Clinical trial NCT03842969
Conditions: Huntington Disease
Sponsor: Hoffmann-La Roche
Start date: 2019-04-23; Completion date: 2022-03-30
Enrollment: 236 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the long-term safety and tolerability of RO7234292 (RG6042) in participants who have completed other F. Hoffmann-La Roche, Ltd.-sponsored and/or Genentech-sponsored studies in the Huntington's disease (HD) in the development program for RG6042.

Detailed description:
Entry into the study should occur at the time the participant completes participation in one of the preceding studies. Upon completion of the inclusion visit, eligible participants will receive either RO7234292 (RG6042) every 8 weeks (Q8W) or RO7234292 (RG6042) every 16 weeks (Q16W) by the bolus intrathecal injection.

Arms: arm 1: Participants who received open-label RO7234292 Q4W in a preceding study or who received RO7234292 Q4W in this study may be randomly allocated to receive RO7234292 Q8W. Participants who previously received open-label of RO7234292 Q8W in a preceding study or are currently receiving RO7234292 Q8W in this study will receive RO7234292 Q8W. Participants who previously received placebo, or did not previously receive treatment with RO7234292 or received short-term treatment with a treatment-free follow-up period may be randomly allocated to receive RO7234292 Q8W. Participants who previously received blinded placebo Q8W may receive RO7234292 Q8W. Participants who received blinded RO7234292 Q8W will receive open-label RO7234929 Q8W. Participants who received blinded placebo Q8W may receive RO7234292 Q8W. Participants who received blinded RO7234292 Q4W or blinded placebo Q4W may be randomly allocated to receive open-label of RO7234292 Q8W. arm 2: Participants who previously received open-label RO7234292 Q4W in a preceding study or who received RO7234292 Q4W in this study may be randomly allocated to receive RO7234292 Q16W. Participants who previously received placebo in a preceding study or did not previously receive treatment with RO7234292 or received short-term treatment with a treatment-free follow-up period may be randomly allocated to receive RO7234292 Q16W. Participants who previously received blinded placebo Q8W will receive RO7234292 Q8W. Participants who previously received blinded RO7234292 Q16W will receive open-label RO7234292 Q16W. Participants who received blinded RO7234292 Q4W or blinded placebo Q4W may be randomly allocated to receive open-label of RO7234292 Q16W. Participants who previously received open-label RO7234292 Q16W will receive open-label RO7234292 Q16W.
Interventions: intervention 1: RO7234292 (RG6042)
Intervention descriptions: intervention 1: Intrathecal injection

Protocol documents:
Prot_SAP_000.pdf: 
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 BN40955, Version 7
PROTOCOL
TITLE:
AN OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND 
TOLERABILITY OF INTRATHECALLY 
ADMINISTERED RO7234292 (RG6042) IN 
PATIENTS WITH HUNTINGTON’S DISEASE
PROTOCOL NUMBER:
BN40955
VERSION NUMBER:
7
EUDRACT NUMBER:
2018-003898-94
NCT NUMBER
NCT03842969
IND NUMBER:
137873
TEST PRODUCT:
Tominersen (RO7234292)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below
 
02-Apr-2021 18:15:14
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7234292F. Hoffmann-La Roche Ltd
2/Protocol BN40955, Version 7
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocol
Version
Date Final
Country
Version
Date Final
7
See electronic date 
stamp on title page
  6 a
16 March 2021 



5
3 September 2020



4
13 February 2020



3
16 April 2019



1
20 November 2018
Germany
2
14 February 2019
a Version 6 was finalized but not distributed to sites or Health Authorities and is superseded by 
Version 7.


RO7234292F. Hoffmann-La Roche Ltd
3/Protocol BN40955, Version 7
PROTOCOL AMENDMENT, VERSION 7:
RATIONALE
Protocol BN40955 has been amended to pause study treatments based on sponsor 
decision.  The GENERATION HD1 phase III study, 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 Q8W and Q16W and placebo) in Study BN40423 be permanently 
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 until study completion as per protocol, 
without study drug administration. Study BN40955 (open-label extension [OLE]) is 
exploring the same dosing 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 effective 22 March 2021 study treatment will 
be paused. Patients already on the study will continue to be followed for safety and 
efficacy outcomes until study completion  (Sections 1.3, 3.1.1, 3.3.1, and 4.5, and 
Appendices 1a, 1b, and 2a ).

It has been clarified that neurologic examinations should continue to be performed 
at each clinic visit and before the lumbar puncture, if there is no study treatment 
administration (Section 4.5.3 and Appendices 1a, 1b, and 12).

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,  
Appendix 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.

Plasma and cerebral spinal fluid (CSF) sample collection for pharmacokinetics (PK) 
analysis has been stopped (Appendices 1a and 1b).

Plasma samples for immunogenicity analysis will continue to be collected while 
study treatment is paused (Appendix 1a).


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4/Protocol BN40955, Version 7

The schedules of activities have been modified to indicate the pause in study 
treatment administration and to clarify the frequency of safety and biomarker 
assessments (Appendices 1a,  1b , 2b, 3, 4, and 7)
–
Neurological examinations, C-SSRS, EQ-5D-5L will continue to be performed 
as per the original schedule
–
In order to reduce patient burden and continue to monitor safety, the LP will be 
performed every 16 weeks for both treatment arms. CSF (for safety and 
biomarkers), and local PT and/or INR, aPTT and platelet count will continue to 
be collected at every LP visit


RO7234292F. Hoffmann-La Roche Ltd
5/Protocol BN40955, Version 7
TABLE OF CONTENTS
1.
BACKGROUND .......................................................................................... 24
1.1
Background on Huntington's Disease.................................... 24
1.2
Background on RO7234292 .................................................. 25
1.3
Study Rationale and Benefit-Risk Assessment...................... 26
2.
OBJECTIVES AND ENDPOINTS ............................................................... 28
2.1
Safety Objective .................................................................... 28
2.2
Exploratory Efficacy Objectives ............................................. 28
2.3
Exploratory Pharmacokinetic/Pharmacodynamic 
Objectives.............................................................................. 29
2.4
Exploratory Immunogenicity Objectives................................. 29
2.5
Exploratory Biomarker Objective ........................................... 29
2.6
Health Status Utility Objective ............................................... 30
3.
STUDY DESIGN......................................................................................... 30
3.1
Description of the Study......................................................... 30
3.1.1
Overview of Study Design ..................................................... 30
3.2
End of Study and Length of Study......................................... 35
3.3
Rationale for Study Design.................................................... 35
3.3.1
Rationale for RO7234292 Dose and Schedule...................... 35
3.3.2
Rationale for Biomarker Assessments................................... 38
3.3.2.1
Cerebrospinal Fluid Biomarkers ............................................ 38
3.3.2.2
Blood Biomarkers .................................................................. 38
3.3.2.3
Magnetic Resonance Imaging ............................................... 38
3.3.2.4
Safety Biomarkers ................................................................. 39
4.
MATERIALS AND METHODS .................................................................... 39
4.1
Patients.................................................................................. 39
4.1.1
Inclusion Criteria.................................................................... 39
4.1.2
Exclusion Criteria................................................................... 41
4.2
Method of Treatment Assignment and Blinding..................... 43
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 44


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4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 44
4.3.1.1
RO7234292 ........................................................................... 44
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 44
4.3.2.1
RO7234292 ........................................................................... 44
4.3.3
Investigational Medicinal Product Accountability ................... 44
4.3.4
Continued Access to RO7234292 ......................................... 45
4.4
Concomitant Therapy ............................................................ 45
4.4.1
Permitted Therapy................................................................. 46
4.4.2
Prohibited Therapy ................................................................ 46
4.5
Study Assessments ............................................................... 46
4.5.1
Informed Consent Forms and Screening Log........................ 47
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 47
4.5.3
Physical and Neurologic Examinations.................................. 48
4.5.4
Vital Signs.............................................................................. 48
4.5.5
Collection of Cerebrospinal Fluid (Lumbar 
Puncture Procedure) ............................................................. 48
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 50
4.5.7
Magnetic Resonance Imaging ............................................... 51
4.5.8
Optional Magnetic Resonance Imaging of Brain 
and Spine with Contrast in Patients from 
Study BN40697 ..................................................................... 52
4.5.9
Electrocardiograms................................................................ 52
4.5.10
Patient-Reported, Clinician-Reported, and 
Performance Outcomes......................................................... 53
4.5.10.1
Composite Unified Huntington's Disease Rating 
Scale...................................................................................... 54
4.5.10.2
Total Functional Capacity Scale ............................................ 54
4.5.10.3
Total Motor Score.................................................................. 54
4.5.10.4
Symbol Digit Modalities Test ................................................. 54
4.5.10.5
Stroop Word Reading Test .................................................... 55
4.5.10.6
Independence Scale.............................................................. 55
4.5.10.7
Huntington's Disease Daily Activities Scale........................... 55


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4.5.10.8
Clinical Global ImpressionSeverity and Change 
Scales.................................................................................... 55
4.5.10.9
Montreal Cognitive Assessment ............................................ 56
4.5.10.10
Columbia-Suicide Severity Rating Scale ............................... 56
4.5.10.11
EuroQol 5-Dimension, 5-Level Questionnaire ....................... 56
4.5.10.12
Roche HD Mobile Application:  Remote Testing 
(Smartphone and Wrist-Worn Wearable)............................... 56
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 58
4.6.1
Study Treatment Discontinuation........................................... 58
4.6.2
Patient Discontinuation from Study........................................ 58
4.6.3
Study Discontinuation............................................................ 59
4.6.4
Site Discontinuation............................................................... 59
5.
ASSESSMENT OF SAFETY....................................................................... 59
5.1
Safety Plan ............................................................................ 59
5.1.1
Known Risks Associated with Lumbar Puncture.................... 60
5.1.1.1
PostLumbar Puncture Syndrome......................................... 61
5.1.1.2
Spinal Hematoma.................................................................. 62
5.1.1.3
Meningitis .............................................................................. 62
5.1.2
Potential Risks Associated with RO7234292......................... 62
5.1.2.1
Neurologic Changes .............................................................. 62
5.1.2.2
Elevations in CSF WBCs and Protein.................................... 63
5.1.2.3
Thrombocytopenia................................................................. 64
5.1.2.4
Kidney Effects........................................................................ 64
5.1.2.5
Liver Effects........................................................................... 64
5.1.2.6
Hydrocephalus....................................................................... 65
5.1.2.7
Neuropsychiatric Changes..................................................... 65
5.1.2.8
Potential Risk due to Reduction of Target Protein 
HTT........................................................................................ 65
5.1.3
Management of Patients who Experience 
Adverse Events ..................................................................... 66
5.1.3.1
Dose Modifications ................................................................ 66
5.1.3.2
Treatment Interruption ........................................................... 66
5.1.3.3
Management Guidelines........................................................ 67


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8/Protocol BN40955, Version 7
5.2
Safety Parameters and Definitions ........................................ 70
5.2.1
Adverse Events ..................................................................... 71
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 71
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 72
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 72
5.3.1
Adverse Event Reporting Period ........................................... 72
5.3.2
Eliciting Adverse Event Information....................................... 73
5.3.3
Assessment of Severity of Adverse Events ........................... 73
5.3.4
Assessment of Causality of Adverse Events ......................... 73
5.3.5
Procedures for Recording Adverse Events............................ 74
5.3.5.1
Injection Reactions ................................................................ 74
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 74
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 75
5.3.5.4
Persistent or Recurrent Adverse Events................................ 75
5.3.5.5
Abnormal Laboratory Values ................................................. 75
5.3.5.6
Abnormal Vital Sign Values ................................................... 76
5.3.5.7
Abnormal Liver Function Tests.............................................. 77
5.3.5.8
Deaths ................................................................................... 77
5.3.5.9
Preexisting Medical Conditions.............................................. 77
5.3.5.10
Lack of Efficacy or Worsening of Huntington's 
Disease.................................................................................. 78
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 78
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 78
5.3.5.13
Patient-Reported Outcome Data ........................................... 79
5.3.5.14
Safety Biomarker Data........................................................... 79
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 80
5.4.1
Emergency Medical Contacts................................................ 80
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 81


RO7234292F. Hoffmann-La Roche Ltd
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5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 81
5.4.2.2
Events That Occur after Study Drug Initiation........................ 81
5.4.3
Reporting Requirements for Pregnancies.............................. 81
5.4.3.1
Pregnancies in Female Patients............................................ 81
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 82
5.4.3.3
Abortions ............................................................................... 82
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 82
5.5
Follow-Up of Patients after Adverse Events .......................... 82
5.5.1
Investigator Follow-Up........................................................... 82
5.5.2
Sponsor Follow-Up ................................................................ 83
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 83
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 83
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 83
6.1
Analysis Populations ............................................................. 83
6.2
Determination of Sample Size ............................................... 84
6.3
Summaries of Conduct of Study............................................ 84
6.4
Summaries of Treatment Group Comparability ..................... 84
6.5
Safety Analyses..................................................................... 84
6.6
Exploratory Efficacy Analyses ............................................... 85
6.7
Exploratory Pharmacokinetic Analyses.................................. 85
6.8
Exploratory Immunogenicity Analyses................................... 85
6.9
Exploratory Biomarker Analyses............................................ 86
6.10
Health Status Utility Analysis................................................. 86
6.11
Optional Interim Analyses...................................................... 86
7.
DATA COLLECTION AND MANAGEMENT ............................................... 86
7.1
Data Quality Assurance......................................................... 86
7.2
Electronic Case Report Forms............................................... 87
7.3
Electronic Patient-Reported, Clinician-Reported, 
and Performance Outcome Data........................................... 87
7.4
Electronic Data Obtained by the Roche HD 
Digital Mobile Application....................................................... 87


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7.5
Source Data Documentation.................................................. 88
7.6
Use of Computerized Systems .............................................. 88
7.7
Retention of Records............................................................. 89
8.
ETHICAL CONSIDERATIONS.................................................................... 89
8.1
Compliance with Laws and Regulations ................................ 89
8.2
Informed Consent.................................................................. 89
8.3
Institutional Review Board or Ethics Committee.................... 91
8.4
Confidentiality........................................................................ 91
8.5
Financial Disclosure .............................................................. 92
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 92
9.1
Study Documentation ............................................................ 92
9.2
Protocol Deviations................................................................ 92
9.3
Management of Study Quality ............................................... 93
9.4
Site Inspections ..................................................................... 93
9.5
Administrative Structure......................................................... 93
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 93
9.7
Protocol Amendments ........................................................... 94
10. REFERENCES ........................................................................................... 95
LIST OF TABLES
Table 1
Treatment Regimen in Study BN40955 Based on Previous 
Study Treatment ......................................................................... 33
Table 2
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 68
Table 3
Adverse Event Severity Grading Scale ....................................... 73
Table 4
Causal Attribution Guidance ....................................................... 74


RO7234292F. Hoffmann-La Roche Ltd
11/Protocol BN40955, Version 7
LIST OF APPENDICES
Appendix 1a
Schedule of Activities for All Patients Except Those 
Undergoing Screening ................................................................ 98
Appendix 1b
Schedule of Activities for Patients who were Eligible for the 
GENERATION-HD1 Study but not Randomized due to 
Logistical Challenges Resulting from the COVID-19 
Pandemic.................................................................................. 106
Appendix 2a
Visit Schedule for the First 2 Years of Treatment...................... 114
Appendix 2b Visit Schedule for the First 2 Years of Study Participation 
While on Treatment Pause........................................................ 115
Appendix 3
Clinician-Reported Outcomes ................................................... 116
Appendix 4
Patient-Reported Outcomes, Performance Outcomes, and 
Roche HD Mobile Application ................................................... 117
Appendix 5
Clinical Assessments Order and Duration for Patients 
Required to Undergo Screening Only ....................................... 119
Appendix 6
Diagnostic Confidence Level for Patients Required to 
Undergo Screening Only........................................................... 120
Appendix 7
Clinical Assessments Order and Duration ................................ 121
Appendix 8
Remote Clinical Assessments Order and Duration 
(COVID-19 Impacted Sites where a Patient Cannot Attend 
the Clinic or the Investigator Site Has Closed due to 
Restrictions Imposed as a Result of COVID-19)....................... 122
Appendix 9
Roche HD Mobile Application:  Active Test............................... 123
Appendix 10
Grading Scale for Adverse Events Relating to Laboratory 
Abnormalities ............................................................................ 128
Appendix 11
List of Preceding Clinical Trials................................................. 131
Appendix 12
Guidance for Neurological Examination.................................... 132


