Clinical trial NCT04000594
Conditions: Huntingtons Disease
Sponsor: Hoffmann-La Roche
Start date: 2019-09-02; Completion date: 2022-01-18
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to characterize the PK of RO7234292 (RG6042) in plasma and CSF as well as the acute time course and recovery profile of CSF mHTT lowering in response to RO7234292 (RG6042) treatment after intrathecal (IT) administration of RO7234292 (RG6042) to patients with manifest Hungtington's disease (HD).

Detailed description:

Arms: arm 1: Participants will receive dose level 1 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29. arm 2: Participants will receive dose level 2 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29. arm 3: Participants will receive dose level 3 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29.
Interventions: intervention 1: RO7234292 (RG6042)
Intervention descriptions: intervention 1: RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.

Protocol documents:
Prot_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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 BP40410, Version 4
PROTOCOL
TITLE:
AN OPEN-LABEL, ADAPTIVE MULTIPLE-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
PROTOCOL NUMBER:
BP40410
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003010-40
NCT NUMBER:
NCT04000594
TEST PRODUCT:
RO7234292
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  11 December 2018
DATES AMENDED:
Version 2: 30 January 2019
Version 3:  27 May 2019
Version 4:  See electronic date stamp below
 
24-Feb-2020 14:34:23
Title
Approver's Name
Company Signatory
Date and Time (UTC)


RO7234292—F. Hoffmann-La Roche Ltd
2/Protocol BP40410, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol BP40410 has been amended for the following reasons:  

To address the reporting of two serious adverse events of lumbar abscess after 
removal of intrathecal (IT) catheter, an Urgent Safety Measure Dear Investigator 
Letter was submitted on 8 and 11 February 2020 in the United Kingdom and the 
Netherlands, respectively, requesting immediate suspension of RO7234292
administration via IT catheter.  Consequently, enhanced antiseptic measures prior to 
IT catheter insertion, additional monitoring for infection while the catheter is 
indwelling and after catheter removal, improved guidance for monitoring in the event 
of back pain, and reduction of the catheter implantation duration have been 
incorporated in this amendment and will be implement upon approval of protocol 
Version 4.

Magnetic resonance imaging (MRI) has been added as an assessment during the 
screening period and at the follow-up visit 6 months after the last study drug 
administration (or at early termination visit, if applicable).  MRI is a non-invasive 
method to assess structure and function of the human brain and can provide 
insights into the pathophysiological mechanisms of neurologic and neuropsychiatric 
diseases.  Standard safety sequences will be acquired; structural MRI will be used 
to assess brain volume.  If clinically indicated, optional diffusion-weighted and 
resting state functional MRI sequences will be acquired.  MRI assessments will 
primarily serve as a safety measure to exclude any contraindication to IT catheter 
insertion and lumbar puncture and any overall contraindication to participation in 
Study BP40410.  In addition, both screening and 6-month follow-up MRI 
assessments will serve as a baseline assessment to enable ongoing safety 
monitoring for those patients who enroll in the open-label extension study (OLE) 
Study BN40955 upon completion of Study BP40410.

The dose level used for enrolled patients in the third dose group has been modified 
from 90 mg to 30 mg. This change will potentially enable a reduction in the total 
number of patients to be recruited and to undergo IT catheter insertion, as relevant 
data will be collected from the first 12 patients (as originally planned). Data 
generated in recently completed Phase I/IIa Study (ISIS 443139-CS1) and 
ongoing OLE Study BN40697 have enabled refinement of model-based simulations, 
leading to the indication that 30 mg doses of RO723429 may be more informative 
than 90 mg doses to enable characterization of the pharmacokinetics, 
pharmacodynamics, and pharmacokinetic/pharmacodynamic relationships of 
RO723429, i.e. addressing the primary study objectives.

Safety Section 5.1 has been updated with recent data from the 15-month data 
analysis of the ongoing OLE Study BN40697. 


RO7234292—F. Hoffmann-La Roche Ltd
3/Protocol BP40410, Version 4
Changes to the protocol are summarized below:

Because duration of the catheter presence is believed to be one of the risk factors
for infection, the indwelling ITcatheter duration has been reduced from 96 hours to 
48 hours by eliminating the insertion 24 hours predose and the final day of sampling 
postdose.  Thus, the catheter will be inserted prior to dosing on Day 1 and will be 
removed 48 hours after dosing.  Applicable changes have been made to Section 1.3, 
Figure 1 and the schedules of activities (Appendix 1 and Appendix 2). 

The 90 mg dose level has been replaced with 30 mg in Sections 3.1 and 4.3.2, and 
data supporting the change of dose level have been added in Section 3.3.1. 

A subsection to the Rationale for Biomarker Assessments (Section 3.3.3.5) has 
been added to summarize the use of different MRI techniques to assess structure 
and function of the human brain and provide insights into the pathophysiological 
mechanisms of neurologic and neuropsychiatric diseases.

An inclusion criterion for the ability to undergo and tolerate MRI scans has been
added to Section 4.1.1. An exclusion criterion for preexisting intra-axial or 
extra-axial lesions has been added to Section 4.1.2.

Language on the prohibition of the use of anti-anxiety medication during scheduled 
MRI scans has been added to Section 4.4.2.

Language has been added to Section 4.5.1 detailing instructions for a separate 
optional procedure consent and to include MRI among the assessments not 
required at re-screening. 

Additional safety measures pre- and post-insertion of the IT catheter have been 
added in Section 4.5.5 and Section 4.5.6 as preventive and monitoring measures to 
limit the risk of infection. Known risks associated with an indwelling catheter have 
been added in a new subsection 5.1.1.4, to reflect updated safety data.  Additional 
safety assessments, including skin and nasal swabs for methicillin-resistant 
Staphylococcus aureus (MRSA) screening, blood tests (CRP, ESR and hematology), 
CSF sample culture, and culture of the catheter tip upon removal of the catheter 
have been added. The schedules of activities (Appendix 1 and Appendix 2) have 
been updated accordingly. Table 1 has been updated to provide guidance for 
management of a persistent back pain event.

