
x
TMS s, cc
x
x
x
x
x
x
x
x
x
x
x
CGI-S
x
x
x
x
x
x
x
x
x
x
CGI-C
x
x
x
x
x
x
x
x
x
SDMT s
x
x
x
x
x
x
x
x
x
x
SWR s
x
x
x
x
x
x
x
x
x
x
AES
x
x
x
x
x
x
x
x
x
SMDDS
x
x
x
x
x
x
x
x
x
NeuroQoL
x
x
x
x
x
x
x
x
x
x
EQ-5D-5L (in-clinic)
x
x
x
x
x
x
x
x
x
x
HUI(in-clinic)
x
x
x
x
x
x
x
x
x
x
PGI-S
x
x
x
x
x
x
x
x
x
x
PGI-C
x
x
x
x
x
x
x
x
x
Roche HD mobile app 
in-clinic assessments
x
x
x
x
x
x
x
x
Roche HD mobile app 
remote data collection 
Continuous remote data collection t

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
147/Protocol BN40423, Version 4
Screening a
BL
Treatment Period
EoT b
EoT 
for 
ETT ETT b SFU
Month
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25
25
29
Week
4 to 1
1
5
9
13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97
101
101
117
Day (Window) 28 to 2
1
1
(3) dd
Optional exit interview u
x
x
Blood sample for RBR 
DNA (optional) v
x
Blood sample for RBR 
RNA (optional) v
x
x
x
x
x
Serum sample for RBR
(optional) v
x
x
x
x
x
Change in medical 
information since 
previous visit w
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Lumbar puncture x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x y
x y
Study drug 
administration
x
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
x z
x
xz
x
xz
Concomitant 
medications aa
x
x
x
x
x
x
x
x
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 bb
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAanti-drug antibody; AESApathy Evaluation Scale; BLbaseline; CGI-C Clinical Global Impression, Change; CGI-S Clinical Global 
Impression, Severity; CSF cerebrospinal fluid; CSSRS Columbia-Suicide Severity Rating Scale; cUHDRS composite Unified Huntington's 
Disease Rating Scale; DCLdiagnostic confidence level; eCRF electronic Case Report Form; EoT end of treatment; EQ-5D-5LEuroQol 
5-Dimension, 5-Level Questionnaire; ETT early treatment termination; FAFunctional Assessment; HBsAghepatitis B surface antigen;
HCVhepatitis C virus; HD Huntington disease; HD-DASHD Daily Activities Scale; HUIHealth Utilities Index; MoCA Montreal Cognitive
Assessment; MRI magnetic resonance imaging; Neuro-Qol Quality of Life in Neurological Disorders; PGI-C Patient Global Impression,

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
RO7234292F. Hoffmann-La Roche Ltd
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Change; PGI-S Patient Global Impression, Severity; PKpharmacokinetic; Q8W every 8 weeks; RBR Research Biosample Repository; 
SDMT Symbol Digit Modalities Test; SFU safety follow-up; SMDDS Symptoms of Major Depressive Disorder Scale; SWR Stroop Word 
Reading; TFC Total Functional Capacity Scale; TMS Total Motor Score; UHDRSUnified Huntington's Disease Rating Scale.
Notes:  All assessments should be performed at the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be 
performed prior to dosing, unless otherwise specified.  
a A maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for patients who fail the initial screening (e.g., as a 
consequence of abnormal laboratory values or general medical status not meeting inclusion or exclusion criteria).  If re-screening is required, 
CAG repeat length testing does not need to be repeated and the screening MRI and viral serology from the initial screening may be acceptable 
as part of the re-screening assessments, if performed within 12 weeks of the baseline visit.  
b Patients who complete the treatment period will return to the clinic for a treatment completion visit at Week 101 (i.e., the EoT visit).  All patients 
who discontinue study treatment prematurely but do not withdraw consent for continued participation in the study will return to the clinic for study 
visits at Weeks 53 and 69 (if not already completed) and at Week 101 (i.e., the EoT for ETT visit) for collection of at least the data for the primary 
and secondary endpoints (see Sections 2.1.1, 2.1.2, and 2.2).  If the ETT visit falls within 30 days of either scheduled visits at Week 53 or 
Week 69, then only ETT will be considered.  The ETT visit should be performed 28 days (3 days) after the last dose.  Patients will also attend 
the scheduled EoT for ETT visit at Week 101 for limited assessments including the collection of the primary and secondary endpoints (see 
Sections 2.1.1, 2.1.2, and 2.2).  Study visits should be planned as per the study schedule, however under exceptional circumstances, time 
window of 3 days can be utilized. 
c Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
d Medical history, including clinically significant diseases, surgeries, HD history (including past hospitalizations [i.e., number, duration, and reason]), 
over the last 2 years, reproductive status, smoking history, and use of alcohol and drugs of abuse will be recorded at baseline.
e Assessments may take place on Day 1 or Day 1.
f
Viral serology: HBsAg and HCV antibody
g Thyroid panel:  thyroid-stimulating hormone and free thyroxine (also known as T4) levels. 
h Vital signs include respiratory rate, pulse, temperature, and systolic and diastolic blood pressure while the patient is in a seated position after 
resting for approximately 5 minutes.  Record abnormalities observed at baseline (Day -1 or Day 1) on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
A complete physical examination, performed at screening and other specified visits, should include an evaluation of the head, eyes, ears, nose, 
and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems (including fundoscopy); 
genitourinary examinations may be performed if clinically indicated.   The physical examinations should be conducted in the same manner on 
each occasion to ensure comparability to previous examinations. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as 
adverse events on the Adverse Event eCRF.  Height will be measured at baseline only.