RO7234292F. Hoffmann-La Roche Ltd
12/Protocol BN40955, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL EXTENSION STUDY TO 
EVALUATE THE LONG-TERM SAFETY AND 
TOLERABILITY OF INTRATHECALLY 
ADMINISTERED RO7234292 (RG6042) IN 
PATIENTS WITH HUNTINGTON’S DISEASE
PROTOCOL NUMBER:
BN40955
VERSION NUMBER:
7
EUDRACT NUMBER:
2018-003898-94
NCT NUMBER
NCT03842969
IND NUMBER:
137873
TEST PRODUCT:
Tominersen (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
13/Protocol BN40955, Version 7
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE 
LONG-TERM SAFETY AND TOLERABILITY OF INTRATHECALLY 
ADMINISTERED RO7234292 (RG6042) IN PATIENTS WITH 
HUNTINGTON’S DISEASE
PROTOCOL NUMBER:
BN40955
VERSION NUMBER:
7
EUDRACT NUMBER:
2018-003898-94
NCT NUMBER
NCT03842969
IND NUMBER:
137873
TEST PRODUCT:
Tominersen (RO7234292)
PHASE:
Phase III
INDICATION:
Huntington's disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the long-term safety and tolerability of RO7234292 in patients with 
Huntington's disease (HD).  In addition, the study will obtain long-term data on the efficacy, 
immunogenicity, exposure, and biomarkers of RO7234292.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Objectives will be achieved primarily by using data collected in this open-label extension (OLE) 
study, but may also be informed by using previously collected data from participants of the 
preceding Roche studies.  Data may be linked and, if appropriate, may be analyzed by pooling 
data.
Safety Objective
The safety objective for this study is to evaluate the safety and tolerability of RO7234292 on the 
basis of the following endpoints:

Incidence and severity of adverse events (AEs), with severity determined according to the 
Adverse Event Severity Grading Scale

Change from baseline in targeted vital signs

Change from baseline in physical findings

Change from baseline in neurological findings

Change from baseline in behavioral findings, as assessed by the Columbia-Suicide Severity 
Rating Scale (C-SSRS)

Change from baseline in cognition

Change from baseline in targeted ECG results

Change from baseline in targeted clinical laboratory test results

Relationship between laboratory parameter change and safety-targeted endpoints

Relationship between MRI parameter change and safety-targeted endpoints


RO7234292F. Hoffmann-La Roche Ltd
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Exploratory Efficacy Objective
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292 on the 
basis of the following endpoints:

Change from baseline in the composite Unified Huntington's Disease Rating Scale score as
assessed every 16 weeks (Q16W)

Change from baseline in scores for the following individual scales as assessed Q16W:
–
Total Functional Capacity Scale.
–
Total Motor Score.
–
Symbol Digit Modalities Test.
–
Stroop Word Reading Test.

Change from baseline in the Clinical Global Impression, Severity Scale score as assessed 
Q16W

Proportion of patients with an unchanged or improved score on the Clinical Global 
Impression, Change Scale score from baseline as assessed Q16W

Change from baseline in the Huntington's Disease Daily Activities Scale score as assessed 
Q16W

Change from baseline in the sensor-based measures collected by the Roche HD mobile 
application (smartphone and wrist-worn wearable) as assessed Q16W
Exploratory Pharmacokinetic/Pharmacodynamic Objectives
The exploratory pharmacokinetic (PK) objective for this study is to characterize the RO7234292 
PK trough plasma and trough cerebrospinal fluid (CSF) samples on the basis of the following 
endpoints:

Trough concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints
The exploratory PK/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 trough plasma and/or trough CSF concentrations of PK parameters 
for RO7234292 and efficacy endpoints

Relationship between trough plasma and/or trough CSF concentrations of PK parameters 
for RO7234292 and safety endpoints
Exploratory Immunogenicity Objective
The exploratory immunogenicity objectives for this study are as follows:

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.
–
Determination of the ADA specificity followed by assessments of the magnitude (titer) 
of the ADA response.

To evaluate potential effects of ADAs on the basis of the following endpoint:
–
Relationship between ADA status and efficacy, safety, or PK endpoints.
Exploratory Biomarkers Objective
The exploratory biomarker objective for this study is to identify biomarkers that 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 AEs or can lead to improved AE monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of RO7234292 activity (i.e., PD 


RO7234292F. Hoffmann-La Roche Ltd
15/Protocol BN40955, Version 7
biomarkers), or can increase the knowledge and understanding of disease biology and drug 
safety, on the basis of the following endpoints:

Relationship between biomarkers (e.g., tau and neurofilament light chain protein [NfL]) in 
plasma and CSF efficacy, safety, PK, immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers 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-reported EuroQol 5-Dimension, 5-Level Questionnaire 
(EQ-5D-5L) Index and Visual Analog Scale (VAS) scores at specified timepoints
Study Design
Description of Study
This OLE study will evaluate the long-term safety and tolerability of RO7234292 administered 
intrathecally (IT) to patients with HD.  In addition, the study will obtain long-term data on the 
efficacy, immunogenicity, exposure, and biomarkers of RO7234292.
Effective 22 March 2021, dosing is paused, including enrollment. Patients already on the 
study will continue to be followed for safety and efficacy outcomes until study completion.
Only patients with prior enrollment in a Roche-sponsored or Genentech-sponsored study in HD 
for the RO7234292 development program that made provision for entry into an OLE study will 
be eligible for this OLE study.  The preceding Roche-sponsored or Genentech-sponsored study 
must have been approved by the relevant national competent authority and applicable 
Institutional Review Board/Ethics Committee in a country in order for a patient from that country 
to be included in the OLE.
For patients who have participated in previous Roche studies, entry into this long-term, 
open-label extension study will occur at an inclusion visit. This inclusion visit is a combined visit 
with the preceding study's last applicable visit where patients are due for their end of treatment 
visit, last CSF collection, or safety follow-up unless otherwise specified, and serves as the 
baseline visit for the long-term, open-label extension study. For participants who have not 
participated in a previous Roche study, a separate screening visit will occur to determine 
eligibility into the long-term, open-label extension study. Patients who successfully meet 
eligibility criteria will then enter the study and attend the baseline study visit.  Patients who were 
enrolled in Study BN40423 before implementation of Version 4 of that protocol will be 
prematurely discontinued by the Sponsor from Study BN40423 and offered treatment in this 
study (Study BN40955) when it is available at sites.
If dosing at the inclusion visit is not possible, the Medical Monitor should be consulted and a 
short treatment interruption may be permitted.  For patients entering from Study BN40423 prior 
to implementation of protocol Version 4, the inclusion visit should occur at the end-of-treatment 
visit for Study BN40423.
Patients Impacted by Covid-19 during Study BN40423 Screening
Patients who were screened and eligible for the placebo-controlled Phase III Study BN40423 
(Generation-HD1) but were not randomized prior to the close of Study BN40423 enrollment due 
to logistical challenges resulting from the COVID-19 pandemic, will be offered open-label 
RO7234292 as part of this study, Study BN40955.  Participation can occur once approved and 
available at sites and so long as the patient meets Study BN40955 eligibility.  These patients 
will undergo screening assessments during a 4-week screening period.  A maximum of 1 re-
screening will be allowed within 8 weeks of an initial screening failure in Study BN40955.
The CAG repeat length testing from Q2 Solutions will be accepted for this study.  If re-screening 
is required, the CAG repeat length testing from Q2 Solutions does not need to be repeated.  
The screening MRI and viral serology from the initial screening, including from other Roche 
RO7234292 studies, may be acceptable as part of the screening assessments if performed 
within 12 weeks of the inclusion visit.


RO7234292F. Hoffmann-La Roche Ltd
16/Protocol BN40955, Version 7
For patients entering from Study BN40697, in the event of any delay in start-up activities where 
it is not possible to conduct the inclusion visit at the time of the last applicable visit in 
Study BN40697, a separate inclusion visit should be scheduled.  For patients entering from 
Study ML41885, the inclusion visit will take place at the safety follow-up visit of Study ML41885 
(i.e., SFU1).
Upon completion of the inclusion visit, eligible patients will receive either 120 mg RO7234292 
Q8W (RO7234292 Q8W arm) or 120 mg RO7234292 Q16W (RO7234292 Q16W arm) by bolus 
IT injection. Patients will be assigned to treatment groups as described below:
Preceding Study Treatment
Treatment Regimen
Open-label 120 mg RO7234292 Q4W
Randomized 1:1 to 120 mg RO7234292 Q8W 
or 120 mg RO7234292 Q16W
Open-label 120 mg RO7234292 Q8W
120 mg RO7234292 Q8W
No treatment or 4 doses of 120 mg or 
less RO7234292 with a treatment-free 
follow-up period
Randomized 1:1 to 120 mg RO7234292 Q8W 
or 120 mg RO7234292 Q16W 
Blinded placebo Q8W
Randomized 1:1 to 120 mg RO7234292 Q8W 
or 120 mg RO7234292 Q16W 
Blinded 120 mg RO7234292 Q8W
120 mg RO7234292 Q8W
Blinded 120 mg RO7234292 Q16W
120 mg RO7234292 Q16W
For Patients enrolled into Study BN40423 prior to implementation of Study BN40423 
Protocol Version 4:
Blinded 120 mg RO7234292 Q4W 
Randomized 1:1 to 120 mg RO7234292 Q8W 
or 120 mg RO7234292 Q16W
Blinded 120 mg RO7234292 Q8W 
120 mg RO7234292 Q8W
Blinded Placebo Q4W 
Randomized 1:1 to 120 mg RO7234292 Q8W 
or 120 mg RO7234292 Q16W 
Open-label 120 mg RO7234292 Q16W
120 mg RO7234292 Q16W
Q4Wevery 4 weeks; Q8Wevery 8 weeks; Q16Wevery 16 weeks.
For patients who did not previously receive treatment with RO7234292 (e.g., from a natural 
history study) or received short-term treatment (4 doses), the end of study visit for the 
preceding study will serve as the inclusion visit for Study BN40955.  For patients who completed 
the full treatment course in the preceding study, the inclusion visit for Study BN40955 will take 
place at the visit at which the last dose was administered.  For patients enrolled in 
Study BN40423 prior to implementation of Protocol Version 4 who were prematurely 
discontinued, the inclusion visit for Study BN40955 will take place at the end-of-treatment visit 
for Study BN40423.  For patients entering from Study BN40697, in the event of any delay in 
start-up activities where is not possible to conduct the inclusion visit for Study BN40955 at the 
time of last applicable visit in Study BN40697, a separate inclusion visit should be scheduled. 
At the inclusion visit for Study BN40955, clinical ratings and assessments that are common 
between the preceding study and Study BN40955 will be completed once and will serve both 
studies.  Clinical ratings and assessments required in Study BN40955 that were not completed 
as part of the preceding study will also need to be completed at the inclusion visit. Patients who 
were eligible for Study BN40423 (GENERATION-HD1) but were not randomized due to 
logistical challenges resulting from the COVID-19 pandemic will undergo screening and 
inclusion visits.


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Patients will undergo safety and tolerability evaluations that include neurologic examinations, 
vital signs, ECGs, clinical laboratory tests, Montreal Cognitive Assessment (MoCA), C-SSRS, 
neuroimaging assessments and reporting of AEs and concomitant medications. Patients 
enrolling from Study BN40697 will have an optional MRI of brain and spine with contrast media, 
in addition to the other brain neuroimaging assessments.
In case of a failed IT bolus dosing procedure (e.g., due to an inadequate establishment of 
access to the IT space), a second dosing attempt may occur up to 7 days after the originally 
scheduled dosing attempt. For this additional visit, safety and tolerability evaluations on the day 
of lumbar puncture (LP) administration will be performed as detailed in Appendix 1a and
Appendix 1b, including neurological examination (predose and postdose), vital signs, and a 
review of AEs and concomitant medication. If the second dosing attempt occurs more than 
72 hours after the last coagulation panel and platelets test, 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.
Telephone safety follow-up calls will be conducted between dosing visits to check for any 
change in patient status (i.e., AEs, concomitant medications) since last visit. Depending on the 
patient’s health status, an unscheduled clinic visit may be arranged. If a patient is due for a 
telephone safety call and they are in-clinic then this telephone safety follow-up call can be 
completed in-clinic at the site’s discretion. As a result of the COVID-19 pandemic, only where 
sites are impacted, these telephone safety calls can be conducted instead of an in-clinic visit.
Number of Patients
Up to approximately 1100 patients with HD will be enrolled in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form (ICF)
If capacity to consent is in question, formal capacity assessment by an appropriately 
qualified professional should be obtained.  In cases where capacity to consent is not 
fully present, but the participant is known previously to have favored participation in an 
open-label study and is able to assent, consent may be obtained by a legally
authorized representative.  (Note:  Patients in Germany who are not fully capable of 
providing informed consent are not eligible for inclusion).

Prior enrollment in a Rochesponsored or Genentech-sponsored study in HD for the 
RO7234292 development program that made provision for entry into an OLE study

Ability and willingness to comply with the study protocol including the visit schedule and all 
assessments, in the investigator's judgment

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 2 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.


RO7234292F. Hoffmann-La Roche Ltd
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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.
The following eligibility criteria only apply to patients who were eligible for Study BN40423 
(GENERATION-HD1) but were not randomized due to logistical challenges resulting from the 
COVID-19 pandemic.
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at the inclusion visit prior to randomization and study drug dosing):

Signed ICF

Age 2565 years, inclusive, at the time of signing the ICF 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 CAG-Age product (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 LPs

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

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to screening 
and at the time of enrollment
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Withdrawal of consent from the preceding study

Permanent discontinuation of RO7234292 for any drug-related safety concern during the 
preceding study or meeting of any study treatment discontinuation criteria specified in the 
preceding study at the time of enrollment into this study


RO7234292F. Hoffmann-La Roche Ltd
19/Protocol BN40955, Version 7

An ongoing, unresolved, clinically significant medical problem that in the judgment of the 
investigator would make it unsafe for the patient to participate in this study

Antiplatelet or anticoagulant therapy within 14 days prior to inclusion 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.