Language regarding MRI assessments during the screening period and at the 
follow-up visit has been added to Section 4.5 (new subsection 4.5.9) and the 
schedule of activities (Appendix 1).
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


RO7234292—F. Hoffmann-La Roche Ltd
4/Protocol BP40410, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 22
1.1
Background on Huntington’s Disease.................................... 22
1.2
Background on RO7234292 .................................................. 23
1.3
Study Rationale and Benefit-Risk Assessment...................... 25
2.
OBJECTIVES AND ENDPOINTS ............................................................... 26
2.1
Primary Objectives ................................................................ 26
2.1.1
Primary Endpoints ................................................................. 27
2.2
Secondary Objectives............................................................ 27
2.2.1
Secondary Endpoints ............................................................ 27
2.3
Exploratory Objectives/Endpoints.......................................... 27
3.
STUDY DESIGN......................................................................................... 28
3.1
Description of the Study......................................................... 28
3.2
End of Study and Length of Study......................................... 30
3.3
Rationale for Study Design.................................................... 30
3.3.1
Rationale for RO7234292 Dose and Schedule...................... 30
3.3.2
Rationale for Patient Population ............................................ 31
3.3.3
Rationale for Biomarker Assessments................................... 31
3.3.3.1
Cerebrospinal Fluid Biomarkers ............................................ 31
3.3.3.2
Blood-Derived Biomarkers..................................................... 32
3.3.3.3
Genetic Testing to Determine CAG Repeat 
Length.................................................................................... 32
3.3.3.4
Clinical Genotyping................................................................ 32
3.3.3.5
Magnetic Resonance Imaging................................................ 32
4.
MATERIALS AND METHODS .................................................................... 33
4.1
Patients.................................................................................. 33
4.1.1
Inclusion Criteria.................................................................... 33
4.1.2
Exclusion Criteria................................................................... 35
4.2
Method of Treatment Assignment and Blinding..................... 37


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4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 38
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 38
4.3.1.1
RO7234292 ........................................................................... 38
4.3.1.2
Diluent ................................................................................... 39
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 39
4.3.3
Investigational Medicinal Product Accountability ................... 40
4.3.4
Continued Access to RO7234292 ......................................... 40
4.4
Concomitant Therapy ............................................................ 41
4.4.1
Permitted Therapy................................................................. 41
4.4.2
Prohibited Therapy ................................................................ 42
4.5
Study Assessments ............................................................... 42
4.5.1
Informed Consent Forms and Screening Log........................ 43
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 43
4.5.3
Physical Examinations........................................................... 44
4.5.4
Vital Signs.............................................................................. 44
4.5.5
Collection of Cerebrospinal Fluid (Lumbar 
Puncture Procedure) ............................................................. 45
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 46
4.5.7
Electrocardiograms................................................................ 48
4.5.7.1
Holter ECG Monitoring........................................................... 48
4.5.8
Performance Outcome and Clinician-Reported 
Outcomes .............................................................................. 49
4.5.8.1
Total Functional Capacity Scale ............................................ 50
4.5.8.2
Independence Scale.............................................................. 50
4.5.8.3
Huntington’s Disease Daily Activities Scale........................... 50
4.5.8.4
Total Motor Scale .................................................................. 50
4.5.8.5
Clinical Global Impression – Severity .................................... 51
4.5.8.6
Clinical Global Impression – Change..................................... 51
4.5.8.7
Montreal Cognitive Assessment ............................................ 51
4.5.8.8
Symbol Digit Modalities Test ................................................. 51


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4.5.8.9
Stroop Word Reading Test .................................................... 51
4.5.8.10
Columbia-Suicide Severity Rating Scale ............................... 51
4.5.9
Magnetic Resonance Imaging................................................ 52
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 53
4.5.10.1
Overview of the Research Biosample Repository.................. 53
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 53
4.5.10.3
Sample Collection.................................................................. 53
4.5.10.4
Confidentiality........................................................................ 54
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 55
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 55
4.5.10.7
Monitoring and Oversight....................................................... 55
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 56
4.6.1
Study Treatment Discontinuation........................................... 56
4.6.2
Patient Discontinuation from Study........................................ 56
4.6.3
Study Discontinuation............................................................ 57
4.6.4
Site Discontinuation............................................................... 57
5.
ASSESSMENT OF SAFETY....................................................................... 57
5.1
Safety Plan ............................................................................ 57
5.1.1
Known Risks Associated with Lumbar Puncture.................... 58
5.1.1.1
Post-Lumbar Puncture Syndrome ......................................... 59
5.1.1.2
Spinal Hematoma.................................................................. 59
5.1.1.3
Meningitis .............................................................................. 59
5.1.1.4
Known Risks Associated with an Indwelling 
Catheter ................................................................................. 60
5.1.2
Potential Risks Associated with RO7234292......................... 60
5.1.2.1
Neurological Changes ........................................................... 60
5.1.2.2
Elevations in CSF WBCs and Protein.................................... 60
5.1.2.3
Thrombocytopenia................................................................. 61
5.1.2.4
Kidney Effects........................................................................ 61