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
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j
A neurologic examination, performed at screening and at every clinical visit, should include assessment of mental status, level of consciousness, 
cranial nerve function, motor function, sensory function, reflexes, and coordination.  The neurologic examinations should be conducted in the 
same manner on each occasion to ensure comparability to previous examinations. Neurologic examinations should be performed before and 
after treatment on each dosing day.  Weight should also be measured at each visit. 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 patient notes.  New or 
worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as adverse 
events on the Adverse Event eCRF.  
k Triplicate ECG are to be performed after the patient has been in a supine position for approximately 10 minutes.  ECGs for each patient should 
be obtained from the same machine whenever possible.  At screening, baseline (Day 1 or Day 1) and other visits, pre-dose ECG should be 
performed prior to any blood draws and where applicable before the lumbar puncture.  
l
Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, basophils,
monocytes, lymphocytes).
m Serum chemistry panel:  includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, uric acid, 
gamma-glutamyl transferase, and CPK.
n All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts,
crystals, epithelial cells, bacteria).
p At the Week 37 visit, PK samples will be collected prior to dosing and at 1, 2, and 4 hours post-dose.  All patients will remain in clinic at least 
4 hours after lumbar puncture.
q At Weeks 13, 37, and 69 and at the EoT visit, the MRI should be scheduled to occur before the lumbar puncture.  It can be scheduled in the days 
prior to the lumbar puncture (provided it occurs within the visit window).  After patient enrollment, the MRI scan should be performed 714 days 
prior to the lumbar puncture to allow time for re-scanning if the quality of the initial MRI is inadequate. MRI should take place as early as 
possible within the screening window but may take place at any time during screening.  Results must be available before the patient can be 
enrolled in the study.
r
The C-SSRS will be used to assess eligibility for the study (full version at baseline, requiring approximately 20 minutes to administer) and to 
monitor the patients throughout the study at clinic visits (follow-up version, requiring approximately 5 minutes to administer, assuming absence of 
suicidal ideation and no change in clinical status from previous administration).
s The cUHDRS is a composite motor, cognitive, and global functional clinical outcome measure in patients with HD comprised of the TFC, the 
TMS, the SDMT, and the SWR scores.
t
The electronic devices for remote data collection will be supplied to patients at screening and must be returned to the clinic in cases where the 
patient does not meet eligibility criteria, at the end of the study, or upon early termination from the study.  