Concurrent participation in any therapeutic clinical trial (other than the preceding study)

Study treatment (RO7234292) is commercially marketed in the patient’s country for the 
patient-specific disease and is accessible to the patient

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 urine pregnancy test at the 
inclusion visit (obtained as part of the preceding study assessments).
The following exclusion criteria only apply to patients who were eligible for Study BN40423 
(GENERATION-HD1) but were not randomized due to logistical challenges resulting from the 
COVID-19 pandemic.
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 completed 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

Presence of an implanted shunt for the drainage of CSF or an implanted central nervous 
system (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 (ASO; 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


RO7234292F. Hoffmann-La Roche Ltd
20/Protocol BN40955, Version 7

Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives prior to 
screening, whichever is longer

History of gene therapy, cell transplantation, or any experimental brain surgery

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 intravenous (IV) antibiotics within 14 days prior to and during 
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, hydrocephalus, subdural haematoma) 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 a minimum of 6 months after the last patient is enrolled.
Length of Study
The total length of the study, from enrollment of the first patient to the end of the study, is 
expected to be approximately 6 years.  It is expected that patients may participate for a 
minimum of 6 months and a maximum of approximately 6 years in Study BN40955.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is RO7234292.
Statistical Methods
Primary Analysis
The safety analysis population will consist of all randomized patients who received at least one 
dose of study drug, with patients grouped according to treatment received.
All verbatim AE terms will be mapped to Medical Dictionary of Regulatory Activities (MedDRA)
thesaurus terms.  The Adverse Event Severity Grading Scale will be used for assessing 
AE severity.  Laboratory values determined as an AE should be graded as detailed in the 
protocol and based on the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v5.0.
All safety data, including AEs, laboratory tests, neurologic examination, C-SSRS, 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 AEs will be summarized on the basis of body systems and dictionary preferred 
terms.  The incidence of AEs by severity and relationship to study drug or study procedure and 
incidence of marked abnormal laboratory test results will be provided.


RO7234292F. Hoffmann-La Roche Ltd
21/Protocol BN40955, Version 7
Determination of Sample Size
The sample size for this study is determined by the number of patients from preceding studies 
who may be eligible for enrollment in this study and is estimated to be up to approximately 
1100 patients.
Optional Interim Analyses
The Sponsor may choose to conduct one or more interim analyses including safety, PK, PD 
biomarkers and clinical endpoints as relevant.  Details of each interim analysis will be described 
in a dedicated Statistical Analysis Plan (SAP), which will be finalized before the conduct of the 
interim analysis.


RO7234292F. Hoffmann-La Roche Ltd
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
app
application
ASO
antisense oligonucleotide
CAG
cytosine, adenine, guanine
CAP
CAG-Age Product
CGI-C
Clinical Global ImpressionChange
CGI-S
Clinical Global ImpressionSeverity
ClinRO
clinician-reported outcome
CSF
cerebrospinal fluid 
C-SSRS
Columbia-Suicide Severity Rating Scale
cUHDRS
composite Unified Huntington's Disease Rating Scale
DCL
diagnostic confidence level
DIL
Dear Investigator Letter
EC
Ethics Committee
Ecrf
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
FDA
Food and Drug Administration
HA
health authority
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HD
Huntington's disease
HD-DAS
Huntington's Disease Daily Activities Scale
HDID
Huntington's Disease Identification Number
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
HTT
huntingtin (gene)
HTT
huntingtin (protein)
ICF
Informed Consent Form
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board


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23/Protocol BN40955, Version 7
Abbreviation
Definition
IS
Independence Scale
IT
intrathecal
ITT
intent-to-treat (population)
IxRS
interactive voice or web-based response system
LP
lumbar puncture
MAD
multiple ascending dose
mHTT
mutant huntingtin (protein)
MoCA
Montreal Cognitive Assessment
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NfL
neurofilament light chain (protein)
OLE
open-label extension
PD
pharmacodynamic
PerfO
performance outcome
PK
pharmacokinetic
PRO
patient-reported outcome
Q4W
every 4 weeks
Q8W
every 8 weeks
Q16W
every 16 weeks
QTc
corrected QT interval
SAE
serious adverse event
SAP
Statistical Analysis Plan
SDMT
Symbol Digit Modalities Test
SWR
Stroop Word Reading
TFC
Total Functional Capacity Scale
TMS
Total Motor Score
UHDRS
Unified Huntington's Disease Rating Scale
USM
Urgent Safety Measure
VAS
Visual Analog Scale
WPAI
Work Productivity and Activity impairment
wtHTT
wild-type huntingtin (protein)


RO7234292F. Hoffmann-La Roche Ltd
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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 cytosine, adenine, and guanine (CAG) repeats in exon 1 of the 
Huntingtin gene (HTT) 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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).
The manifest disease period can be subdivided into 5 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.  
Stage 5 represents severe disability and dependence on full-time care 
(Shoulson and Fahn 1979).  The 5 clinical stages are defined by the score on the 
Unified Huntington's Disease Rating Scale (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 and Fahn 1979).
To date, there are no approved treatments able to slow or stop the clinical progression 
of HD.  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 (AEs), 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.


RO7234292F. Hoffmann-La Roche Ltd
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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).
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 ISIS 443139 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 (Cerritelli and Crouch 2009; Crooke and Bennett 1996), including 
cells of interest in the CNS (e.g., neurons and neuroglia).  Reduction of the HTT gene 
mRNA could potentially inhibit downstream toxic effects of mHTT and lead to a
sustained reversal in HD symptoms.
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, 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 (Kordasiewiecz et al. 2012; Stanek et al. 2013).
Nonclinical proof-of-concept studies with ASOs targeting 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, BACHD 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.


RO7234292F. Hoffmann-La Roche Ltd
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The pharmacokinetics (PK) 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, 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) 4 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 
IT 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 supported 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 analysis conducted when all individuals in Study BN40967 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 
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
This study is designed to assess the long-term safety and tolerability of IT administered 
RO7234292 in patients who have completed or have participated in other
F. Hoffmann-La Roche, Ltd.sponsored (hereafter referred to as Roche) and/or 
Genentech-sponsored studies in HD in the development program for RO7234292.  
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 HD.  Current planned or ongoing studies in the RO7234292 clinical 
development plan are designed for durations of up to approximately 2 years.  This study 
is designed to collect safety data in a larger number of patients and will also study the 


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27/Protocol BN40955, Version 7
benefit and potential risks of RO7234292 when administered by IT bolus injection Q8W 
or every 16 weeks (Q16W) over a longer period.
Review of preliminary 9-month safety and tolerability data for RO7234292 from the 
Phase II OLE (Study BN40697) suggested 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 AEs, decreased proportion of patients with moderate AEs, and fewer 
AEs considered possibly related to study drug in the Q8W regimen compared to the 
Q4W regimen (for details see the RO7234292 Investigator’s Brochure).
There were no acute safety concerns meriting a change to the ongoing Phase II OLE 
study protocol (Study BN40697).  However, given the 9-month CSF mHTT results, which 
suggested 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 justified a change in Study BN40955 to 
explore less frequent dosing regimens by continuing the Q8W RO7234292 arm 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 approximately 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 approximately 25% 
is predicted to be maintained in a 120 mg Q16W paradigm.
A pre-planned review of safety and efficacy data from the GENERATION HD1 phase 
III 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 permanently 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 until 
study completion as per protocol, without study drug administration. Study BN40955 
(open-label extension [OLE]) is exploring the same dosing regimens (i.e., tominersen 
[RO7234292] 120 mg Q8W and Q16W); therefore, the Sponsor made a decision to 
pause dosing in the OLE until further data assessments can be conducted.
The known potential risks associated with RO7234292 and additional risks related to 
lumbar punctures (LPs), along with mitigation measures, are elaborated in Section 5.1.


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the long-term safety and tolerability of RO7234292 in patients
with HD.  In addition, the study will obtain long-term data on the efficacy, immunogenicity, 
exposure, and biomarkers of RO7234292.  Specific objectives and corresponding 
endpoints for the study are outlined below.
Objectives will be achieved primarily by using data collected in this OLE study, but may 
also be informed by using previously collected data from participants of the preceding 
Roche studies.  Data may be linked and, if appropriate, may be analyzed by pooling data.
2.1
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of RO7234292
on the basis of the following endpoints:

Incidence and severity of AEs, with severity determined according to the Adverse 
Event Severity Grading Scale (see Table 3)

Change from baseline in targeted vital signs

Change from baseline in physical findings

Change from baseline in neurological findings

Change from baseline in behavioral findings, as assessed by the 
Columbia-Suicide Severity Rating Scale (C-SSRS)

Change from baseline in cognition

Change from baseline in targeted ECG results

Change from baseline in targeted clinical laboratory test results

Relationship between laboratory parameter change and safety-targeted endpoints

Relationship between magnetic resonance imaging (MRI) parameter change and 
safety-targeted endpoints
2.2
EXPLORATORY EFFICACY OBJECTIVES
The exploratory efficacy objective for this study is to evaluate the efficacy of RO7234292
on the basis of the following endpoints:

Change from baseline in the composite Unified Huntington's Disease Rating Scale 
(cUHDRS) score as assessed Q16W

Change from baseline in scores for the following individual scales as assessed 
Q16W:
–
Total Functional Capacity Scale.
–
Total Motor Score (TMS).
–
Symbol Digit Modalities Test (SDMT).
–
Stroop Word Reading (SWR) test.


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
Change from baseline in the Clinical Global Impression, Severity Scale (CGI-S) 
score as assessed Q16W

Proportion of patients with an unchanged or improved score on the Clinical Global 
Impression, Change Scale (CGI-C) score from baseline as assessed Q16W

Change from baseline in the Huntington's Disease Daily Activities Scale (HD-DAS) 
score as assessed Q16W

Change from baseline in the sensor-based measures collected by the Roche HD 
mobile application (app; smartphone and wrist-worn wearable) as assessed Q16W
2.3
EXPLORATORY PHARMACOKINETIC/PHARMACODYNAMIC
OBJECTIVES
The exploratory PK objective for this study is to characterize the RO7234292 PK trough 
plasma and trough CSF samples on the basis of the following endpoints:

Trough concentration of RO7234292 in plasma at specified timepoints

Trough concentration of RO7234292 in CSF at specified timepoints
The exploratory PK/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 trough plasma and/or trough CSF concentrations of 
PK parameters for RO7234292 and efficacy endpoints

Relationship between trough plasma and/or trough CSF concentrations of PK 
parameters for RO7234292 and safety endpoints
2.4
EXPLORATORY IMMUNOGENICITY OBJECTIVES
The exploratory immunogenicity objectives for this study are as follows:

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.
–
Determination of the ADA specificity followed by assessments of the 
magnitude (titer) of the ADA response.

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
EXPLORATORY BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to identify biomarkers that 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 AEs or can lead to improved AE monitoring 
or investigation (i.e., safety biomarkers), can provide evidence of RO7234292 activity 


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30/Protocol BN40955, Version 7
(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 (e.g., tau and neurofilament light chain protein 
[NfL]) in plasma and CSF (listed in Section 4.5.6) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints

Relationship between imaging biomarkers 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-reported EuroQol 5-Dimension, 5-Level 
Questionnaire (EQ-5D-5L) Index and Visual Analog Scale (VAS) scores at specified 
timepoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This OLE study will evaluate the long-term safety and tolerability of RO7234292
administered IT to patients with HD.  In addition, the study will obtain long-term data on 
the efficacy, immunogenicity, exposure, and biomarkers of RO7234292.
Effective 22 March 2021, dosing is paused, including enrollment. Patients already on 
the study will continue to be followed for safety and efficacy outcomes until study 
completion (see Appendix 1a, Appendix 1b, and Appendix 2b).
Only patients with prior enrollment in a Roche-sponsored or Genentech-sponsored study 
in HD for the RO7234292 development program that made provision for entry into an 
OLE study will be eligible for this OLE study.  The preceding Roche-sponsored or 
Genentech-sponsored study must have been approved by the relevant national 
competent authority and applicable Institutional Review Board (IRB)/Ethics Committee 
(EC) in a country in order for a patient from that country to be included in the OLE.
For patients who have participated in previous Roche studies, entry into this long-term, 
open-label extension study will occur at an inclusion visit. This inclusion visit is a 
combined visit with the preceding study's last applicable visit where patients are due for 
their end of treatment visit, last CSF collection, or safety follow-up unless otherwise 
specified, and serves as the baseline visit for the long-term, open-label extension study.  
For participants who have not participated in a previous Roche study, a separate 
screening visit will occur to determine eligibility into the long-term, open-label extension 
study. Patients who successfully meet eligibility criteria will then enter the study and 
attend the baseline study visit.  Patients who were enrolled in Study BN40423 before 
implementation of Version 4 of that protocol will be prematurely discontinued by the 


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31/Protocol BN40955, Version 7
Sponsor from Study BN40423 and offered treatment in this study (Study BN40955) 
when it is available at sites.
If dosing at the inclusion visit is not possible, the Medical Monitor should be consulted 
and a short treatment interruption may be permitted.  For patients entering from 
Study BN40423 prior to implementation of Protocol Version 4, the inclusion visit should 
occur at the end-of-treatment visit for Study BN40423.
Patients who were screened and eligible for the placebo-controlled Phase III 
Study BN40423 (Generation-HD1) but were not randomized prior to the close of 
Study BN40423 enrollment due to logistical challenges resulting from the COVID-19 
pandemic, will be offered open-label RO7234292 as part of this study, Study BN40955.
Participation can occur once approved and available at sites and so long as the patient 
meets Study BN40955 eligibility. These patients will undergo screening assessments 
during a 4-week screening period. A maximum of 1 re-screening will be allowed within 
8 weeks of an initial screening failure in Study BN40955.
The CAG repeat length testing from Q2 Solutions will be accepted for this study. If 
re-screening is required, the CAG repeat length testing from Q2 Solutions does not need 
to be repeated. The screening MRI and viral serology from the initial screening, 
including from other Roche RO7234292 studies, may be acceptable as part of the 
screening assessments if performed within 12 weeks of the inclusion visit.
For patients entering from Study BN40697, in the event of any delay in start-up activities
where it is not possible to conduct the inclusion visit at the time of the last applicable visit 
in Study BN40697, a separate inclusion visit should be scheduled (see Appendix 1a).
Upon completion of the inclusion visit, eligible patients will receive either 120 mg 
RO7234292 Q8W (RO7234292 Q8W arm) or 120 mg RO7234292 Q16W 
(RO7234292 Q16W arm) by bolus IT injection. Patients will be assigned to treatment 
groups as described below and in Table 1:

Patients who previously received open-label 120 mg RO7234292 Q4W in a 
preceding study or who are currently receiving open-label 120 mg RO7234292 Q4W 
in Study BN40955 will be randomly allocated to receive 120 mg of RO7234292 
Q8W or 120 mg of RO7234292 Q16W.
Patients who previously received open-label 120 mg of RO7234292 Q8W in a 
preceding study or are currently receiving open-label 120 mg RO7234292 Q8W 
in Study BN40955 will receive 120 mg of RO7234292 Q8W.
Patients who previously received placebo in a preceding study will be randomly 
allocated to receive either 120 mg of RO7234292 Q8W or RO7234292 Q16W.
The drug administered at the inclusion visit will be the last dose or at the last 
CSF collection of the preceding study (if the inclusion visit is at the last visit in 


RO7234292F. Hoffmann-La Roche Ltd
32/Protocol BN40955, Version 7
the preceding study) or will be the first dose in Study BN40955 if a separate 
inclusion visit is required (see Appendix 1a).

After implementation of Study BN40955 Protocol Version 3, patients who are 
already enrolled in Study BN40955 will sign the amended Informed Consent Form 
(ICF) at or before their next clinic visit, and will be assigned to either the 120 mg 
RO7234292 Q8W or 120 mg RO7234292 Q16W arm, and then follow the schedule
of activities for Protocol Version 3 (see Appendix 1a)matching treatment week 
according to Appendix 2at the clinic visit and going forward.

Patients who did not previously receive treatment with RO7234292 (e.g., from a 
natural history study, eligible patients from Study BN40423 study who were not 
randomized due to logistical challenges resulting from the COVID-19 pandemic) or 
received short-term treatment (4 doses) with a treatment-free follow-up period will 
be randomly allocated to receive 120 mg of RO7234292 Q8W or 120 mg of
RO7234292 Q16W.  The first dose in Study BN40955 will take place at the inclusion 
visit.

Patients who previously received blinded placebo Q8W will be randomly allocated to 
receive 120 mg of RO7234292 Q8W or 120 mg of RO7234292 Q16W.  The first 
dose in Study BN40955 will take place at the inclusion visit.