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7/Protocol BP40410, Version 4
5.1.2.5
Liver Effects........................................................................... 62
5.1.2.6
Hydrocephalus....................................................................... 62
5.1.2.7
Neuropsychiatric Changes..................................................... 62
5.1.2.8
Potential Risk Due to Reduction of Target Protein 
HTT........................................................................................ 62
5.1.3
Management of Patients Who Experience 
Adverse Events ..................................................................... 63
5.1.3.1
Dose Modifications ................................................................ 63
5.1.3.2
Treatment Interruption ........................................................... 63
5.1.3.3
Management Guidelines........................................................ 64
5.2
Safety Parameters and Definitions ........................................ 67
5.2.1
Adverse Events ..................................................................... 67
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 68
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 69
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 69
5.3.1
Adverse Event Reporting Period ........................................... 69
5.3.2
Eliciting Adverse Event Information....................................... 70
5.3.3
Assessment of Severity of Adverse Events ........................... 70
5.3.4
Assessment of Causality of Adverse Events ......................... 70
5.3.5
Procedures for Recording Adverse Events............................ 71
5.3.5.1
Injection Reactions ................................................................ 71
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 71
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 72
5.3.5.4
Persistent or Recurrent Adverse Events................................ 72
5.3.5.5
Abnormal Laboratory Values ................................................. 72
5.3.5.6
Abnormal Vital Sign Values ................................................... 73
5.3.5.7
Abnormal Liver Function Tests.............................................. 74
5.3.5.8
Deaths ................................................................................... 74
5.3.5.9
Preexisting Medical Conditions.............................................. 75
5.3.5.10
Lack of Efficacy or Worsening of HD..................................... 75
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 75


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5.3.5.12
Safety Biomarker Data........................................................... 76
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 76
5.4.1
Emergency Medical Contacts................................................ 76
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 77
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 77
5.4.2.2
Events That Occur after Study Drug Initiation........................ 77
5.4.3
Reporting Requirements for Pregnancies.............................. 78
5.4.3.1
Pregnancies in Female Patients............................................ 78
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 78
5.4.3.3
Abortions ............................................................................... 78
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 79
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 79
5.5
Follow-Up of Patients after Adverse Events .......................... 80
5.5.1
Investigator Follow-Up........................................................... 80
5.5.2
Sponsor Follow-Up ................................................................ 80
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 81
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 81
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 81
6.1
Determination of Sample Size ............................................... 81
6.2
Summaries of Conduct of Study............................................ 82
6.3
Analysis Populations ............................................................. 82
6.3.1
Safety Analysis Population .................................................... 82
6.3.2
Pharmacokinetic Analysis Population.................................... 82
6.3.3
Pharmacodynamic Analysis Population................................. 82
6.4
Safety Analyses..................................................................... 82
6.4.1
Adverse Events ..................................................................... 82
6.4.2
Clinical Laboratory Test Results............................................ 83
6.4.2.1
Standard Reference Ranges and Transformation 
of Data................................................................................... 83


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6.4.2.2
Definition of Laboratory Abnormalities................................... 83
6.4.3
Vital Signs.............................................................................. 83
6.4.4
12-/ead ECG........................................................................83
6.4.5
Concomitant Medications ...................................................... 84
6.5
Pharmacokinetic Analyses..................................................... 84
6.6
Immunogenicity Analyses...................................................... 85
6.7
Biomarker Analyses............................................................... 85
7.
DATA COLLECTION AND MANAGEMENT ............................................... 86
7.1
Data Quality Assurance......................................................... 86
7.2
Electronic Case Report Forms............................................... 86
7.3
Source Data Documentation.................................................. 86
7.4
Use of Computerized Systems .............................................. 87
7.5
Retention of Records............................................................. 87
8.
ETHICAL CONSIDERATIONS.................................................................... 88
8.1
Compliance with Laws and Regulations ................................ 88
8.2
Informed Consent.................................................................. 88
8.3
Institutional Review Board or Ethics Committee.................... 89
8.4
Confidentiality........................................................................ 89
8.5
Financial Disclosure .............................................................. 90
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 90
9.1
Study Documentation ............................................................ 90
9.2
Protocol Deviations................................................................ 90
9.3
Site Inspections ..................................................................... 91
9.4
Administrative Structure......................................................... 91
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 91
9.6
Protocol Amendments ........................................................... 92
10. REFERENCES ........................................................................................... 93


RO7234292—F. Hoffmann-La Roche Ltd
10/Protocol BP40410, Version 4
LIST OF TABLES
Table 1
Guidelines for Management of Patients Who Experience 
Adverse Events........................................................................... 65
Table 2
Adverse Event Severity Grading Scale ....................................... 70
Table 3
Causal Attribution Guidance ....................................................... 71
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 29
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 97
Appendix 2
Schedule of Detailed Assessments During the In-house 
Periods...................................................................................... 106
Appendix 3
Clinician-Reported Outcomes ................................................... 109
Appendix 4
Performance Outcomes ............................................................ 110
Appendix 5
Diagnostic Confidence Level..................................................... 111
Appendix 6
Order of Assessments .............................................................. 112
Appendix 7
Grading Scale for Adverse Events Related to Laboratory 
Abnormalities ............................................................................ 113


RO7234292—F. Hoffmann-La Roche Ltd
11/Protocol BP40410, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, ADAPTIVE MULTIPLE-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
PROTOCOL NUMBER:
BP40410
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003010-40
NCT NUMBER:
NCT04000594
TEST PRODUCT:
RO7234292
MEDICAL MONITOR:
, M.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
12/Protocol BP40410, Version 4
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, ADAPTIVE MULTIPLE-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
PROTOCOL NUMBER:
BP40410
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-003010-40
NCT NUMBER:
NCT04000594
TEST PRODUCT:
RO7234292
PHASE:
I
INDICATION:
Huntington’s disease
SPONSOR:
F.  Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of 
RO7234292 in patients with Huntington’s disease (HD).  Specific objectives and corresponding 
endpoints for the study are outlined below.
Primary Objectives and Endpoints
The primary objectives for this study are as 
follows:

To characterize the PK of RO7234292 in 
CSF and plasma following administration 
of multiple (2) IT doses of RO7234292

To characterize mHTT CSF protein time 
course following administration of 
multiple (2) IT doses of RO7234292 in 
patients with HD