Appendix 9: Schedule of Assessments for Patients Enrolled before Implementation of Protocol Version 4 (cont.)
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u
Optional exit interviews will be conducted within approximately 1 week after the EoT visit; these interviews can be conducted by telephone.
v Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients at participating sites who have 
provided written informed consent to participate.
w At the time of each study drug administration, an interval medical history should be obtained and any changes in medications, any major 
procedures or hospitalizations, and any physician visits for HD or general medical care should be recorded.
x Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR, aPTT, PT) and platelets must be 
conducted and the results reviewed.  Collection for these local laboratory tests may occur at any time in the 72 hours prior to the lumbar 
puncture.  The lumbar puncture should be performed at approximately the same time at each visit (ideally in the morning between 8:00 a.m. and 
12:00 noon or in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters.  CSF fluid 
(20 mL) is to be collected for analyses using a lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a minimum 
of 5 mL should be collected over a maximum of 60 minutes.  If only 5 mL is collected after 60 minutes, the operator must confirm CSF flow is 
present prior to injecting drug at 60 minutes.  A 24G Whitacre (atraumatic) needle should be used.  Depending on institutional guidelines, local 
anesthesia should be used for the procedure.  Sedation may not be used.  Spinal ultrasound may be used for the lumbar puncture procedure if 
deemed necessary, but is not required.  Ultrasound guidance may be used if attempts at lumbar puncture without imaging are unsuccessful, if it 
is local practice to use ultrasound, or if institutional guidelines dictate use of ultrasound with each lumbar puncture.  Patients will be discouraged 
from resting supine after the lumbar puncture procedure and will be encouraged to mobilize immediately by walking around at a minimum and, if 
feasible, walking briskly.
y The last CSF sample will be obtained at the Week 101 EoT visit, but no study drug will be administered.
z Patients in Q8W arm will receive placebo at these visits.
aa Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from screening to the study completion/discontinuation visit.
bb After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 5 months after the final dose of study drug.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior study drug treatment.  
cc The DCL will be assessed at screening only (i.e., without the full TMS assessment).  The TMS scale will be assessed (excluding the DCL) at all 
other timepoints.
dd Excluding MRIs, which have a visit window of 14 days.

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Appendix 10 Clinician-Reported Outcomes for Patients Enrolled before Implementation of 
Protocol Version 4
Assessment
Name
Items
Concepts
Approx. 
Duration
Timing
FA
UHDRS Functional 
Assessment
25
Daily function
15 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
IS
Independence Scale
1
Functional disability
3 min
Screening, baseline, and Weeks 5, 
21, 37, 53, 69, 85, and 101 and 
ETT visits
TFC
Total Functional 
Capacity Scale
5
Overall function
10 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
TMS
Total Motor Score
31
Motor function
15 min
DCL only: Screening
TMS without DCL: Baseline and 
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits
C-SSRS
Columbia-Suicide 
Severity Scale
5
Suicidal ideation 
and behavior
20 min full 
version; 
5 min follow-up 
version
Full version at screening in clinic; 
follow-up version at baseline and all 
post-baseline clinic visits 
CGI-S
Clinical Global 
Impression
Severity
1
Overall severity of 
patient status
2 min
Baseline and Weeks 5, 21, 37, 53, 
69, 85, and 101 and ETT visits
CGI-C
Clinical Global 
Impression
Change
1
Overall change in 
patient status
2 min
Weeks 5, 21, 37, 53, 69, 85, and 
101 and ETT visits 
HD-DAS
Huntington's 
Disease Daily 
Activities Scale 
25
Daily function
25 min
Screening and Weeks 13, 29, 45, 
61, 77, and 93
DCLdiagnostic confidence level.

Appendix 11: Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4 (cont.)
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Assessment
Name
Item
s
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
HD-SDI
Huntington's 
DiseaseSpeaking 
Difficulty Item 
1
Speech
1
PRO
Weekly
Roche HD 
mobile app
HD-CIAOS
Huntington's 
DiseaseCompanion
-Reported Irritability
and Angry Outbursts 
Scale
3
Irritability and angry 
outbursts
2
ObsRO
Weekly
Electronic 
device
HUI
Health Utilities Index
15
Health-related quality of 
life
10
ObsRO
Baseline, Weeks 5, 21, 37, 
53, 69, 85, and 101 and ETT
In-clinic
Weekly
Electronic 
device
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10
PerfO
Screening, baseline, 
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT
In-clinic
Neuro-Qol 
Cog Func
Neuro-Qol Cognitive 
Function Short Form
8
Cognition
5
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 
In-clinic
PGI-C
Patient Global 
ImpressionChange
1
Overall change in 
patient status
2
PRO
Weeks 5, 21, 37, 53, 69, 85, 
and 101 and ETT visits
In-clinic
PGI-S
Patient Global 
ImpressionSeverity
1
Overall severity of 
patient status
2
PRO
Baseline and Weeks 5, 21, 
37, 53, 69, 85, and 101 and 
ETT
In-clinic