Patients who previously received blinded 120 mg of RO7234292 Q8W will receive 
open-label 120 mg of RO7234292 Q8W.

Patients who previously received blinded 120 mg of RO7234292 Q16W will receive 
open-label 120 mg of RO7234292 Q16W.
For patients who enrolled from Study ML41885, the inclusion visit will take place at the 
first safety follow-up visit of Study ML41885 (i.e., safety follow-up [SFU1]).  The drug 
administered at the inclusion visit will be the first dose in Study BN40955.  Patients who 
consent to be enrolled into this study (Study BN40955) will be assigned to a treatment 
group as shown below:

Patients who received open-label 120 mg of RO7234292 Q16W will receive 
open-label 120 mg of RO7234292 Q16W.
Patients enrolled in Study BN40423 prior to implementation of Protocol Version 4 will be 
prematurely discontinued from that study.  Patients who consent to be enrolled into this 
study (Study BN40955) will be assigned to treatment groups as shown below:

Patients who received blinded 120 mg of RO7234292 Q4W will be randomly 
allocated to receive open-label 120 mg of RO7234292 Q8W or 120 mg of 
RO7234292 Q16W.

Patients who received blinded 120 mg of RO7234292 Q8W will receive open-label 
120 mg of RO7234292 Q8W.

Patients who received blinded placebo Q4W will be randomly allocated to receive 
open-label 120 mg of RO7234292 Q8W or 120 mg of RO7234292 Q16W.


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Table 1
Treatment Regimen in Study BN40955 Based on Previous 
Study Treatment
Preceding Study Treatment
Treatment Regimen
Open-label 120 mg RO7234292 Q4W
Randomized 1:1 to 120 mg RO7234292 Q8W or 
120 mg RO7234292 Q16W
Open-label 120 mg RO7234292 Q8W
120 mg RO7234292 Q8W
No treatment or 4 doses of 120 mg or less
RO7234292 with a treatment-free follow-up 
period
Randomized 1:1 to 120 mg RO7234292 Q8W or 
120 mg RO7234292 Q16W 
Blinded placebo Q8W
Randomized 1:1 to 120 mg RO7234292 Q8W or 
120 mg RO7234292 Q16W 
Blinded 120 mg RO7234292 Q8W 
120 mg RO7234292 Q8W 
Blinded 120 mg RO7234292 Q16W
120 mg RO7234292 Q16W 


RO7234292F. Hoffmann-La Roche Ltd
34/Protocol BN40955, Version 7
Table 1
Treatment Regimen in Study BN40955 Based on Previous 
Study Treatment (cont.)
Preceding Study Treatment
Treatment Regimen
For Patients enrolled into Study BN40423 prior to implementation of Study BN40423 Protocol 
Version 4:
Blinded 120 mg RO7234292 Q4W
Randomized 1:1 to 120 mg RO7234292 Q8W or 
120 mg RO7234292 Q16W
Blinded 120 mg RO7234292 Q8W
120 mg RO7234292 Q8W
Blinded Placebo Q4W
Randomized 1:1 to 120 mg RO7234292 Q8W or 
120 mg RO7234292 Q16W
Open-label 120 mg RO7234292 Q16W
120 mg RO7234292 Q16W
Q4Wevery 4 weeks; Q8Wevery 8 weeks; Q16Wevery 16 weeks.
For patients who did not previously receive treatment with RO7234292 (e.g., from a 
natural history study) or received short-term treatment (4 doses), the end of study visit 
for the preceding study will serve as the inclusion visit for Study BN40955.  For patients 
who completed the full treatment course in the preceding study, the inclusion visit for 
Study BN40955 will take place at the visit at which the last dose was administered. 
For patients enrolled in Study BN40423 prior to implementation of Protocol Version 4 
who were prematurely discontinued, the inclusion visit for Study BN40955 will take place 
at the end-of-treatment visit for Study BN40423. For patients entering from 
Study BN40697, in the event of any delay in start-up activities where is not possible to 
conduct the inclusion visit for Study BN40955 at the time of last applicable visit in 
Study BN40697, a separate inclusion visit should be scheduled (see Appendix 1a). 
At the inclusion visit for Study BN40955, clinical ratings and assessments that are 
common between the preceding study and Study BN40955 will be completed once and 
will serve both studies. Clinical ratings and assessments required in Study BN40955 
that were not completed as part of the preceding study will also need to be completed at 
the inclusion visit. Patients who were eligible for Study BN40423 (GENERATION-HD1) 
but were not randomized due to logistical challenges resulting from the COVID-19 
pandemic will undergo screening and inclusion visits, see details of assessments in 
Appendix 1b and Appendix 5.
Patients will undergo safety and tolerability evaluations that include neurologic 
examinations, vital signs, ECGs, clinical laboratory tests, Montreal Cognitive 
Assessment (MoCA), C-SSRS, neuroimaging assessments and reporting of AEs and 
concomitant medications, as detailed in Appendix 1a and Appendix 1b. Patients 
enrolling from Study BN40697 will have an optional MRI of brain and spine with contrast 
media, in addition to the other brain neuroimaging assessments.


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In case of a failed IT bolus dosing procedure (e.g., due to an inadequate establishment 
of access to the IT space), a second dosing attempt may occur up to 7 days after the 
originally scheduled dosing 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), vital signs, 
and a review of AEs and concomitant medication. If the second dosing attempt occurs 
more than 72 hours after the last coagulation panel and platelets test, 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 and 
Appendix 1b).
Telephone safety follow-up calls will be conducted between dosing visits to check for 
any change in patient status (i.e., AEs, concomitant medications) since last visit
(see Appendix 2). Depending on the patient’s health status, an unscheduled clinic visit 
may be arranged.  If a patient is due for a telephone safety call and they are in-clinic 
then this telephone safety follow-up call can be completed in-clinic at the site’s discretion. 
As a result of the COVID-19 pandemic, only where sites are impacted, these telephone 
safety calls can be conducted instead of an in-clinic visit.
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 a minimum of 6 months after the last patient is 
enrolled.
The total length of the study, from enrollment of the first patient to the end of the study, is 
expected to be approximately 6 years. It is expected that patients may participate for a 
minimum of 6 months and a maximum of approximately 6 years in Study BN40955.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for RO7234292 Dose and Schedule
Effective 22 March 2021 dosing in this study (BN40955) is paused. On 18 Mar 2021, 
the BN40423 iDMC recommended that dosing be stopped in the Phase III randomized 
controlled trial.  Because the OLE is exploring the same dosing regimens (i.e., 
RO7234292 120 mg Q8W and Q16W) the Sponsor made a decision to pause dosing in 
the OLE until further data assessments can be conducted.
In this study, RO7234292 will be administered either Q8W (RO7234292 Q8W arm) or 
Q16W (RO7234292 Q16W arm) by IT injection.  The dose and dosing regimen 
administered in this study was initially the same as the dose and dosing regimen 
selected for the Phase III Study BN40423, a double-blind, placebo-controlled study of 
RO7234292 administered Q4W and Q8W by IT injection over 25 months in patients with 
manifest HD. However, based on preliminary 9-month data from the open-label 
Study BN40697, the Phase III Study BN40423 was amended to replace the 


RO7234292F. Hoffmann-La Roche Ltd
36/Protocol BN40955, Version 7
120 mg Q4W regimen with a 120 mg Q16W regimen.  The same change was made to 
this study.
Until completion of Phase III Study BN40423, 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, 2 active dosing regimens will be used in this study:  
RO7234292 Q8W (RO7234292 Q8W arm) and RO7234292 Q16W (RO7234292 Q16W 
arm), by IT injection.
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 nonclinical 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 IT Q4W for 
4 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 5 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% 


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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 3 or 4 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 ongoing Phase II 
OLE suggests 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 AEs, decreased proportion of patients with moderate 
AEs, and fewer AEs 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 and updated clinical PK/PD model predicted the 
observed Q8W 9-month reductions (for details see the 
RO7234292 Investigator’s Brochure).  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 IT in clinical trials.  Intrathecal 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.
In summary, a 120 mg Q8W dosing regimen and the less frequent dosing regimen of 
120 mg Q16W have been selected for this OLE extension study to be consistent with 


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changes to the Phase III Study BN40423 in order to evaluate the long-term safety and 
tolerability of RO7234292 in patients with HD.
3.3.2
Rationale for Biomarker Assessments
3.3.2.1
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).  Mutant HTT 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).  Neurofilament light chain protein 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.
3.3.2.2
Blood Biomarkers
Neurofilament light chain protein levels in blood correlate with NfL levels in CSF and 
could serve as prognostic blood biomarkers of disease onset and progression in HD 
(Byrne et al. 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.
3.3.2.3
Magnetic Resonance Imaging
Magnetic resonance imaging 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.
All patients will undergo MRIs every 32 weeks to assess the effect of long-term 
treatment and LP on brain structure and function. All of the measures will be assessed 
in a consistent manner with the preceding study, including those designated to be 
optional. 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.
Unscheduled MRIs in 3 patients who received monthly IT procedures in Study BN40697 
reported enhancement in the cauda equina region; MRIs will be explored in this 
extension study to further assess the impact of frequent IT procedures.


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For this purpose, in consenting patients from Study BN40697, optional MRI scans of 
brain and spine with contrast media will be collected upon study entry and every 
32 weeks thereafter (for additional details refer to 
Study BN40955 Ixico Safety Read Manual). The contrast brain and spine MRI will be 
reviewed in-house or by ad-hoc independent external neuroimaging experts to look for 
the occurrence of abnormal MRI findings.
3.3.2.4
Safety Biomarkers
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
identification of safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation.  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.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Up to approximately 1100 patients with HD will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed ICF
If capacity to consent is in question, formal capacity assessment by an 
appropriately qualified professional should be obtained.  In cases where 
capacity to consent is not fully present, but the participant is known previously 
to have favored participation in an open-label study and is able to assent, 
consent may be obtained by a legally authorized representative.  
(Note: Patients in Germany who are not fully capable of providing informed 
consent are not eligible for inclusion).

Prior enrollment in a Rochesponsored or Genentech-sponsored study in HD for the 
RO7234292 development program that made provision for entry into an OLE study
(refer to Appendix 11)
Ability and willingness to comply with the study protocol including the visit schedule and 
all assessments, in the investigator's judgment

For women of childbearing potential:  Agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, as defined below:


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Women must remain abstinent or use 2 methods of contraception, including at 
least 1 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 post-menarchal, 
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.
The following eligibility criteria only apply to patients who were eligible for 
Study BN40423 (GENERATION-HD1) but were not randomized due to logistical 
challenges resulting from the COVID-19 pandemic.
Patients must meet the following criteria for study entry during screening (some will be 
reassessed at the inclusion visit prior to randomization and study drug dosing):

Signed ICF

Age 2565 years, inclusive, at the time of signing of ICF and at the time of first dose 
administration

Manifest HD diagnosis, defined as a diagnostic confidence level (DCL) score of 4 
(refer to Appendix 6)


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
Independence Scale (IS) score 70

Genetically confirmed disease by direct DNA testing with a CAG-Age product (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 LPs

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

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to 
screening and at the time of enrollment
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Withdrawal of consent from the preceding study

Permanent discontinuation of RO7234292 for any drug-related safety concern
during the preceding study or meeting of any study treatment discontinuation criteria 
specified in the preceding study at the time of enrollment into this study

An ongoing, unresolved, clinically significant medical problem that in the judgment of 
the investigator would make it unsafe for the patient to participate in this study

Antiplatelet or anticoagulant therapy within 14 days prior to inclusion 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.


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
Concurrent participation in any therapeutic clinical trial (other than the preceding 
study)

Study treatment (RO7234292) is commercially marketed in the patient’s country for 
the patient-specific disease and is accessible to the patient

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 urine pregnancy test at 
the inclusion visit (obtained as part of the preceding study assessments).
The following exclusion criteria only apply to patients who were eligible for 
Study BN40423 (GENERATION-HD1) but were not randomized due to logistical 
challenges resulting from the COVID-19 pandemic.
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 
completed 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

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 ASO (including small interfering RNA)


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
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

Treatment with investigational therapy within 4 weeks or 5 drug-elimination half-lives 
prior to screening, whichever is longer

History of gene therapy, cell transplantation, or any experimental brain surgery

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, hydrocephalus, subdural haematoma) as assessed by 
a centrally read MRI scan during the screening period
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
All patients in this study will have the opportunity to receive treatment with either 
120 mg RO7234292 Q8W or 120 mg RO7234292 Q16W and will be assigned to 
treatment as described in Table 1. An independent interactive voice or web-based 
response system (IxRS) provider will assign patients to treatment and conduct 
randomization where required. If, during the course of the study, a single regimen is 
selected for the development program, all patients will then be assigned to the selected 
regimen.
All patients, study site personnel, Sponsor agents, and Sponsor personnel will be 
unblinded to the treatment assignment of this study; however, the treatment assignment 
from a blinded preceding study will remain blinded until the preceding study is unblinded.


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An IxRS provider will hold the treatment assignment code to maintain the integrity of the 
blinding (active versus placebo) in the preceding study.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is RO7234292.
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), 2 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, study drug preparation, storage, and handling of 
RO7234292, 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 AEs, should be reported as described in Section 5.3.5.12.
Guidelines for treatment interruption or discontinuation for patients who experience AEs
are provided in Section 5.1.3.
4.3.2.1
RO7234292
Each dose of RO7234292 (120 mg) will be administered as a single IT bolus injection of 
20 mL by a qualified physician experienced in performing LPs.  In exceptional 
circumstances, study staff who are licensed physician assistants or nurse practitioners 
with extensive experience of performing LPs and administrating IMP for ASOs IT may be 
acceptable with Sponsor approval.
Guidelines for treatment interruption or discontinuation for patients who experience AEs
are provided in Section 5.1.3.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO7234292) will be provided by the 
Sponsor where required by local health authority (HA) regulations.  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.


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IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
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 website:
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 


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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 the time of entry into Study BN40955 to the study 
completion/discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy
Throughout the study, investigators or treating physicians may prescribe concomitant 
medications or treatment deemed necessary to provide adequate supportive care or for 
treatment of AEs.
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.
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 LP or IT bolus procedures in the study
Depending on institutional guidelines, local anesthesia is permissible for the LP
procedure.

Anti-anxiety medication is strongly discouraged during scheduled MRI scans.
If anti-anxiety medication is used, the scan must be performed at the end of the 
assessment day (before the LP) or preferably on a different day, to avoid impacting 
other assessments.
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1a
and Appendix 1b.  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, dosing is paused, including enrollment.  Patients already on the study will 
continue to be followed for safety and efficacy outcomes until study completion (see
Appendix 1a, Appendix 1b, and Appendix 2b).


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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 any screening evaluations, 
if applicable).  Informed Consent Forms for patients 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 is judged to have questionable capacity, then assent 
of the patient in addition to signed consent by a legally authorized representative is 
required for study participation.  (Note: Patients in Germany who are not fully capable of 
providing informed consent are not eligible for inclusion).  If the patient’s capacity is 
confirmed, the investigator may proceed with the patient's signing of the ICF.
All screening (if required) and inclusion visit 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 evaluated
and to confirm eligibility or record reasons for inclusion failure, as applicable.
Patients who are required to undergo screening will be allowed a maximum of 
1 re-screening 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). The CAG repeat length testing from 
Q2 Solutions will be accepted for this study. If re-screening is required, the CAG repeat 
length testing from Q2 Solutions does not need to be repeated.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, and reproductive 
status will be recorded at screening (patients required to undergo screening only) and
baseline (inclusion visit).  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient from the time of entry into Study BN40955 to the study 
completion/discontinuation visit.  At the time of each study drug administration, an 
interval medical history should be obtained and any changes in medications 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 will be recorded at 
screening (patients required to undergo screening only) and baseline (inclusion visit) for 
all patients except those undergoing screening.  Race/ethnicity is recorded because of 
the potential contribution of this variable to differences in observed PK, PD, toxicity, 
and/or response to treatment.