To investigate the PK/PD relationship of 
multiple (2) IT doses of RO7234292 on 
mHTT in CSF
The corresponding primary endpoints are as 
follows:

CSF and plasma concentrations of 
RO7234292

Change from baseline of mHTT 
concentrations in CSF

Relationship between plasma and/or 
CSF concentration or PK parameters 
and biomarker measures (mHTT in CSF)


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Secondary Objectives and Endpoints
The secondary objectives for this study are 
as follows:

To assess the safety and tolerability of 
multiple (2) IT doses of RO7234292 in 
patients with HD

To evaluate the immunogenicity of 
RO7234292

To characterize the PK of RO7234292 in 
urine following administration of an IT 
dose of RO7234292
The corresponding secondary endpoints are 
as follows:

Incidence and severity of adverse 
events, with severity determined 
according to the Adverse Event Severity 
Grading Scale 

Changes in vital signs, ECGs, and 
clinical laboratory results

Proportion of patients with suicidal 
ideation or behavior, as assessed by 
C-SSRS score at visits indicated in the 
schedule of assessments, including 
detailed focus on any individual cases 
identified as having severe ideation or 
behavior during the study conduct

Incidence of ADAs at specified timelines 
relative to the prevalence of ADAs at 
baseline

Titer and antibody subtype, determined if 
ADAs are identified

Urine concentrations of RO7234292
Exploratory Objectives and Endpoints
The exploratory objectives for this study 
would be to evaluate the effects of 
RO7234292 compared on the basis of the 
exploratory endpoints.
The corresponding exploratory endpoints 
are as follows:

Change from baseline in exploratory 
biomarkers in CSF (e.g. NfL)

Relationship between exploratory fluid 
biomarkers in CSF and blood (e.g. CSF 
and plasma NfL)

Relationship between biomarkers, safety 
(including Holter monitoring), PK, and 
immunogenicity

Relationship of biomarkers to clinical 
severity at baseline using the Unified 
Huntington’s Disease Rating Scale and 
Clinical Global Impression
ADA=anti-drug antibodies; CSF=cerebrospinal fluid; C-SSRS=Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; HD=Huntington's disease; IT=intrathecal; mHTT=mutant 
Huntingtin; NfL=neurofilament light chain; PD=pharmacodynamics; PK=pharmacokinetic.


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Study Design
Description of the Study
Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to generate 
more granular time course data on PK, PD, and the PK/PD relationship after intrathecal (IT) 
administration of RO7234292 to patients with manifest HD.  
Up to a maximum of 20 patients will be enrolled in the study.  Prospective patients will undergo 
screening assessments during a 4-week screening period.  A maximum of one re-screening will 
be allowed within 4 weeks of the initial screening failure for patients who fail the initial screening.
Patients will undergo safety and tolerability evaluations that include physical and neurological 
examinations, vital signs, electrocardiograms (ECGs), magnetic resonance imaging (MRI) 
scans, clinical laboratory safety tests, Columbia-Suicide Severity Rating Scale (C-SSRS), and 
adverse event monitoring including related concomitant medications, as detailed in Appendix 1.
The following tentative dose levels are planned for the study:

Dose level 1: 120 mg RO7234292 (n=4 patients)

Dose level 2: 60 mg RO7234292 (n=4 patients)

Dose level 3: 30 mg RO7234292 (n=4 patients)
Patients will be assigned to a dose level in the order in which they are enrolled into the study.  
The final number of dose levels and total number of patients assigned to a given dose level will 
be defined during the study.  Up to a maximum of 20 patients may be enrolled in the study, in 
order to enable investigation of additional dose levels other than those planned, or to repeat a 
dose level if required to fully characterize the PK, PD, safety and tolerability, or other 
pharmacological responses.
The highest tested RO7234292 dose in this study will not exceed 120 mg, which is the highest 
test dose in the previous Phase I/IIa clinical study (ISIS 443139-CS1).
After ongoing review of all available medical data (including adverse events, ECGs, vital signs, 
laboratory safety data, PK, and biomarker data) of the initial three dose groups of 120 mg, 
60 mg, and 30 mg, the decision will be made if any should be repeated, adjusted downwards, or 
if intermediate doses should be investigated.
Patients who complete the treatment period will return to the clinic for the follow-up visit, at 
6 months 2 weeks after the last study drug administration.  Patients will then be given the 
option, on an individual basis, of receiving RO7234292 in an open-label extension (OLE) study 
(Study BN40955) upon completion of Study BP40410, provided they meet eligibility criteria, the 
data from the ongoing RO7234292 program support continued development, and approval of 
the OLE study is granted by the relevant competent authority and Ethics Committee.
Number of Patients
Approximately 20
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form.

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form.

Manifest HD diagnosis, defined as a diagnostic confidence level (DCL) score of 4 (see 
Appendix 3 and Appendix 5).

Independence Scale score of 70. 

Genetically confirmed disease by direct deoxyribonucleic acid testing with a cytosine, 
adenine, and guanine base sequence found in DNA which is translated into glutamine 
(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 the patient’s native language. 


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
Ability to walk unassisted without a cane or walker and move about without a wheelchair on 
a daily basis as reviewed at screening and baseline visit.
Long distance use of wheelchairs for convenience (e.g., greater than 50 meters) for transfer 
is permitted.

Body mass index 16 and 32 kg/m2; total body weight 40 kg.

Ability to tolerate blood draws and lumbar punctures.

Estimated glomerular filtration rate 60 mL/min/1.73 m2 (Cockcroft-Gault formula).

Ability and willingness, in the Investigator's judgment, to comply with all aspects of the 
protocol including completion of interviews and assessments 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.