Appendix 11: Patient-Reported, Observer-Reported, and Performance Outcomes and Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4 (cont.)
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Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, 
Behavior
Timing
Location
SDMT/
eSDMT
Symbol Digit 
Modalities Test
Max 
number in 
90 seconds
Cognitive
5
PerfO
SDMT at baseline and 
Weeks 5, 21, 37, 53, 61 69, 
85, and 101 and ETT visits 
In-clinic
eSDMT at screening, 
baseline, and 
Week 101 in last block 
post-SDMT assessment
Roche HD 
mobile app 
(eSDMT)
SMDDS
Symptoms of Major 
Depressive 
Disorder Scale
16
Depression, anxiety, 
irritability, sleep
10
PRO
Baseline and Weeks 13, 
29, 45, 61, 77, 93, and 101 
In-clinic
SWR/eSWR
Stroop Word 
Reading Test
Max 
numbers in 
45 seconds
Cognitive
5
PerfO
SWR at baseline and 
Weeks 5, 21, 37, 53, 61 69, 
85, and 101 and ETT visits
In-clinic
eSWR at screening, 
baseline, and Week 101 in 
last block post-SWR 
assessment
Roche HD 
mobile app 
(eSWR)
WPAI
Work Productivity 
and Activity 
Impairment
6
Work productivity
5
PROObsRO
Monthly 
Roche HD 
mobile app 
and electronic 
device
appapplication; ETT early treatment termination; HD Huntington disease; ObsRO observer-reported outcome; PerfO performance outcome; 
PROpatient-reported outcome.

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Appendix 12 Clinical Assessments Order and Duration for 
Patients Enrolled before Implementation of Protocol Version 4
Table 1
Screening Visit Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Diagnostic Confidence Level
Huntington's Disease Daily Activities Scale
Independence Scale
MoCA
C-SSRS
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Roche HD mobile application
~20
Qualified 
study 
personnel
C-SSRColumbia-Suicide Severity Rating Scale; HDHuntington disease; MoCA Montreal
Cognitive Assessment.

Appendix 12: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
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Table 2
Baseline and Week 101 Clinical Assessments (for Primary 
Analysis)
Block
Assessments
Total 
Duration 
(minutes)
Site Staff Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic 
Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
(post-baseline visits only)
~60
Qualified study physician
Break (if needed)
~2030
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified study 
personnel
Break (if needed)
~10
3 a
Apathy Evaluation Scale (patient and 
companion)
Symptoms of Major Depressive Disorder 
Scale
~20
Qualified study 
personnel
Break (if needed)
~1020
4 a
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level 
Questionnaire (patient and companion)
Health Utilities Index (companion: self and 
proxy)
Patient/Companion-reported Global 
ImpressionSeverity
Patient/Companion-reported Global 
ImpressionChange (post-baseline visits 
only)
~20
Qualified study 
personnel
Break (if needed)
~1020
5 a
Roche HD mobile application
~20
Qualified study 
personnel
HDHuntington disease; MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in 
Neurological Disorders; UHDRSUnified Huntington's Disease Rating Scale.
a At the baseline visit and at week 101, Blocks 3, 4, and 5 can be completed on the same day 
after Blocks 1 and 2, or on the following day, but must be completed predose at the baseline 
visit.  