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The protocol number and patient number of the preceding study will be collected, as well 
as the patient’s Huntington’s disease identification number (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 specified visits (see Appendix 1a and 
Appendix 1b), 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 at each visit. 
Height will be obtained from the preceding study. For patients required to undergo 
screening, height will be collected at screening only.
A neurologic examination, including fundoscopy, performed at screening (patients 
required to undergo screening only), inclusion 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 12).  
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, or before the 
lumbar puncture, if there is no study treatment administration.
Any abnormality identified at screening (patients required to undergo screening only) 
and baseline (inclusion visit) 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 AEs 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 at least 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 LP, local laboratory analysis of 
coagulation factors (INR and/or PT, aPTT) and platelets must be conducted and the 
results reviewed.  The LP should be performed at approximately the same time at each 
visit (ideally in the morning between 8:00 a.m. and 12:00 p.m. or in the early afternoon 
between 12:00 p.m. and 3:00 p.m.) to minimize potential diurnal variation of CSF 
parameters.  Cerebrospinal fluid (20 mL) is to be collected for analyses using a 
LP collection kit.  If there are difficulties in collecting 20 mL of CSF, a minimum of 5 mL 


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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LP 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 LP procedure if 
deemed necessary, but ultrasound is not required.  Ultrasound guidance may be used if 
attempts at LP without imaging are unsuccessful, if it is local practice to use ultrasound, 
or if institutional guidelines dictate use of ultrasound with each LP. Fluoroscopy 
guidance can also be used, if local institutional guidelines dictate and local ECs/IRBs
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 LP and IT bolus dosing procedure, refer to the LP procedure and CSF 
collection guidelines and instructional video.
When applicable, study treatment administration will occur via a LP 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 
preexisting experience using LP/IT bolus dosing in the sitting position and prefers the 
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 in the 
same position, to limit the risk of the needle losing position while the spinal needle is 
inserted. Subsequent LP administrations should preferably occur using the same 
position.
Patients will be discouraged from resting supine after the LP procedure and will be 
encouraged to mobilize immediately by walking around at a minimum and, if feasible, 
walking briskly for approximately 30 minutes.  If applicable, the postdose neurological 
examination can occur after walking.  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 case of a failed IT bolus dosing procedure (e.g., due to an inadequate establishment 
of access to the IT space), a second dosing attempt may occur up to 7 days after the 
originally scheduled dosing 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), vital signs, 
and a review of AEs and concomitant medication. If the second dosing attempt occurs 
more than 72 hours after the last coagulation panel and platelet test, local laboratory 


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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 and 
Appendix 1b).
Lumbar punctures will be performed as specified in the schedule of activities 
(see Appendix 1a, Appendix 1b, and Appendix 2b), with the last CSF sample obtained at 
the end-of-treatment visit for this study.  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).

Cerebrospinal fluid for safety:  cell count (including RBCs and WBCs), glucose, and 
protein
Samples for the following laboratory tests 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

Serum pregnancy test
Serum pregnancy tests will be performed for women of childbearing potential to 
confirm a positive urine pregnancy test (if applicable).
Serum pregnancy test will be performed for women of childbearing potential at 
screening (patients undergoing screening only). At subsequent visits it will be 
performed to confirm a positive urine pregnancy test (if applicable).

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)

Cerebrospinal fluid and blood (plasma) samples for PK analyses

Blood (plasma) samples for immunogenicity analyses

Cerebrospinal fluid samples for analysis of mHTT

Plasma and CSF samples for exploratory research on biomarkers and biomarker 
assay development


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Patients who are required to undergo screening will have the following additional 
laboratory tests sent to central laboratory:

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)

Blood sample for determination of CAG repeat length in HTT for patient eligibility. 
The CAG repeat length testing from Q2 Solutions will be accepted for this study.
Exploratory biomarkers research may include, but will not be limited to, total HTT or 
isoforms of HTT, NfL, tau, and other proteins related to HD, neurodegeneration, and 
inflammation.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exceptions:

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

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; these samples will nevertheless 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 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 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy in the study data publication.
4.5.7
Magnetic Resonance Imaging
Mandatory structural MRI will be used to assess brain volume, optional 
diffusion-weighted MRI/Neurite Orientation Dispersion and Density Imaging will be used 


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to examine structural brain connectivity, and optional 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 and will continue as in the preceding study. Patients will 
be required to undergo and tolerate the mandatory structural MRI. Patients who are 
required to undergo screening will undergo structural MRI at screening to confirm 
eligibility for the study. Patients will be encouraged to receive the diffusion-weighted 
MRI/Neurite Orientation Dispersion and Density Imaging and Resting-State functional 
MRI scans, but they will not 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.  Magnetic resonance 
imaging scans will be managed by a central laboratory to monitor and ensure the 
integrity and quality of the acquired data.  During central review, the Sponsor and/or site 
staff will be notified of any unexpected findings requiring clinical follow-up.
At specified timepoints, the MRI should be scheduled to occur before the LP
(see Appendix 1a and Appendix 1b). The MRI scan should be performed 714 days 
prior to the LP 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 LP, then it can be conducted the day after 
the LP, as long as there are no post-LP contraindications and it occurs within 2 weeks of 
the original scan.
Anti-anxiety medication is strongly discouraged during scheduled scans, as described in 
Section 4.4.2.
4.5.8
Optional Magnetic Resonance Imaging of Brain and Spine with 
Contrast in Patients from Study BN40697
Optional MRI scans of brain and spine with contrast media will be collected in patients 
from Study BN40697, with MRI performed as described in Section 4.5.7.  The optional 
MRIs will be obtained at specified timepoints, as outlined in Appendix 1a. The contrast 
brain and spine MRI will be reviewed in-house or by ad-hoc independent external 
neuroimaging experts to look for the occurrence of abnormal MRI findings.
4.5.9
Electrocardiograms
Single ECG recording will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1a and Appendix 1b), 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.  
Electrocardiogram recording must be performed after the patient has been resting in a 
supine position for at least 10 minutes.  Electrocardiograms for each patient should be 


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obtained from the same machine whenever possible.  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.
4.5.10
Patient-Reported, Clinician-Reported, and Performance
Outcomes
Patient-reported outcome (PRO), clinician-reported outcome (ClinRO), and performance 
outcome (PerfO) data will be collected in the clinic to document the change from 
baseline over time.  Additionally, PRO and PerfO data will be collected remotely in 
patients issued with devices.  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 HA 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 LP procedure.
Patients and clinicians will use an electronic device to capture ClinRO, PRO, and PerfO 
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.  Patients who were issued with a smartphone and wrist-worn 
wearable in their preceding study will continue to use the smartphone and wrist-worn 
wearable to capture outcome data remotely and at specified visits 
(see Section 4.5.10.11).
In exceptional circumstances where a patient cannot attend clinic or investigator site has 
closed due to restrictions imposed as a result of the COVID-19 pandemic, ClinRO (refer 
to Appendix 8) can be collected remotely via telephone. For all other situations these all 
need to be completed in the clinic, otherwise it is a protocol deviation.
See Appendix 1a and Appendix 1b for the schedule of activities and Appendix 3 and 
Appendix 4 for a summary of timing and duration of each PRO, ClinRO, and PerfO 
assessment.  Appendix 7 shows the order and approximate timing of assessments at 
each clinic visit.  Appendix 5 shows the clinical assessments order and duration for 
patients required to undergo screening only.  Appendix 8 shows the remote clinical 
assessments order and duration for patients who could not attend an in-clinic visit due to 
COVID-19 pandemic.


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4.5.10.1
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:
cUHDRS = TFC −8.8
2.8
 −TMS −34.4
17.4
 + SDMT −25.2
12.4
 + SWRT −58
21.2
 + 10.0
4.5.10.2
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.  The 
TFC score ranges from 0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 specified clinic visits.
4.5.10.3
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124, with a higher score representing more severe impairment.  The TMS 
takes approximately 15 minutes to administer and will be completed at clinic specified 
visits.
4.5.10.4
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 


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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 specified clinic 
visits and can be completed in less than 5 minutes.  It will also be administered at 
specified timepoints on the Roche HD mobile app (via electronic SDMT) in patients 
issued with devices.
4.5.10.5
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 on the Roche 
HD mobile app (via electronic SWR) in patients issued with devices.
4.5.10.6
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. It is a 
subscale of the UHDRS. The scale consists of 19 discrete levels ranging from 10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 bedcare.  This scale will only be 
performed for patients who were screened and eligible for Study BN40423 but could not 
be randomized due to challenges relating to the COVID-19 pandemic.
4.5.10.7
Huntington's Disease Daily Activities Scale
The HD-DAS assesses patients' daily function.  Following a semi-structured interview 
with the patient, 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. The HD-DAS can be completed in 
approximately 25 minutes.
4.5.10.8
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, 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 post-baseline 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.


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4.5.10.9
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.  
The MoCA will be used in this study to assess cognitive status at regular intervals 
throughout the study and takes approximately 10 minutes to administer.
4.5.10.10
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. Food and Drug 
Administration (FDA) draft guidance for assessment of suicidality in clinical trials 
(FDA 2012).  The C-SSRS will be used to assess eligibility for the study for patients 
required to undergo screening (full version at screening, requiring approximately 
20 minutes to administer) and to monitor 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.
4.5.10.11
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 by the patient at study drug administration visits on an electronic device.  In 
addition, it will be completed remotely by the patient on the Roche HD mobile app.
4.5.10.12
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; 


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Lipsmeier et al. 2018).  If a patient already has a preconfigured smartphone and 
wrist-worn wearable with installed software for the Roche HD mobile app assessments 
from the preceding study, they will continue to use those devices in this study.  Although 
the majority of assessments on the Roche HD mobile app are consistent across the 
preceding studies, some of the PROs will differ. Patients will continue to complete the 
PROs from the preceding study, thus not all patients will complete all PROs (e.g., the 
WHODAS 2.0 will not be completed by patients previously in Study BN40423). Details 
of remote assessments are contained in Appendix 7. If patients did not have a 
preconfigured smartphone and wrist-worn wearable in the preceding study, they will not 
be provided devices in this study. Patients screened in Study BN40423 but not 
randomized due to logistical challenges resulting from COVID-19 will be provided with a 
smartphone and wrist-worn wearable. 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 asked to complete 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, and voice) and non-motor symptoms (processing 
speed, voice).  These tasks are described in Appendix 9.  Testing will last approximately 
510 minutes in total on a typical day of testing.  Not all tests are daily.  Additional 
information on the approach, tasks, and schedule are available in the Roche HD mobile 
app manual.
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.
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 Wifi.  Patients will be asked to 
charge the devices overnight.  If patients have a Wifi network at home, they will be 
encouraged to connect their smartphone to enable data transfer.  If no Wifi network is 
available, the sensor data will be transferred during clinic visits or after the devices have 
been returned.
Devices may reach the end of their lifespan or be broken during this study.  In those
cases, they may be replaced upon discussion on a case-by-case basis.


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During the course of this study (ca. 2022), the Roche HD mobile app may be available 
for download by study participants with compatible smartphones.  All patients, will have 
the option to download the app on their personal smartphones and continue (or restart) 
with the Roche HD mobile app assessments and passive monitoring.  If patients 
download the app on their personal smartphone, they should return the provisioned 
devices.
4.5.10.12.1
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.  Every 16 weeks, when clinical 
ratings will occur, patients will be asked to conduct the In-Clinic Assessments 
(Full active test) under the supervision of trained site staff, with the exception of the 
EQ-5D-5L, which will be completed on the electronic device at the site. Patients should 
be instructed to not complete the Roche HD mobile app EQ-5D-5L on days that coincide 
with the study drug administration visit.
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.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
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
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for an end-of-treatment visit and safety follow-up visit 
(if applicable) after the final dose of study drug (see Appendix 1a and Appendix 1b for 
additional details).
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent


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
Study termination or site closure

Loss of capacity to consent, if legal guardian consent is not possible
Note:  Withdrawal of patients who lose capacity to consent is a requirement in 
Germany.
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 AEs 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.  Safety risks for the LP 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.


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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 AEs.  Guidelines for managing
AEs, 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5.1.1.3) are potential risks associated with LP.
In the completed Phase I/IIa study, the most commonly reported AEs across all 
treatment groups (RO7234292, N34; placebo, N12) were procedural pain 
(54% of patients) and postLP 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-
lumbar puncture syndrome (14% each).
As of 07 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 LP can be avoided by the mandatory use of a 24G 
atraumatic needle with a stylet, adherence to procedural guidelines (see LP manual and 
instructional video), and careful assessment of the patient, including neurologic 
examination with fundoscopy both prior to and postLP procedure.  Lumbar puncture
should be avoided when a contraindication is present.
Cerebrospinal fluid 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 LP, 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 


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space) can be avoided by use of a needle with stylet, which is mandatory.  Rarely, brain 
herniation can occur in the setting of LP and increased intracranial pressure.
There are specific contraindications to performing LP.  These include unstable 
cardiorespiratory status, where positioning patient for LP 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, LP (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.
In the setting of HD, for the purposes of LP 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 LP injection.  PostLP syndrome 
(e.g., headaches, nausea, vomiting, infection, hemorrhage, nerve irritation pain) can 
occur with IT administration.  Experience to date with postLP 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 the Study BN40423 ODC, post-LP syndrome events (post-LP syndrome, headache, 
migraine, nausea, vomiting or procedural headache) occurring within 5 days of LP were 
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 07 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LP, (see Section 4.3.2.1 ). However, if a patient develops a 
headache after the LP 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 


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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 LP.  Patients may present with headache, meningism, 
photophobia, neck stiffness, and pyrexia.  Guidelines for management of patients with 
suspected meningitis are provided in Table 2.
5.1.2
Potential Risks Associated with RO7234292
The potential risks identified below have been considered in relation to clinical data 
available as of 07 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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.
In the Phase I/IIa multiple ascending dose (MAD) study (ISIS 443139-CS1), no adverse 
trends in neurological examinations were detected and only a few drug-related 
neurological AEs 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 


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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 not 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. 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 IT 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 04 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.


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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 LP.  See Table 2 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 I/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.
Kidney function will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased renal function are provided in Table 2.
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 drug-related clinically significant hepatic 
abnormality has been observed to date.


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Liver enzymes will be monitored at each study visit.  Guidelines for management of 
patients who develop decreased liver function are provided in Table 2.
5.1.2.6
Hydrocephalus
Hydrocephalus is included as a warning in the labeling 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 Investigators 
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 
(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 C-SSRS and the MoCA 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.  Antisense oligonucleotide-mediated mHTT 
lowering provides therapeutic benefits and often restores normal functioning in 
transgenic and fully humanized animal models of HD, with generally similar results 


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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 I/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.
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 at every study drug administration either on 
a Q8W or Q16W basis as assigned by IxRS).
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.


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5.1.3.3
Management Guidelines
Guidelines for management of specific AEs are outlined in Table 2. 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 2
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 3 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 2× 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 2
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Event
Action to Be Taken
Thrombocytopenia

If platelet count is 100,000/mm3:
–
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:
–
Withhold study drug until the platelet count has recovered 
to 100,000/mm3.
–
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:
–
Permanently discontinue study drug.
–
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.

Treatment per standard of care should be considered for 
patients whose platelet count is 25,000/mm3.