Signed study companion consent for participation if a study companion is available and 
fulfills the following criteria:
–
Age 18 years.
–
Reliable and competent, in the Investigator’s judgement.
–
Sufficiently knowledgeable of the patient’s condition to complete study companion 
assessments of the patient, and likely to remain sufficiently knowledgeable throughout the 
study, in the Investigator’s judgment.
–
Able to comment on the study participant’s symptoms and functioning experience, as 
required per Appendix 1.
Note:  Companions with genetic confirmation of the mutant gene can only participate if they 
do not have confirmation of motor symptoms onset and, in the opinion of the Investigator, 
do not display any disease symptoms (i.e., the companion must have a DCL of < 4, as well 
as no cognitive or behavioral change that would question the validity of the acquired 
observer-reported data).
All effort should be made to retain the study companion; however, should this not be 
possible, a study companion can be replaced and new consent obtained.

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods, and agreement to 
refrain from donating eggs, as defined below:
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.  Women must refrain from donating eggs during this same 
period.
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).
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.
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 study and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.


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
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for 5 months after 
the last 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 study 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.

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).
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that 
required hospital visit and/or change in level of care within 12 months prior to screening.
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
Investigator.  If suicidal ideation is present, a risk assessment should be done by an 
appropriately qualified mental health professional to assess whether it is safe for the 
patient to participate in the study.  Mild passive suicidal ideation (i.e., occasional 
thoughts that life is not worth living or is hard) without history of attempts or 
hospitalization over the past 12 months is generally acceptable for study participation, 
but final decision on participation should be made carefully and in consultation with 
appropriately qualified mental health professional.

Current active psychosis, confusional state, or violent behavior.

Any serious medical condition or clinically significant laboratory, vital signs, or ECG 
abnormalities at screening that, in the Investigator's judgment, precludes the patient's safe 
participation in and completion of the study.

Increased QTc interval (QT interval corrected through use of Fridericia's formula > 470 ms), 
baseline resting bradycardia < 45 bpm, or baseline resting tachycardia > 100 bpm.

Family history of long QT syndrome or other risk factors for torsades de pointes.

History known to the Investigator or presence of an abnormal ECG that is clinically 
significant in the Investigator’s opinion, including complete left bundle branch block, 
second- or third-degree atrioventricular heart block, or evidence of prior myocardial 
infarction.

Clinical diagnosis of chronic migraines or history of low pressure headache after lumbar 
puncture requiring hospitalization or blood patch.

Pregnant or breastfeeding, or intending to become pregnant during the study or until the 
follow-up visit (6 months 2 weeks after the last dose of study drug).
Women of childbearing potential must have a negative serum pregnancy test result within 
14 days prior to initiation of study drug.

Presence of implanted shunt for the drainage of cerebrospinal fluid (CSF) or an implanted 
central nervous system catheter.

Positive for hepatitis C virus antibody or hepatitis B surface antigen at screening.

Positive for human immunodeficiency virus (HIV)-1 or HIV-2 at screening.

Current or previous use of an antisense oligonucleotide (ASO) (including small interfering 
ribonucleic acid).


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
Current or previous use of antipsychotics 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 of enrollment.

Current use of antipsychotics for motor symptoms or mood stabilization (i.e., irritability or 
aggressive behavior) at a dose that has not been stable for at least 12 weeks prior to 
screening or is anticipated to change between screening and treatment initiation.

Current use of tetrabenazine, valbenazine, or deutetrabenazine within 2 weeks prior to 
screening or within 6 the elimination half-life of the medication prior to screening 
(whichever is longer) or anticipated use during the study.

Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose that has not 
been stable for at least 6 weeks prior to screening or is anticipated to change during the 
study.

Current use of antidepressant or benzodiazepine at a dose that has not been stable for at 
least 12 weeks prior to screening or is anticipated to change between screening and 
treatment initiation. 

Treatment with investigational therapy within 4 weeks prior to screening or 5 drug 
elimination half-lives of investigational therapy, whichever is longer.

Antiplatelet or anticoagulant therapy within the 14 days prior to screening or anticipated use 
during the study, including, but not limited to, aspirin (unless 81 mg/day), clopidogrel, 
dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban.

History of bleeding diathesis or coagulopathy.

Platelet count less than the lower limit of normal.
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as the 
Investigator confirms there is no evidence of current bleeding diathesis or coagulopathy.

History of gene therapy or cell transplantation or any other experimental brain surgery.

Concurrent or planned concurrent participation in any interventional clinical study, including 
explicit pharmacological and non-pharmacological interventions.  Observational studies 
(e.g., ENROLL-HD prospective study) are acceptable.

Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse or 
psychological or physiological dependency within 12 months prior to screening, as per the 
Investigator's judgment.
Abuse is defined as a maladaptive pattern of use that leads to failure to fulfill major 
work or social obligations or use in situations where it leads to physical danger or legal 
problems, and may be the focus of clinical attention.

Unable or unsafe to perform lumbar puncture on the patient.

Previous lumbar surgery that is likely, in the opinion of the Investigator or surgical team, to 
make IT catheter insertion or IT injection unduly difficult or hazardous.

Poor peripheral venous access.

Scoliosis or spinal deformity making IT injection not feasible in the outpatient setting.

Serious infection requiring oral or intravenous antibiotics within 14 days prior to screening.

Antiretroviral medications.

Malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been successfully treated.

Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous malformation, 
meningiomas) as assessed by a centrally read MRI scan during the screening period.