Appendix 12: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
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Table 3
Follow-Up Clinical Assessments at Weeks 5, 21, 37, 53, 69, 
and 85
Block
Assessments
Total 
Duration 
(minutes)
Site Staff 
Responsible
1
UHDRS Functional Assessment 
Independence Scale
Total Functional Capacity Scale 
Total Motor Score (without Diagnostic Confidence Level)
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity 
Clinical Global ImpressionChange 
~60
Qualified 
study 
physician
Break (if needed)
~20-30
2
Symbol Digit Modalities Test
Stroop Word Reading Test
MoCA
~20
Qualified 
study 
personnel
Break (if needed)
~10
3
Neuro-Qol Cognition Function Short Form
EuroQol 5-Dimension, 5-Level Questionnaire (patient 
and companion)
Health Utilities Index (companion: self and proxy)
Patient/Companion-reported Global ImpressionSeverity
Patient/Companion-reported Global ImpressionChange 
~30
Qualified 
study 
personnel
MoCAMontreal Cognitive Assessment; Neuro-QoLQuality of Life in Neurological Disorders; 
UHDRSUnified Huntington's Disease Rating Scale
Table 4
Follow-Up Clinical Assessments at Weeks 13, 29, 45, 61, 77, 
and 93
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1 a
Apathy Evaluation Scale (patient and companion)
Symptoms of Major Depressive Disorder Scale
~20
Qualified 
study 
personnel
Break (if needed)
~10
2
Huntington's Disease-Daily Activities Scale
~25
Qualified 
study 
physician
a To be completed prior to safety assessments.

Appendix 12: Clinical Assessments Order and Duration for Patients Enrolled before 
Implementation of Protocol Version 4 (cont.)
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Table 5
Digital Monitoring Platform Assessment Supervised by Study 
Staff in Clinic at Weeks 25, 49, 73
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Roche HD mobile application
~20
Qualified 
study 
personnel
HDHuntington disease.

Appendix 13 Roche HD Mobile Application for Patients 
Enrolled before Implementation of Protocol Version 4:  Active 
Test
The following tasks are part of the "active tests" conducted on the Roche Huntington's Disease 
(HD) mobile application by the patient. 
Daily Questions
Two daily single-item questions on mood and physical energy will be assessed, asking patients 
about their mood and physical health at the time they are performing the “Active” tests. The 
assessments aim to capture daily mood fluctuations and will be used as a control for the other 
motor and cognitive assessments. 
Cognitive Test (eSDMT)
The Cognitive Test asks participants to match symbols with numbers according to a key as 
quickly and accurately as possible.  The key, symbols, numbers are all displayed on a 
smartphone screen.  The test assesses visuo-motor integration, and measures visual attention 
and motor speed.  It is modelled on the pen and paper Symbol Digit Modalities Test (SDMT) 
(Smith, 1968).  The SDMT has been shown to be sensitive to symptom changes in early HD 
patients (Tabrizi 2012) and is part of the Unified Huntington's Disease Rating Scale (UHDRS) 
assessment (Huntington’s Study Group, 1996).
Word Reading Test (eSWR)
The Word Reading Test asks participants to read aloud color words written in black font on a 
smartphone screen. Their voice will be recorded.  The test assesses cognitive processing speed, 
and is modelled on the Stroop Word Reading (SWR) (Ridley 1935).  The "Word Reading" part of 
the SWR Test has been shown to be sensitive to symptom changes in patients with early HD 
(Tabrizi 2012) and is part of the UHDRS assessment (Huntington’s Study Group 1996). 
Speeded Tapping Test
The Speeded Tapping Test asks participants to tap the smartphone screen as fast and regularly 
as possible, using the index finger of both the left and right hands.  The test assesses 
bradykinesia. Performance will also be impacted by chorea and dystonia.  It is modelled on 
tapping tests shown to be sensitive to symptom changes in early HD (Bechtel et al. 2010; Tabrizi 
et al. 2012). A similar finger tapping task is also included as part of the UHDRS assessment 
(Huntington’s Study Group 1996).
Draw a Shape Test
The Draw a Shape Test asks participants to trace a series of increasingly complex shapes on the 
smartphone screen. The shapes include lines, a square, a circle, an eight, and a spiral.  This test 
is designed to assess visuomotor coordination and fine motor impairment in early HD patients.  It 
is modelled on circle tracing tasks that have been shown to be sensitive to symptom changes in 
early HD (Say et al. 2011; Tabrizi et al. 2013). 
Chorea Test
The Chorea Test asks participants to hold the smartphone still in their hand with their arm 
outstretched, and wear the wrist-worn wearable.  As a dual task, participants will also need to 
count backwards aloud.  To ensure correct execution, voice will be recorded.  The test is 