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Table 2
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
Event
Action to Be Taken
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:
–
eGFR or CrCl (using Cockcroft-Gault) 60 mL/min.
–
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:
–
Monitor weekly until ALT and AST return to 1.2ULN.
–
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):
–
ALT or AST 5ULN.
–
ALT or AST 3ULN, combined with total bilirubin 
2ULN or INR 1.5.
–
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.
–
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 AEs, including serious 
adverse events (SAEs) and adverse events of special interest (AESIs), 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 AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE 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 SAE is any AE that meets any of the following criteria:

Is fatal (i.e., the AE actually causes or leads to death)

Is life-threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death)
This does not include any AE 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 AE 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 AE (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).


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Severity and seriousness need to be independently assessed for each AE 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 AEs (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 AE 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 AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient's 
medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only SAEs
caused by a protocol-mandated intervention (e.g., invasive procedures such as LP) 
should be reported (see Section 5.4.2 for instructions for reporting SAEs).
After initiation of study drug, all adverse events will be reported until 5 months after the 
final dose of study drug.
Instructions for reporting AEs that occur after the AE 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 
AE 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 3 provides guidance for
assessing AE severity.  Laboratory values determined as an AE should be graded as per
Appendix 10, which is based on the NCI CTCAE (v5.0).
Table 3
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 
AE 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 4):

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


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
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 4
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 AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only 1 AE 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 AEs 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 AEs based on signs and symptoms 
should be nullified and replaced by one AE report based on the single diagnosis, with a 
starting date that corresponds to the starting date of the first symptom of the eventual 
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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, AEs 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 AE 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 3 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 AEs 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 AE 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 AE 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 SAEs.
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE 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 AE.  A laboratory test result must be 
reported as an AE 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)


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
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 AE.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., elevated potassium,as opposed to abnormal potassium).  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the AE.  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 AEs).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported
as an AE 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 AE.
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 AEs).


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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 AE 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 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event); either as a SAE 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 AE 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 AE 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 inclusion 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 AE 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 


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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 AEs.  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 AE.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any AE that results in hospitalization (i.e., inpatient admission to a hospital) or prolonged 
hospitalization should be documented and reported as a SAE (per the definition of SAE
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 AE or a SAE:

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 AE.
An event that leads to hospitalization under the following circumstances is not 
considered to be a SAE, but should be reported as an AE 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 AEs, but may result in AEs.  
Each AE associated with a special situation should be recorded separately on the 
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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, AEs associated with special situations 
should be recorded as described below for each situation:

Accidental overdose:  Enter the AE term.  Check the Accidental overdoseand 
Medication errorboxes.

Medication error that does not qualify as an overdose:  Enter the AE term.  
Check the Medication errorbox.

Medication error that qualifies as an overdose:  Enter the AE term.  Check the 
Accidental overdoseand Medication errorboxes.
In addition, all special situations associated with RO7234292, regardless of whether they 
result in an AE, 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 Outcome Data
Adverse event reports will not be derived by the Sponsor from PRO or digital wearable 
device (HD mobile app) data, and safety analyses will not be performed using PRO or 
digital wearable device data.  Sites are not expected to review the PRO or digital 
wearable device data for AEs.
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 SAEs to the local 
HA 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 SAEs
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 e-mail address provided to 
investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, SAEs and AESIs 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 e-mail 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 SAEs 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 e-mail 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 SAEs 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 


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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 ICF 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 e-mail 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
Any abortion should be classified as a SAE (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).
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 SAE, 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 AE 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 SAEs considered 
to be related to study drug or trial-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient's medical record to facilitate source data 
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All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For SAEs, AESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, e-mail, and/or a monitoring visit to obtain additional case details and 
outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any SAE that 
occurs after the end of the AE reporting period (defined as 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 e-mail address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all SAEs and AESIs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRBs, ECs, and applicable HAs based on applicable legislation.
To determine reporting requirements for single AE 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
6.1
ANALYSIS POPULATIONS
The intent-to-treat (ITT) population will consist of all patients who received any study 
treatment.  Randomized patients who received incorrect therapy from that intended will 
be summarized in the group according to their planned randomized treatment.


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The ITT population will be the primary population for all analyses of efficacy and 
biomarker variables.
The safety population will consist of all patients who received 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.
6.2
DETERMINATION OF SAMPLE SIZE
The sample size for this study is determined by the number of patients from preceding 
studies who may be eligible for enrollment in this study and is estimated to be up to 
approximately 1100 patients.
6.3
SUMMARIES OF CONDUCT OF STUDY
The number 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.
6.4
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics 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.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received.
All verbatim AE terms will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) thesaurus terms.  The Adverse Event Severity Grading Scale (see 
Section 5.3.3) will be used for assessing AE severity.  Laboratory values determined as 
an AE should be graded as per Appendix 10, which is based on the NCI CTCAE (v5.0).
All safety data, including AEs, laboratory tests, neurologic examination, C-SSRS, 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 AEs will be summarized on the basis of body systems and dictionary 
preferred terms. The incidence of AEs by severity and relationship to study drug or 
study procedure and incidence of marked abnormal laboratory test results will be 
provided.


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6.6
EXPLORATORY EFFICACY ANALYSES
The efficacy endpoints will be summarized by treatment arm for each assessment time 
using summary tables, in terms of both absolute values and change from baseline.
Additional statistical modeling may be considered and will eventually be specified in the 
Statistical Analysis Plan (SAP).
6.7
EXPLORATORY PHARMACOKINETIC ANALYSES
The PK population will include all patients who received at least 1 dose of RO7234292 
and had sufficient sampling to permit PK evaluation.
For patients in the PK population, 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., average trough plasma concentration) will be 
computed and used to explore the exposure-response relationship on selected 
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.
6.8
EXPLORATORY 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. 
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.
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 


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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).
6.9
EXPLORATORY BIOMARKER ANALYSES
The biomarker endpoints will be summarized by treatment arm for each assessment 
time using summary tables, in terms of both absolute values and change from baseline.
Additional statistical modeling may be considered and will eventually be specified in the 
SAP.
6.10
HEALTH STATUS UTILITY ANALYSIS
The health status utility endpoints will be summarized using tables, listings, and graphs, 
as appropriate.  Additional statistical modeling may be considered.
6.11
OPTIONAL INTERIM ANALYSES
The Sponsor may choose to conduct one or more interim analyses including safety, PK, 
PD biomarkers and clinical endpoints as relevant.  Details of each interim analysis will 
be described in a dedicated SAP, which will be finalized before the conduct of the interim 
analysis.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data, 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.
Electronic Case Report Forms 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.
Patient-reported outcome, ClinRO, and PerfO data will be collected through the use of 
an electronic device provided by a vendor (see Section 7.3 for details).


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7.2
ELECTRONIC CASE REPORT FORMS
Electronic Case Report Forms 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.  Electronic Case Report Forms 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.  
Electronic Case Report Forms 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-REPORTED, CLINICIAN-REPORTED, 
AND PERFORMANCE OUTCOME DATA
An electronic device will be used to capture in-clinic PRO, ClinRO, and PerfO data.  
The device is 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 
MOBILE APPLICATION
During active testsand passive monitoring,the smartphone and wrist-worn wearable 
records 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.


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Roche HD mobile app (smartphone and wrist-worn wearable) sensor data are encrypted 
and uploaded to secure servers whenever the smartphone is connected to Wifi. 
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 HAs.
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 
HA 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 


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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, PerfO, and ClinRO data (if applicable), 
ICFs, 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 HAs, 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 HAs, 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 U.S. 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 (E.U.) 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 ICF (and ancillary sample ICFs) 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 ICFs or any alternate consent forms proposed by the site (collectively, 
the Consent Forms) before IRB/EC submission.  The final IRB/ECapproved Consent 
Forms must be provided to the Sponsor for HA submission purposes according to local 
requirements.
If applicable, the ICF will contain separate sections for any optional procedures.  The 
investigator or authorized designee will explain to each patient the objectives, methods, 


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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 or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.  If the legally 
authorized representative signs the Consent Form with the patient, the patient will still 
need to provide assent in the case he/she is no longer capable of providing consent.  
Assent implies willingness or, minimally, lack of objection to taking part and will need to 
be documented by the site.  (Note: Patients in Germany who are not fully capable of 
providing informed consent are not eligible for participation).
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 HA 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 legally 
authorized representative signs the Consent Form for the patient, the patient will still 
need to provide assent in the case that he/she is no longer fully capable of providing 
consent.  (Note: Patients in Germany who are not fully capable of providing informed 
consent are not eligible for participation).
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 U.S., 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 ICFs, 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 AEs to the Sponsor, investigators must 
comply with requirements for reporting SAEs to the local HA 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 HA 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 ICF (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 in the 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 HAs, 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 


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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-HD, 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. It is expected that 
patients from preceding studies have a pre-existing HDID number.  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 HAs.  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, ICFs, and documentation of IRB/EC and governmental approval.  In 
addition, at the end of the study, the investigator will receive the patient data, including 
an audit trail containing a complete record of all changes to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 


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whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to HAs.  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., AE 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 HAs; 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 100 sites globally will participate to enroll up to approximately 
1100 patients.  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.
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 website:


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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.
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 All Patients Except Those Undergoing Screening
Inclusion Visit ª
Treatment Period b
EoT c
SFU d
Week
Last applicable 
visit of preceding 
study ª
Treatment and Assessment Frequency
4 weeks
20 weeks
Day (Window)
1 week e
1 week
1 week
Signed informed consent f
x
Review of inclusion and exclusion criteria
x
Demographic data
x
Medical history and baseline conditions g
x
Vital signs h
x i
At each clinic visit
x
x
Complete physical examination j
x i
Q32W
x
x
Neurologic examination l
x i
At each clinic visit (see Appendix 12)
x
x
ECG m
x i
Q32W
x
x
Hematology n
x i
At each clinic visit
x
x
Chemistry o
x i
x
x
Pregnancy test p
x i
x
x
Urinalysis q
x i
x
x
Local PT and/or INR, aPTT, platelet 
count s
x i
At each study drug administration visit
x
x


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Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
Inclusion Visit ª
Treatment Period b
EoT c
SFU d
Week
Last applicable 
visit of preceding 
study ª
Treatment and Assessment Frequency
4 weeks
20 weeks
Day (Window)
1 week e
1 week
1 week
Plasma sampling for PK r
x i
Q16W for 48 weeks and then Q32W thereafter
Plasma sampling for immunogenicity 
testing r
x i
x
x
Plasma samples for biomarkers
x i
x
x
CSF sample for PK/safety/biomarkers s
x i
At each study drug administration
x
MoCA
x i
Q16W
x
C-SSRS t
x i
At each study drug administration
x
Mandatory Structural MRI u
x i
Q32W k
x
Optional resting-state functional MRI and 
diffusion-weighted MRI / NODDI u
x i
Q32W k
x
Optional MRI brain and spine with 
contrast media for patients from 
Study BN40697 v
x
Q32W
x


RO7234292F. Hoffmann-La Roche Ltd
100/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
Inclusion Visit ª
Treatment Period b
EoT c
SFU d
Week
Last applicable 
visit of preceding 
study ª
Treatment and Assessment Frequency
4 weeks
20 weeks
Day (Window)
1 week e
1 week
1 week
HD-DAS
x i
Q16W
x
TFC w
x i
x
TMS w
x i
x
CGI-S
x i
x
CGI-C
x
SDMT w
x i
x
SWR w
x i
x
Roche HD mobile app
x i
Continuous remote data collection, as well as Q16W
in-clinic x
x
EQ-5D-5L
x
At each study drug administration y
x
Q8W study drug administration s, cc
x
Q8W
Q16W study drug administration s, cc
x
Q16W
Telephone Safety follow-up z
Q8W:  Q8W (alternating with in-clinic visits) for 1 year
Q16W arm: Q8W (alternating with in-clinic visits) for 
1 year; then Q16W
Concomitant medications aa
x
Each clinic visit and telephone safety follow-up call
x
x
Adverse events bb
x
Each clinic visit and telephone safety follow-up call
x
x


RO7234292F. Hoffmann-La Roche Ltd
101/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
CGI-CClinical Global Impression, Change; CGI-SClinical Global Impression, Severity; CSSRSColumbia-Suicide Severity Rating Scale; 
CSFcerebrospinal fluid; 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; HDHuntington's disease; HD-DASHD Daily Activities Scale; 
LPlumbar puncture; MoCAMontreal Cognitive Assessment; MRImagnetic resonance imaging; NODDINeurite Orientation Dispersion and 
Density Imaging; PKpharmacokinetic; SDMTSymbol Digit Modalities Test; SFUsafety follow-up; SWRStroop Word Reading; TFCTotal 
Functional Capacity Scale; TMSTotal Motor Score; Q8Wevery 8; Q16Wevery 16 weeks; Q32Wevery 32 weeks.
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 Inclusion visit should be the last applicable visit of the preceding study as defined in Section 3.1.1.  For patients entering from Study BN40423
prior to implementation of Protocol Version 4, the inclusion visit should occur at the end-of-treatment visit for Study BN40423.  For patients 
entering from Study BN40697, in the event of any delay in start-up activities where it is not possible to conduct the inclusion visit at the time of 
the last applicable visit in Study BN40697, a separate inclusion visit should be scheduled 4 weeks or 8 weeks (1 week) for a patient previously 
treated Q4W or 8 weeks (1 week) later for a patient previously treated Q8W.
b If dosing at the inclusion visit is not possible, the Medical Monitor should be consulted and a short treatment interruption may be permitted.
c Patients who complete treatment (e.g., will continue treatment on commercially available drug) or who discontinue study drug prematurely will 
return to the clinic for a treatment completion visit 4 weeks (7 days) after the decision to discontinue.  For patients continuing treatment with 
RO7234292 outside of the study, the end of study visit should occur before the patient's next dose of RO7234292.
d Safety follow-up visit occurs 20 weeks after EoT.
e Excluding MRIs, which have a visit window of 14 to 7 days.
f
Informed consent must be documented before any Study BN40955specific procedure is performed and may be obtained up to 12 weeks before 
initiation of Study BN40955 study treatment.
g Medical history, including clinically significant diseases, surgeries, and reproductive status, will be recorded at baseline (inclusion visit).
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 at least 5 minutes.  Record abnormalities observed at the inclusion visit on the General Medical History and Baseline Conditions 
eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.


RO7234292F. Hoffmann-La Roche Ltd
102/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
i
Assessments do not need to be repeated if completed as part of the last visit in the preceding study and the inclusion visit occurs at the last visit 
in the preceding study.  If the inclusion visit is delayed (see footnote a), then the following assessments should be repeated: vital signs; 
complete physical examination; neurologic examination; ECG; hematology; chemistry; pregnancy test; local PT and/or INR, aPTT, platelet count; 
urinalysis; plasma sample for PK/immunogenicity/biomarkers; CSF sample for PK/safety/biomarkers; C-SSRS; and any clinical outcome 
assessments (i.e., HD-DAS, TFC, TMS, CGI-S, SDMT, SWR) that were not completed at the last visit in the preceding study.
j
A 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.  
The physical examinations should be conducted in the same manner on each occasion to ensure comparability to previous examinations, 
including weight.  Any abnormality identified at baseline (inclusion visit) 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.  Height will be obtained from preceding study.
k For patients who are already enrolled in this study who previously had an MRI before they transitioned to the new dosing regimen, the scheduled
post-inclusion visit MRI should be calculated from the date of the inclusion visit. As the 32-week time point for MRI collection have been reached 
for patients from Study BN40697 prior to approval of Study BN40955 Protocol v4.0, these patients will have their Week 48 MRI collected then 
follow the 32-weekly schedule thereafter. For example: MRI will be collected at Week 49, followed by Week 65 and Week 97. Patients from 
Study BN40423 (enrolled prior to Study BN40423 protocol Versions 4) who have reached or have passed the 32-week visit schedule prior to 
Study BN40955 Protocol v4.0 approval at site will have unscheduled MRI at the next clinic visit once the site is active on Protocol v4.0 then 
continue with the 32-weekly schedule thereafter. For example: unscheduled MRI (next clinic visit following protocol being active at site), then 
followed by Week 65 and Week 97. Patients from Study BP40410 who have completed inclusion visit prior to Study BN40955 Protocol v4.0 or to 
Study BP40410 v4.0 approval at site will have unscheduled MRI at the next clinic visit once the site is active on Study BN40955 Protocol v4.0
then continue with the 32-weekly schedule thereafter. For example: unscheduled MRI (next clinic visit following protocol being active at site), 
then followed by Week 33, Week 65, and Week 97.