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End of Study
The end of this study is defined as the date when the last patient, last visit occurs.
The end of the study is expected to occur approximately 6 months (2 weeks) after the last 
study drug administration has occurred.  
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2 years.  
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product for this study is RO7234292.
Patients will receive two IT doses of the same dose strength of RO7234292 at an interval of 
28 days during the treatment period (Day 1 and Day 29).  Each dose of RO7234292 will be 
administered as a single IT bolus injection.
RO7234292 drug product is provided as 6.0 mg/mL RO7234292 for IT injection.  The drug 
product is supplied as sterile, preservative-free liquid in a 20-mL single-use vial containing 
10 mL of 6.0 mg/mL RO7234292 drug product having a pH of approximately 7.2.  In addition to 
the active drug substance, the liquid is also composed of sodium dihydrogen phosphate 
dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, potassium chloride, calcium 
chloride dihydrate, and magnesium chloride hexahydrate.  
Statistical Methods
All patients who have received at least 1 dose of the study drug, whether prematurely withdrawn 
from the study or not, will be included in the safety analyses.
Patients will be excluded from the PK analysis population if they did not receive treatment or 
otherwise significantly deviated from the protocol, violated inclusion or exclusion criteria, or if 
data are unavailable or incomplete which may influence the PK analysis.  
Patients will be excluded from the PD analysis population if they did not receive treatment or 
otherwise significantly deviated from the protocol, violated inclusion or exclusion criteria, or if 
data are unavailable or incomplete which may influence the PD analysis. 
Safety Analyses
All safety analyses will be based on the safety analysis population.  The safety data, including 
adverse events, reasons for withdrawal from study, laboratory data, ECG, concomitant 
medications, vital signs, physical and neurological examinations, and C-SSRS, will be reported 
in individual listings and summarized by treatment for each assessment time using descriptive 
statistics. 
The incidence of adverse events will be summarized on the basis of body systems and Medical 
Dictionary for Regulatory Affairs preferred terms.  The incidence of adverse events by severity 
and relationship to study drug or study procedure and incidence of marked abnormal laboratory 
test results will be provided.
Pharmacokinetic Analyses
All PK analyses will be based on the PK analysis population.
Individual and mean PK concentration data at each sampling timepoint of RO7234292 (and its 
metabolite[s] as appropriate) in plasma, CSF, and urine, and calculated PK parameters thereof, 
will be presented by listings and descriptive summary statistics including arithmetic means, 
geometric means, ranges, standard deviations, and coefficients of variation.  Individual and 
mean concentration versus time of RO7234292 (and its metabolite[s] as appropriate) will be 
plotted on linear or semi-logarithmic scales as appropriate.
All PK parameters will be presented by individual listings and summary statistics including 
arithmetic means, geometric means, medians, ranges, standard deviations, and coefficients of 
variation.


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Immunogenicity Analyses
The immunogenicity analysis population will consist of all patients with at least 1 anti-drug 
antibody (ADA) assessment.  Patients will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at baseline 
(baseline prevalence) will be summarized by treatment group.  For those who are ADA-positive, 
titers will be estimated as well as antibody subtype.  In addition, the numbers and proportions of 
ADA-positive patients and ADA-negative patients at baseline (baseline prevalence) and after 
drug administration (post-baseline incidence) will be summarized for patients on active 
treatment only.  
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints may be 
explored.
Biomarker Analyses
Although no formal statistical analysis of exploratory biomarkers will be performed, data may be 
analyzed in the context of this study and in aggregate with data from other studies.  
Determination of Sample Size  
Up to 20 patients with HD may be enrolled in this study.  Due to the exploratory nature of this 
study, the actual number of patients will be determined during the study.
While there is no formal statistical basis for the sample size of 20 patients (at maximum), it has 
been selected based on prior experience with second generation 2 ASOs given by IT injection 
to ensure that the PK and PD will be adequately assessed while minimizing patient exposure.  
However, the number of patients may be adapted during the study to sufficiently characterize 
the PK/PD relationship in CSF of RO7234292, while not exceeding 20.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
ASO
antisense oligonucleotide
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
CAG
cytosine, adenine, guanine base sequence found in 
DNA which is translated into glutamine 
CAP
CAG age product
CGI-C
Clinical Global Impression – Change
CGI-S
Clinical Global Impression – Severity
ClinRO
clinician-reported outcome
CNS
central nervous system
CRP
C-reactive protein
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
DCL
diagnostic confidence level
DNA
deoxyribonucleic acid
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
HD
Huntington's disease
HD-DAS
Huntington's Disease -Daily Activities Scale
HIV
human immunodeficiency virus
HTT
Huntingtin gene
ICH
International Council for Harmonisation
IMP
investigational medicinal product
INR
international normalized ratio
IRB
Institutional Review Board
IT
intrathecal
MAD
multiple ascending dose
mHTT
mutant Huntingtin 
MoCA
Montreal Cognitive Assessment


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MOE
methoxyethyl
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MRSA
methicillin-resistant Staphylococcus aureus
NfL
neurofilament light chain 
OLE
open-label extension
PD
pharmacodynamics(s)
PerfO
performance outcome
PK
pharmacokinetic(s)
PT
prothrombin time
QTc
corrected QT interval
QTcF
QT interval corrected through use of Fridericia's 
formula
Q4W
every-4-weeks
Q8W
every-8-weeks
RBC
red blood cell
RBR
Research Biosample Repository
RNA
ribonucleic acid
SDMT
Symbol Digit Modalities Test
SI
Système International d’Unités
SWRT
Stroop Word Reading Test
TFC
Total Functional Capacity 
TMS
Total Motor Scale
UHDRS
Unified Huntington's Disease Rating Scale
ULN
upper limit of normal
WBC
white blood cell
WES
whole exome sequencing
WGS
whole genome sequencing
wtHTT
wild-type huntingtin