designed to assess chorea.  It draws on other sensor-based approaches to measure chorea 
(Reilmann et al. 2010, 2011; Kegelmeyer et al. 2017). A chorea assessment is also part of the 
UHDRS (Huntington’s Study Group 1996). 
RO7234292F. Hoffmann-La Roche Ltd
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Appendix 13: Roche HD Mobile Application for Patients Enrolled before 
Implementation of Protocol Version 4: Active Test (cont.)
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Balance Test
The Balance Test asks participants to stand still while wearing the smartphone and wrist-worn 
wearable.  It is an assessment for patients’ static balance function.  Sensor-based approaches for 
measuring static balance have been shown to be sensitive to differences in symptoms in early 
HD (Dalton et al. 2013).  The test is also part of established scales like the Berg Balance Scale 
(Berg et al. 1992), which are used in HD (Busse et al. 2009; Rao et al. 2009).  The test is 
anchored to the UHDRS assessments for maximal dystonia, maximal chorea, and tandem 
walking (Huntington Study Group 1996).
U-Turn Test
The U-Turn Test asks participants to walk and turn safely between two points that are at least
four steps apart, while wearing the smartphone and wrist-worn wearable.  They need to make at
least five turns.  The test is designed to assess gait and lower-body bradykinesia, which are also
assessed by the UHDRS.  It is modelled on the Timed Up and Go Test, which has been clinically
validated for the HD population (Busse et al. 2009; Rao et al. 2009).  The test is anchored to the
UHDRS gait, bradykinesia body, and tandem walking items (Huntington Study Group 1996).
Walk Test
The Walk Test asks participants walk as fast as is safely possible for 200 meters or 2 minutes 
every day.  Ideally, the test is done in a straight path with no obstacles (e.g., in a park).  
Sensor-based approaches for measuring gait have been shown to be sensitive to differences in 
symptoms in early HD (Dalton et al. 2013).  The test is anchored to the UHDRS gait, bradykinesia 
body, and tandem walking items (Huntington Study Group 1996).
Tasks are automatically scheduled as shown below in Figure 1 and take no more than 5 minutes 
per day.  If the patient does not complete the active test on a certain day, scheduled tasks that 
occur less frequently than every second day (i.e., EuroQol 5-Dimension, 5 Level Questionnaire, 
Work Productivity and Activity Impairment, Huntington's Disease Speaking Difficulty Item, 
2-Minute Walk Test) are rolled over to the next time the active test is completed.
References
Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest 
and symptomatic Huntington disease. Neurology 2010;75:215060.
Berg KO, Wood-Dauphinee SL, Williams JI, et al. Measuring balance in the elderly: validation of 
an instrument. Can J Public Health 1992;83(Suppl 2):S711.
Busse ME, Wiles CM, Rosser AE. Mobility and falls in people with Huntington's disease. J Neurol 
Neurosurg Psychiatry 2009;80:8890.
Dalton A, Khalil H, Busse M, et al. Analysis of gait and balance through a single triaxial 
accelerometer in presymptomatic and symptomatic Huntington’s disease. Gait Posture 
2013;37:4954.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.Kegelmeyer et al. 2017
Rao AK, Muratori L, Louis ED, et al. Clinical measurement of mobility and balance impairments in 
Huntington's disease: validity and responsiveness. Gait Posture 2009;29:4336.

Appendix 13: Roche HD Mobile Application for Patients Enrolled before 
Implementation of Protocol Version 4: Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
161/Protocol BN40423, Version 4
Reilmann R, Bohlen S, Kirsten F, et al. Assessment of involuntary choreatic movements in 
Huntington's disease—toward objective and quantitative measures. Mov Disord 
2011;26:226773.
Reilmann R, Bohlen S, Klopstock T, et al. Grasping premanifest Huntington's disease - shaping 
new endpoints for new trials. Mov Disord 2010;25:285862.
Say MJ, Jones R, Scahill R, et al. Visuomotor integration deficits precede clinical onset in 
Huntington's disease. Neuropsychologia 2011;49:26470.
Smith A. The symbol-digit modalites test: a neuropsychologic test of learning and other cerebral 
disorders. In: Helmuth J, editor. Learning disorders. Seattle: Special Child Publications; 
1968:83–91.
Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:64362.
Tabrizi SJ, Reilmann R, Roos RAC, et al. Potential endpoints for clinical trials in premanifest and 
early Huntington's disease in the TRACK-HD study: analysis of 24 month observational 
data. The Lancet Neurology 2012;11.1:4253.
Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in 
premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-
month observational data. Lancet Neurol 2013;12:63749.