RO7234292F. Hoffmann-La Roche Ltd
103/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
l
A neurologic examination(including fundoscopy), performed 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, 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 (inclusion visit) 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.
m Inclusion visit ECG is in accordance with the preceding study requirements.  Subsequent ECGs should be a single ECG performed after the 
patient has been resting in a supine position for at least 10 minutes.  Lead placement should be as consistent as possible.  ECGs for each 
patient should be obtained from the same machine whenever possible.  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.
n Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes).
o 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.
p Baseline pregnancy test is in accordance with preceding study requirements.  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.
q Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination if clinically indicated (sediment, 
RBCs, WBCs, casts, crystals, epithelial cells, bacteria).
r
Pharmacokinetics and immunogenicity samples will be collected prior to dosing. PK plasma samples are not required to be collected after the 
study treatment is paused. Immunogenicity plasma samples will continue to be collected.


RO7234292F. Hoffmann-La Roche Ltd
104/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
S While study dosing is paused, the CSF sample for safety/biomarkers and local PT and/or INR, aPTT and Platelet count will be collected every 
16 weeks for all patients. Details about the lumbar puncture schedule are addressed in Appendix 2b.  CSF sample for PK analysis is not 
required after the treatment is paused. Within 72 hours prior to performing each scheduled LP, 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 LP.  The LP should be performed at approximately the same time at each visit (ideally in the morning between 
8:00 a.m. and 12:00 p.m. or in the early afternoon between 12:00 p.m. and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters.  
Cerebrospinal fluid (20 mL) is to be collected for analyses using a LP collection kit.  If there are difficulties in collecting 20 mL of CSF, a minimum 
of 5 mL should be collected over a maximum of 60 minutes, once CSF flow has been established.  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 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 LP procedure if deemed necessary, but is not required.  Ultrasound guidance may be 
used if attempts at LP without imaging are unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate use of 
ultrasound with each LP.  Fluoroscopy guidance can also be used, if local institutional guidelines dictate and local IRB/ECs and health authorities 
have approved the use of the technique, but it is not required.  Where fluoroscopy is used, patients should also be informed and consent 
obtained.  Patients will be discouraged from resting supine after the LP 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 case of a 
failed IT bolus dosing procedure (e.g., due to an inadequate establishment of access to the IT space), a second dosing attempt may occur up to 
7 days after the originally scheduled dosing attempt.  For this additional visit, safety and tolerability evaluations on the day of LP administration 
will be performed as detailed in Appendix 1a, including neurological examination (predose and postdose), vital signs, and a review of adverse 
events and concomitant medication.  If the second dosing attempt occurs more than 72 hours after the last coagulation panel and platelets test, 
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.  For patients entering from Study BN40697, the drug administered at the inclusion visit will be the last dose of Study BN40697 
unless the visit is delayed as described in footnote a,in which case it will be the first dose in Study BN40955.  For patients entering from 
Study ML41885, the drug administered at the inclusion visit will be the first dose in Study BN40955.  For all other patients, the first dose in Study 
BN40955 will take place at the inclusion visit.
t
The C-SSRS will be used 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). C-SSRS will continue to be 
performed as per the original schedule even if the study drug administration is paused.


RO7234292F. Hoffmann-La Roche Ltd
105/Protocol BN40955, Version 7
Appendix 1a
Schedule of Activities for All Patients Except Those Undergoing Screening (cont.)
u Magnetic resonance imaging must be scheduled to occur before the LP. The MRI scan should be performed 714 days prior to the LP 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 LP, then it can be conducted the 
day after the LP, as long as there are no post-LP contraindications and it occurs within 2 weeks of the original scan.
v Optional MRI of brain and spine with contrast media will be completed upon study entry or upon transition to the new regimen and then every 
32 weeks thereafter.  This only applies to patients enrolling from Study BN40697.
w 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.
x The electronic devices for remote data collection will be the same devices from the preceding study where possible.  Devices must be returned 
to the clinic at the end of the study or upon early termination from the study.  If patients did not have a preconfigured smartphone and wrist-worn 
wearable in the preceding study, they will not be provided devices in this study.
y The EQ-5D-5L will only be completed in-clinic at each study drug administration visit and in cases where the Roche HD mobile device has 
reached the end of its lifespan or been lost.  If the EQ-5D-5L collection was duplicated in error (i.e., collected in Roche HD mobile app and site 
electronic device) during the study drug administration visit, the EQ-5D-5L data collected in the site electronic device will take precedence. The 
EQ-5D-5L will continue to be performed as per the original schedule even if the study drug administration is paused.
z Telephone safety follow-up will be conducted Q8W (alternating with in-clinic visits) for 1 year for all patients, and then Q16W in between study 
administration visits for Q16W arm to check for any change in patient status (e.g., adverse events and concomitant medications) since their last 
visit and depending on patient’s health status.  An unscheduled clinic visit may be arranged, if needed.  If a patient is due for a telephone safety 
call and they are in-clinic then this telephone safety follow-up call can be completed in-clinic at the site’s discretion.  As a result of the COVID-19 
pandemic, only where sites are impacted, these telephone safety calls can be conducted instead of an in-clinic visit.
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 the time of entry into Study BN40955 to the study completion/discontinuation visit.
bb After initiation of study drug at baseline (inclusion visit), 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 Effective 22 March 2021, Q8W and Q16W study drug administration is paused.


RO7234292F. Hoffmann-La Roche Ltd
106/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic
Screening a
Inclusion visit
Treatment Period
EoT b
SFU bb
Week
4 to 1
1
Treatment Assessment and Frequency
4 weeks
20 weeks
Day (Window)
28 to 2
1
1
1 week v
1 week v
1 week
Signed informed consent c
x
Review of inclusion and exclusion criteria
x
x
Demographic data
x
Medical history and baseline conditions d
x
x e
Blood sample for CAG repeat length a
x
Viral serology f
x
Thyroid panel g
x
Vital signs h
x
x e
At each clinic visit
x
x
Complete physical examination i
x
x e
Q32W
x
x
Neurologic examination j
x
x e
At each clinic visit (see Appendix 9)
x
x
ECG k
x
x e
Q32W
x
x


RO7234292F. Hoffmann-La Roche Ltd
107/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
Screening a
Inclusion 
visit
Treatment Period
EoT b
SFU bb
Week
4 to 1
1
Treatment Assessment and Frequency
4 weeks
20 weeks
Day (Window)
28 to 2
1
1
1 week v
1 week v
1 week
Hematology l
x
x
At each clinic visit
x
x
Chemistry m
x
x
x
x
Pregnancy test n
x
x e
x
x
Urinalysis o
x
x
x
x
Local PT and/or INR, aPTT, Platelet count x, u
x
At each study drug administration visit
x
x
Plasma sample for PK p
x
Q16W for 48 weeks and then Q32W
thereafter
Plasma sample for immunogenicity testing p
x
x
x
Plasma sample for biomarkers
x
x
x
CSF sample for PK/safety/biomarkers u
x
At each study drug administration
X
Mandatory Structural MRI q
x
Q32W
x
Optional resting-state functional MRI and
Diffusion-weighted MRI/NODDI r
X
Q32W
x
Independence Scale
x
MoCA
x
x
Q16W
x
C-SSRS r
x
x e
At each study drug administration
x


RO7234292F. Hoffmann-La Roche Ltd
108/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
Screening a
Inclusion visit
Treatment Period
EoT b
SFU bb
Week
4 to 1
1
Treatment Assessment and Frequency
4 weeks
20 weeks
Day (Window)
28 to 2
1
1
1 week v
1 week v
1 week
HD-DAS
X
Q16W
x
TFC s
x
x
TMS s 
x
x
x
CGI-S
x
x
CGI-C
x
SDMT s
x
x
SWR s
x
x
EQ-5D-5L w
x
At each study drug administration
x
Roche HD mobile app 
x
x
Continuous remote data collection, as 
well as Q16W in-clinic t
Q8W Study drug administration u, cc
x
Q8W
Q16W Study drug administration u, cc
x
Q16W


RO7234292F. Hoffmann-La Roche Ltd
109/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
Screening a
Inclusion visit
Treatment Period
EoT b
SFU bb
Week
4 to 1
1
Treatment Assessment and Frequency
4 weeks
20 weeks
Day (Window)
28 to 2
1
1
1 week v
1 week v
1 week
Telephone Safety follow-up x
Q8W arm: Q8W (alternating with in-clinic 
visits) for 1 year
Q16W arm: Q8W(alternating with 
in-clinic visits) for 1 year, then Q16W
Concomitant medications y
x
x
x
Each clinic visit and telephone safety 
follow-up call
x
x
Adverse events z
x
x
x
Each clinic visit and telephone safety 
follow-up call
x
x
CAGcytosine, adenine, and guanine; 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; HAhealth authority; HBsAghepatitis B surface antigen; HCVhepatitis C virus; HDHuntington disease; HD-DASHD Daily 
Activities Scale; IRB/ECInstitutional Review Board/Ethics Committee; LPlumbar puncture; MoCAMontreal Cognitive Assessment; 
MRImagnetic resonance imaging; NODDINeurite Orientation Dispersion and Density Imaging; PKpharmacokinetic; Q8Wevery 8 weeks; 
Q16Wevery 16 weeks; Q32Wevery 32 weeks; SDMTSymbol Digit Modalities Test; SFUsafety follow-up; SWRStroop Word Reading; 
TFCTotal Functional Capacity Scale; TMSTotal Motor Score.
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.


RO7234292F. Hoffmann-La Roche Ltd
110/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
a A maximum of 1 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). The CAG repeat length 
testing from Q2 Solutions will be accepted for this study. If re-screening is required, the CAG repeat length testing from Q2 Solutions does not 
need to be repeated. 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 inclusion visit.
b Patients who complete treatment (e.g., will continue treatment on commercially available drug) or who discontinue study drug prematurely will
return to the clinic for a treatment completion visit 4 weeks (7 days) after the decision to discontinue. For patients continuing treatment with
RO7234292 outside of the study, the end of study visit should occur before the patient's next dose of RO7234292.
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, reproductive status, will be recorded at screening and at baseline (inclusion 
visit).
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. Record abnormalities observed at screening and at the inclusion visit 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 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. Any abnormality identified screening and at baseline (inclusion visit) 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. 
Height will be obtained from screening and inclusion visit only.


RO7234292F. Hoffmann-La Roche Ltd
111/Protocol BN40955, Version 7
Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
j
A neurologic examination (including fundoscopy), performed 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, or before the lumbar puncture, if there is no study treatment administration. Weight 
should also be measured at each visit. Any abnormality identified at screening and baseline (inclusion visit) 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.
k Electrocardiograms should be triplicate at screening and subsequent ECGs should be a single ECG performed after the patient has been resting 
in a supine position for at least 10 minutes. Lead placement should be as consistent as possible. Electrocardiograms for each patient should be 
obtained from the same machine whenever possible. 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.
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 Pharmacokinetics and immunogenicity samples will be collected prior to dosing. PK plasma samples are not required to be collected after the 
study treatment is paused. Immunogenicity plasma samples will continue to be collected. 
q Magnetic resonance imaging 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 quality control check and the results must 
be available before the patient can be enrolled in the study. Magnetic resonance imaging must be scheduled to occur before the LP.  The follow-
up MRI scan should be performed 714 days prior to the LP 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 LP, then it can be conducted the day after the LP, as long as there are no post-LP contraindications and it 
occurs within 2 weeks of the original scan.


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Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
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). C-SSRS will continue to be performed as per the original 
schedule even if the study drug administration is paused.
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 While study dosing is paused, the CSF sample for safety/biomarkers and local PT and/or INR, aPTT and Platelet count will be collected every 
16 weeks for all patients. Details about the lumbar puncture schedule are addressed in Appendix 2b.  CSF sample for PK analysis is not 
required after the treatment is paused. Within 72 hours prior to performing each scheduled LP, 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 LP. The LP should be performed at approximately the same time at each visit (ideally in the morning between
8:00 a.m. and 12:00 p.m. or in the early afternoon between 12:00 p.m. and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters.  
Cerebrospinal fluid (20 mL) is to be collected for analyses using a LP collection kit. If there are difficulties in collecting 20 mL of CSF, a minimum
of 5 mL should be collected over a maximum of 60 minutes, once CSF flow has been established. 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 atraumatic needle, as specified in the LP procedure and
CSF collection guidelines, should be used. Depending on institutional guidelines, local aesthesia should be used for the procedure. Sedation
may not be used. Spinal ultrasound may be used for the LP procedure if deemed necessary, but is not required. Ultrasound guidance may be 
used if attempts at LP without imaging are unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate use of 
ultrasound with each LP. Fluoroscopy guidance can also be used, if local institutional guidelines dictate and local IRB/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. 
Patients will be discouraged from resting supine after the LP 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 case of a failed IT bolus 
dosing procedure (e.g., due to an inadequate establishment of access to the IT space), a second dosing attempt may occur up to 7 days after the 
originally scheduled dosing attempt. For this additional visit, safety and tolerability evaluations on the day of LP administration will be performed 
as detailed in Appendix 1b, including neurological examination (predose and postdose), vital signs, and a review of adverse events and 
concomitant medication. If the second dosing attempt occurs more than 72 hours after the last coagulation panel and platelets test, 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.


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Appendix 1b
Schedule of Activities for Patients who were Eligible for the GENERATION-HD1 Study but not 
Randomized due to Logistical Challenges Resulting from the COVID-19 Pandemic (cont.)
v
Excluding MRIs, which have a visit window of 14 to 7 days.
w The EQ-5D-5L will only be completed in-clinic at each study drug administration visit. The EQ-5D-5L will continue to be performed as per the 
original schedule even if the study drug administration is paused.
x Telephone safety follow-up will be conducted Q8W (alternating with in-clinic visits) for 1 year for all patients, and then Q16W in between study 
administration visits for Q16W arm to check for any change in patient status (e.g., adverse events and concomitant medications) since their last 
visit and depending on patient’s health status. An unscheduled clinic visit may be arranged, if needed. If a patient is due for a telephone safety 
call and they are in-clinic then this telephone safety follow-up call can be completed in-clinic at the site’s discretion. As a result of the COVID-19 
pandemic, only where sites are impacted, these telephone safety calls can be conducted instead of an in-clinic visit.
y 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 the time of entry into Study BN40955 to the study completion/discontinuation visit.
z 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 at baseline (inclusion visit), 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.
aa Safety follow-up visit occurs 20 weeks after EoT.
bb 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.
cc Effective 22 March 2021, Q8W and Q16W study drug administration is immediately paused.


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Appendix 2a Visit Schedule for the First 2 Years of Treatment
Month
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Week
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
Q8W study drug 
administration a
x
P
x
P
x
P
x
P
x
P
x
P
x
x
x
x
x
x
x b
Q16W study drug 
administration a
x
P
CV
P
x
P
CV
P
x
P
CV
P
x
P
x
P
x
P
x c
Efficacy 
assessments
x
x
x
x
x
x
x d
CVnon-treatment clinic visit; Pphone call; Q8Wevery 8 weeks; Q16Wevery 16 weeks.
Notes: The non-treatment clinic visit includes collection of the following assessments during the first year of assignment to Q16W regimen: 
vital signs, neurologic examination, hematology, chemistry, pregnancy test, urinalysis, concomitant medications, and adverse events.
a Q8W and Q16W study drug administration should be immediately paused until further assessments can be conducted following the release of 
the USM- DIL on March 22, 2021
b Patients will continue Q8W dosing until end-of-treatment.
c Patients will continue alternating telephone safety follow-up and treatment visits until end-of-treatment.
d Patients will continue efficacy assessments Q16W throughout treatment period.