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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 the expansion of cytosine, adenine, guanine base sequence found in 
deoxyribonucleic acid (DNA) which is translated into glutamine (CAG) repeats in exon 1 
of the Huntingtin gene (HTT) on chromosome 4, which encodes for a mutant Huntingtin 
(mHTT) protein. Based upon non-clinical and clinical evidence, mHTT protein 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 to 20 years, 
with pneumonia, heart failure, or other complications frequently cited as the cause of 
death (Sorensen and Fenger 1992). Individuals with end-stage disease have complete 
physical disability and profound body wasting. 
The estimated prevalence of HD in North America, northwestern Europe, and Australia 
ranges from 5.96 to 13.17 cases per 100,000 (Baig et al. 2016). Although genetic 
testing can be used to identify individuals who will develop the disease, the diagnosis of 
HD is clinical through neurologic examination of the motor system. The clinical 
diagnosis of HD is made when the patient exhibits "unequivocal presence of an 
otherwise unexplained extrapyramidal movement disorder" (e.g., chorea, dystonia, 
bradykinesia, and rigidity) or "motor onset" (Huntington Study Group 1996; 
Hogarth et al. 2005). Motor onset is typically confirmed through the use of the 15-item 
motor examination of the Unified Huntington's Disease Rating Scale (UHDRS). After 
completion of the examination, a certified motor rater assigns a diagnostic confidence 
level (DCL) score. Scores range from 0 to 4, with 0 representing no impairment and 
4 representing unequivocal motor signs of HD (99% confidence). Among the 
considerable clinical phenotypic heterogeneity of the disease, motor onset is one of the 
more robust and consistently-agreed-upon disease features. Behavioral features, 
including emotional disorders and personality changes, do not have a uniform 
presentation, are episodic in nature, and do not usually progress steadily over time 
(Ross et al. 2014). 
Individuals with HD can be categorized as having either premanifest disease (diagnosed 
prior to motor onset) or manifest disease (diagnosed on the basis of motor onset). The 
premanifest disease period can be subdivided into presymptomatic and prodromal 
periods. During the presymptomatic period, from birth to young adulthood, individuals 
are not clinically distinguishable from controls. During the prodromal period, which can 
last many years before threshold clinical motor diagnosis, subtle motor changes, and 
variable cognitive and behavioral changes appear but are not sufficient to make the 
clinical diagnosis of HD. 


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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 UHDRS Total 
Functional Capacity (TFC) Scale, with Stage 1 corresponding to TFC scores of 11 to 13, 
Stage 2 to scores of 7 to 10, Stage 3 to scores of 3 to 6, Stage 4 to scores of 1 to 2, and 
Stage 5 to a score of 0 (Shoulson et al. 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, including parkinsonism, 
akathisia, sedation, depression, and suicidal thoughts. They are contraindicated in 
patients who are actively suicidal and in patients with untreated or inadequately treated 
depression. Additionally, they may prolong the corrected QT interval (QTc), and caution 
is advised when used in combination with other drugs or medical conditions that 
potentially prolong the QTc. 
Other medications are utilized in HD to address particular symptoms, such as 
antidepressants (for depression, agitation, and irritability), anticonvulsants (for irritability
and 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 a single gene, inhibiting the expression of this HTT gene is a 
promising therapeutic option (Stanek et al. 2013). 
RO7234292 (RG6042) was originally developed by Ionis Pharmaceuticals, Inc. and was 
formerly known as ISIS443139 and IONIS-HTTRx. This antisense oligonucleotide (ASO) 
was developed to reduce the synthesis of all forms of the HTT protein by targeting the 
HTT messenger ribonucleic acid (mRNA) from both the wild-type and the mutant alleles 
and directing its catalytic degradation through the action of ribonuclease H1, an 
endogenous enzyme present in most mammalian cells (Crooke and Bennett 1996; 
Cerritelli and Crouch 2009), including cells of interest in the central nervous system 
(CNS) (e.g., neurons and neuroglia). Reduction of the HTT gene mRNA, which in turn 


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limits translation of the wild-type and mutant huntingtin protein, could potentially inhibit 
all downstream toxic effects and lead to a sustained reversal in HD symptoms. 
Pharmacology data support selective targeting of HTT mRNA transcripts from both 
alleles as a potentially safe and effective mechanism for the treatment of HD. Using 
ASOs targeting human HTT mRNA in rodents and non-human primates, significant 
reduction of mHTT mRNA transcripts, wild-type HTT mRNA transcripts, and mHTT 
protein has been achieved throughout most brain regions (Kordasiewicz et al. 2012).
Furthermore, transient delivery of these ASOs in transgenic mouse models of HD 
delayed disease progression and mediated a sustained reversal of disease phenotype 
that persisted longer than HTT mRNA knockdown (Kordasiewicz et al. 2012; 
Stanek et al. 2013). 
Non-clinical proof-of-concept studies with ASOs targeting mHTT have been conducted in 
3 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 
human mHTT genomic sequence with 97 CAG/CAA repeats, and R6/2 mice expressing 
exon 1 of the human mHTT gene with 110 to 135 CAG repeats. These studies 
demonstrate that ASOs targeting human HTT mRNA improve motor function and protect 
against human HTT transgene expression in YAC128 mice; improve motor function, 
hypoactivity, and stress response in BACHD mice; and preserve striatal volume and 
increase survival in R6/2 mice. 
The pharmacokinetics (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) four doses of RO7234292 
(ranging from 10 to 120 mg) were well tolerated and achieved significant 
dose-dependent lowering of cerebrospinal fluid (CSF) mHTT protein when administered 
IT every 4 weeks to 46 patients with early manifest HD. Exploratory analyses identified 
a relationship between lowering of mHTT protein and improvement in some clinical 
measures. Taken together, these data support further clinical testing to demonstrate 
definitive clinical benefit of mHTT protein reduction in the CNS. The data from this study 
also supported the initiation of Study ISIS 443139-CS2 (Study BN40697; 
Clinicaltrials.gov Identifier NCT03342053), a Phase II open-label extension (OLE) study 
for patients who participated in Study ISIS 443139-CS1. This on-going open-label study 
is evaluating the longer-term safety and tolerability of RO7234292 and the sustained 
effect of the drug on lowering CSF mHTT protein of both a monthly and bimonthly 
(i.e., every other month) regimen. 