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Appendix 2b 
Visit Schedule for the First 2 Years of Study Participation While on Treatment 
Pause
Month
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Week
1
5
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
77
81
85
89
93
97a
Q8W b, c
LP
P
NLPd
P
LP
P
NLPd
P
LP
P
NLPd
P
LP
NLPd
LP
NLPd
LP
NLPd
LP
Q16W e
LP
P
CV
P
LP
P
CV
P
LP
P
CV
P
LP
P
LP
P
LP
P
LP 
CVnon-treatment clinic visit; Pphone call; Q8Wevery 8 weeks; Q16Wevery 16 weeks; LP=clinic visit with lumbar puncture; NLP= clinic 
visit without lumbar puncture
Notes:  The non-treatment clinic visit includes collection of the following assessments during the first year of assignment to Q16W regimen: 
vital signs, neurologic examination, hematology, chemistry, pregnancy test, urinalysis, concomitant medications, and adverse events.
a All patients should continue performing the corresponding visits as described in Appendix 2b beyond the first 2 years.
b Q8Wpatients randomized to Q8W and paused  from receiving RO7234292 study drug following the USM-DIL (dated 22 March 2021).
c
Patients who were randomized to Q8W study drug administration and paused from receiving RO7234292 study drug will continue to 
undergo clinic visits performing LP and alternate non LP (NLP) visits. At the LP visits, CSF sample for safety/biomarkers will be performed. 
Local PT and/or INR, aPTT, Platelet count and neurological examinations will be performed prior to LP only. CSF sample for PK and plasma 
for PK will not be required after study treatment was paused. Immunogenicity samples will continue to be collected.
d Non-LP visits will continue as described in Appendix 1a and Appendix 1b. CSF samples for PK/safety/biomarkers and local PT/and/or INR, 
aPTT and platelet count are not required at these visits. Neurological examinations should be performed at Non-LP visits.
e
Q16Wpatients randomized to Q16W and paused from receiving RO7234292 study drug following the USM-DIL (dated 22 March 2021)..


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Appendix 3 Clinician-Reported Outcomes
Assessment
Name
Items
Concepts
Approx. 
Duration
Timing
IS
Independence Scale
1
Functional Disability
3
Screening (for patients required to undergo 
screening only)
TFC
Total Functional Capacity Scale
5
Overall function
10 min
Inclusion visit, every 16 weeks, and EoT 
visit
TMS
Total Motor Score
31
Motor function
15 min
DCL only: screening (only for patients 
required to undergo screening)
TMS without DCL: inclusion visit, 
every 16 weeks, and EoT visit
C-SSRS a
Columbia-Suicide Severity 
Scale
5
Suicidal ideation and
behavior
20 min full 
version;
5 min 
follow-up 
version
Full version at screening in-clinic (only for 
patients required to undergo screening);
Follow-up version at each study drug 
administration visit
CGI-S
Clinical Global 
ImpressionSeverity
1
Overall severity of 
patient status
2 min
Inclusion visit, every 16 weeks, and EoT 
visit
CGI-C
Clinical Global 
ImpressionChange
1
Overall change in 
patient status
2 min
Every 16 weeks and EoT visit
HD-DAS
Huntington's Disease Daily 
Activities Scale 
25
Daily function
25 min
Inclusion visit, every 16 weeks, and EoT 
visit
DCLdiagnostic confidence level; EoTend-of-treatment; ISIndependence Scale.
a
C-SSRS will continue to be performed as per the original schedule even if the study drug administration is paused.


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Appendix 4 Patient-Reported Outcomes, Performance Outcomes, and Roche HD Mobile 
Application
Assessment
Name
Items
Concepts
Approx.
Duratio
n (min)
PRO, 
PerfO,
Behavior
Timing
Location
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
10
Sensor 
data, 
PRO, 
PerfO
Remote: up to daily
Clinic visits: Inclusion visit, 
every 16 weeks, and EoT 
visit
Roche HD 
mobile app
EQ-5D-5L a
EuroQol 5-Dimension, 
5-Level Questionnaire
6
Health utilities
5
PRO
Remote:  up to weekly
Roche HD 
mobile app
In-clinic:  at each study 
drug administration visit
In-clinic
HD-SDI
Huntington’s Disease,
Speaking Difficulty 
Item
1
Speech
1
PRO
Remote: up to weekly
Roche HD 
mobile app b
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive 
status
10
PerfO
Screening (only for patients 
required to undergo 
screening), Inclusion visit, 
every 16 weeks, and EoT 
visit
In-clinic


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Appendix 4 Patient-Reported Outcomes, Performance Outcomes, and Roche HD Mobile 
Application (cont.)
Assessment
Name
Items
Concepts
Approx. 
Duratio
n (min)
PRO, 
PerfO, 
Behavior
Timing
Location
SDMT/
eSDMT
Symbol Digit 
Modalities Test
Max number in 
90 seconds
Cognitive
5
PerfO
Inclusion visit, every 
16 weeks, and EoT visit
In-clinic
Remote:  Up to weekly
Roche HD 
mobile app 
(eSDMT)
SWR/eSWR
Stroop Word Reading 
Test
Max numbers 
in 45 seconds
Cognitive
5
PerfO
Inclusion visit, every 
16 weeks, and EoT visit
In-clinic
Remote:  Up to weekly
Roche HD 
mobile app 
(eSWR)
WHODAS 2.0
World Health 
Organisation 
Disability Assessment 
Schedule 2.0
15
Health-related 
quality of life
10
PRO
Remote: Monthly
Roche HD 
mobile app b
WPAI
Work Productivity and 
Activity Impairment
6
Work productivity
5
PRO 
Remote: Monthly
Roche HD 
mobile app b
appapplication; EoTend-of-treatment; HDHuntington disease; NAnot applicable; PerfOperformance outcome; PROpatient-reported 
outcome.
a Complete during in-clinic visit at each study drug administration and in cases where Roche HD mobile has reached the end of its life span or has 
been lost. EQ-5D-5L will continue to be performed as per the original schedule even if the study drug administration is paused.
b Only applicable if previous study also used this remote assessment.


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Appendix 5 Clinical Assessments Order and Duration for 
Patients Required to Undergo Screening Only
Table 1
Screening Visit Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff
Responsible
1
Diagnostic Confidence Level ª
Independence Scale
MoCA
C-SSRS
~60
Qualified study
physician
C-SSRSColumbia-Suicide Severity Rating Scale; DCLDiagnostic Confidence Level; 
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.


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Appendix 6 Diagnostic Confidence Level for Patients Required 
to Undergo Screening Only
The Diagnostic Confidence Level is calculated as shown below (from Unified 
Huntington’s Disease Rating Scale [UHDRS] Total Motor Score [TMS] 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 7 Clinical Assessments Order and Duration
Table 1
Clinical Assessments
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Huntington's Disease Daily Activities Scale
TFC
TMS
C-SSRS a
CGI-S
CGI-C (not required at inclusion visit)
~60
Qualified 
study 
physician
Break (if needed)
~2030
2
MoCA
SDMT
SWR
EQ-5D-5L
~20
Qualified 
study 
personnel
Break (if needed)
~2030
3
Roche HD mobile application
~20
Qualified 
study 
personnel
CGI-CClinical Global Impression, Change; CGI-SClinical Global Impression, Severity; 
C-SSRSColumbia-Suicide Severity Rating Scale; EQ-5D-5LEuroQol 5-Dimension, 5 Level 
Questionnaire; MoCAMontreal Cognitive Assessment; SDMTSymbol Digit Modalities Test; 
SWRStroop Word Reading; TFCTotal Functional Capacity Scale; TMSTotal Motor Score.
a Collected at Screening (for patients required to undergo screening) then repeated at every 
study drug administration clinical visit. C-SSRS will continue to be performed as per the 
original schedule even if the study drug administration is paused.


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Appendix 8 Remote Clinical Assessments Order and Duration 
(COVID-19 Impacted Sites where a Patient Cannot Attend the 
Clinic or the Investigator Site Has Closed due to Restrictions 
Imposed as a Result of COVID-19)
Table 1
Revised Assessment Schedule for Remote Data Collection 
(During COVID-19 Pandemic Only) Every Dosing Visit 
(for C-SSRS), 16 Weeks and EoT Visit
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Huntington's Disease Daily Activities Scale
Total Functional Capacity Scale
Columbia-Suicide Severity Rating Scale
Clinical Global ImpressionSeverity
Clinical Global ImpressionChange
~60
Qualified study 
physician
Huntington's Disease Daily Activities Scale (HD-DAS) and Total Functional 
Capacity (Phone call)

A phone call to the patient should be conducted by the study physician.

The study physician should enter data for the scales directly onto the tablet, and for 
sites that use more than 1 tablet, must ensure that the appropriate tablet that has 
the patient data is used.
Columbia-Suicide Severity Rating Scale (via a phone interview with the patient)

The study physician should also complete the Columbia-Suicide Severity Rating 
Scale (C-SSRS) on the tablet via a phone interview with the patient.

This is a critical safety endpoint, and of particular importance in this population.
Clinical Global Impression scales

The study physician should complete the Clinical Global Impression scales 
(using the tablet) following the phone calls for the other Block 1 assessments.
Symbol Digit Modalities Test, Stroop Word Reading, and Montreal Cognition 
Assessment

For the Performance Outcomes in Block 2 (Symbol Digit Modalities Test [SDMT], 
Stroop Word Reading [SWR], and Montreal Cognition Assessment [MoCA]), 
currently these assessments should not be collected remotely.


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Appendix 9 Roche HD Mobile Application:  Active Test
The following tasks are part of the active testsconducted on the Roche Huntington's disease 
(HD) mobile application by the patient.  This constitutes a comprehensive list; all patient-reported 
outcomes (PROs) (i.e., EuroQol 5-Dimension, 5-Level Questionnaire [EQ-5D-5L], 
Work Productivity and Activity Impairment [WPAI], HD Speaking Difficulty Item [HD-SDI], 
WHO Disability Assessment Schedule [WHODAS 2.0]) are not on all devices.
If a patient already has a preconfigured smartphone and wrist-worn wearable with installed 
software for the Roche HD mobile app assessments from the preceding study, they will continue 
to use these in this study.  If patients did not have a preconfigured smartphone and wrist-worn 
wearable in the preceding study, they will not be provided devices.
Tasks take 510 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., EQ-5D-5L, WPAI, 
HD-SDI, 2-Minute Walk Test) are rolled over to the next time the active test is completed.
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 (electronic Symbol Digit Modalities Test)
The Cognitive Test asks participants to match symbols with numbers according to a key as 
quickly and accurately as possible.  The key, symbols, and numbers are all displayed on a 
smartphone screen.  The test assesses visuomotor integration and measures visual attention and 
motor speed.  It is modeled on the pen and paper Symbol Digit Modalities Test (SDMT; 
Smith 1968).  The SDMT has been shown to be sensitive to symptom changes in patients with 
early HD (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 modeled on the Stroop Word Reading (SWR) (Stroop 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).


Appendix 9: Roche HD Mobile Application: Active Test (cont.)
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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 modeled 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 patients with early 
HD.  It is modeled 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 
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 2 points that are at least 
four steps apart, while wearing the smartphone and wrist-worn wearable.  They need to make at 
least 5 turns.  The test is designed to assess gait and lower-body bradykinesia, which are also 
assessed by the UHDRS.  It is modeled 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).


Appendix 9: Roche HD Mobile Application: Active Test (cont.)
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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 conducted on 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).
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 Visual Analog Scale (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 remotely at specified timepoints by the patient on 
the Roche HD mobile app.
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 numeric rating scale, 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). It will be completed at specified 
timepoints remotely by the patient on the Roche HD mobile app.
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.
WHO Disability Assessment Schedule 2.0
The WHODAS 2.0 (12-item version) assesses disability and aspects of HRQoL.  It is intended for 
use in any disease population, and it is linked to the concepts in the International Classification of 
Functioning, Disability, and Health.  The 12-item version contains 15 items, 12 of which produce a 
total score, with 3 additional questions administered to assess overall difficulty and activity 
impairment.  All items are scored on a 04 Likert-type scale. The total raw score is converted 


Appendix 9: Roche HD Mobile Application: Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
126/Protocol BN40955, Version 7
onto a 0100 point scale, where higher scores indicate greater difficulty.  The WHODAS 2.0 will 
take approximately 10 minutes to complete.
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.
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372.
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.
EuroQol Group. EuroQola new facility for the measurement of health-related quality of life. 
Health Policy 1990;16:199208.
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.
Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. 
Mov Disord 1996;11:13642.Kegelmeyer et al. 2017.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared to 
the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res 
2013;22:171727.
Kegelmeyer DA, Kostyk SK, Fritz NE, et al. Quantitative biomechanical assessment of trunk 
control in Huntington’s disease reveals more impairment in static than dynamci tasks. 
J Neurol Sci 2017;376:2934.
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.
Reilmann R, Bohlen S, Klopstock T, et al. Grasping premanifest Huntington's disease - shaping 
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Say MJ, Jones R, Scahill R, et al. Visuomotor integration deficits precede clinical onset in 
Huntington's disease. Neuropsychologia 2011;49:26470.


Appendix 9: Roche HD Mobile Application: Active Test (cont.)
RO7234292F. Hoffmann-La Roche Ltd
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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 
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month observational data. Lancet Neurol 2013;12:63749.


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Appendix 10 Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities
The following grading recommendations for adverse events relating to laboratory test 
abnormalities are based on the National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0.


Appendix 10:  Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
(cont.)
RO7234292F. Hoffmann-La Roche Ltd
129/Protocol BN40955, Version 7


Appendix 10:  Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
(cont.)
RO7234292F. Hoffmann-La Roche Ltd
130/Protocol BN40955, Version 7
LLNlower limit of normal; ULNupper limit of normal.


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Appendix 11 List of Preceding Clinical Trials
Patients from the following Roche-sponsored or Genentech-sponsored clinical trials are 
eligible for consideration for enrollment in Study BN40955.
Table 1
Preceding Clinical Trials
Protocol Number
Protocol Title
BP40410
AN OPEN-LABEL, ADAPTIVE MULTI-DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS AND 
PHARMACODYNAMICS OF RO7234292 IN CSF AND PLASMA, 
AND SAFETY AND TOLERABILITY FOLLOWING 
INTRATHECAL ADMINISTRATION IN PATIENTS WITH 
HUNTINGTON’S DISEASE
BN40422
A MULTI-SITE, PROSPECTIVE, LONGITUDINAL, COHORT 
STUDY MEASURING CEREBROSPINAL FLUID-MUTANT 
HUNTINGTIN PROTEIN IN PATIENTS WITH HUNTINGTON’S 
DISEASE
BN40423
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
BN40697
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS AND 
PHARMACODYNAMICS OF RO7234292 (ISIS 443139) IN 
HUNTINGTON'S DISEASE PATIENTS WHO PARTICIPATED IN 
PRIOR INVESTIGATIONAL STUDIES OF RO7234292 
(ISIS 443139)
ML41885
A PHASE II, MULTI-CENTER, OPEN-LABEL STUDY TO 
EVALUATE SAFETY/TOLERABILITY OF INTRATHECALLY 
ADMINISTERED TOMINERSEN IN PATIENTS WITH LATE-
ONSET MANIFEST HUNTINGTON’S DISEASE


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Appendix 12 Guidance for Neurological Examination
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 without 
study treatment administration, the neurological examination 
should be performed prior to the lumbar puncture.