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Nine-month clinical data from the ongoing, 15-month, Phase II OLE Study BN40697
including CSF mHTT protein, exploratory fluid biomarkers, and safety/tolerability data
are available for reporting. All individuals in Study BN40967 have reached the 9-month 
timepoint of the planned 15-month study, and several individuals have now received 
RO7234292 for over 1 year on both regimens. Study BN40697 will be continued until its 
anticipated completion by December 2019.  Preliminary data show that a 120 mg every-
8-weeks (Q8W; every 2 months) dosing regimen of RO7234292 achieves 47% median 
CSF mHTT lowering at trough (i.e., sample taken immediately before the next dose) and 
the 120 mg every-4-weeks (Q4W) dosing regimen achieves 66% median lowering at 
trough.  Both results exceed the 20% to 40% target for CSF mHTT lowering at trough 
and steady state based upon efficacy data from nonclinical models, and exceed the 
result of approximately 40% median lowering observed in the completed Phase I/IIa 
study.
Further details on non-clinical and clinical studies can be found in the RO7234292 
Investigator's Brochure.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Presently, there are no therapies available to stop or slow the clinical progression of HD, 
which is relentless until patients experience premature death.  The ASO RO7234292 is 
designed to target the cause of HD and offers the potential to meet this unmet medical 
need.  
To date, non-clinical and clinical data have been generated to support further 
investigation of RO7234292 in patients with early manifest HD.  
Building on the completed Phase I/IIa study and the ongoing OLE Study BN40697, this 
Phase I study (BP40410) will collect clinical PK and pharmacodynamics (PD) data to 
characterize the magnitude and duration of CSF mHTT reduction after short-term IT 
bolus dosing with RO7234292. This study will also further inform the semi-mechanistic 
population PK/PD model that has been developed on the basis of the currently available 
clinical and non-clinical data.  Ultimately, this will guide clinical decision-making about 
optimal treatment regimens by providing information about the relationship between 
RO7234292 dosing and the time course of mHTT reduction, which could not be obtained 
any other way.  
This study is open-label and will be conducted in an early manifest HD population over 
8 months including an approximately 4-week screening period and an approximately 
28-week study period.  
Patients will be admitted to the site in the afternoon/evening of Day -2 or in the morning 
of Day -1 to begin the first in-house period of the study. After completing the safety 
assessments including Holter ECG, an IT catheter will be inserted on the morning of 
Day 1 to facilitate frequent CSF sampling and IT bolus dosing of RO7234292.  After 


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baseline CSF sampling, a single dose of RO7234292 will be given, after which sampling 
will continue for a further 48 hours before the catheter is removed. The patients will be 
discharged on Day 4 after all assessments have been completed.
Patients will return to the site for the second in-house period in the afternoon/evening of 
Day 28 or in the morning on Day 29 and will be discharged on Day 29 after all 
assessments have been completed. The second dose of RO7234292 will occur via a 
lumbar puncture on Day 29.
Patients will return to the site for daily visits on Days 30, 43, 71, 127, and the follow-up 
visit (6 months after the last study drug administration). 
After study completion, participants will be eligible to enroll in an OLE study 
(Study BN40955) with active RO7234292 compound, provided the data from the 
ongoing RO7234292 program support continued development, the patient meets the 
inclusion and exclusion criteria for the OLE, and the OLE is approved by the relevant 
competent authorities and Ethics Committees (ECs).
The known potential risks associated with RO7234292, as well as additional study 
associated risks related to lumbar IT study drug administration, are elaborated in the 
Guidance to Investigator section of the Investigator’s Brochure and Section 5.1 of this 
protocol.  
The patients participating in this study are not expected to benefit given only two doses 
will be administered; appropriate measures have been taken to minimize risks.  The 
study will provide critical data for RO7234292 to potentially enable patients with HD to 
benefit from treatment in the future.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the PK, PD, and safety of RO7234292 in patients with HD.  
Specific objectives and corresponding endpoints for the study are outlined below.
2.1
PRIMARY OBJECTIVES
The primary objectives for this study are as follows:

To characterize the PK of RO7234292 in CSF and plasma following administration 
of multiple (2) IT doses of RO7234292

To characterize mHTT CSF protein time course following administration of multiple 
(2) IT doses of RO7234292 in patients with HD

To investigate the PK/PD relationship of multiple (2) IT doses of RO7234292 on 
mHTT in CSF


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2.1.1
Primary Endpoints
The corresponding primary endpoints are as follows:

CSF and plasma concentrations of RO7234292

Change from baseline of mHTT concentrations in CSF

Relationship between plasma and/or CSF concentration or PK parameters and
biomarker measures (mHTT in CSF)
2.2
SECONDARY OBJECTIVES
The secondary objectives for this study are as follows:

To assess the safety and tolerability of multiple (2) IT doses of RO7234292 in 
patients with HD

To evaluate the immunogenicity of RO7234292

To characterize the PK of RO7234292 in urine following administration of an IT dose 
of RO7234292
2.2.1
Secondary Endpoints
The corresponding secondary endpoints are as follows:

Incidence and severity of adverse events, with severity determined according to the 
Adverse Event Severity Grading Scale (see Section 5.3.3)

Changes in vital signs, electrocardiograms (ECGs), and clinical laboratory results

Proportion of patients with suicidal ideation or behavior, as assessed by 
Columbia-Suicide Severity Rating Scale (C-SSRS) score at visits indicated in the 
schedule of activities, including detailed focus on any individual cases identified as 
having severe ideation or behavior during the study conduct

Incidence of anti-drug antibodies (ADAs) at specified timelines relative to the 
prevalence of ADAs at baseline

Titer and antibody subtype, determined if ADAs are identified

Urine concentrations of RO7234292
2.3
EXPLORATORY OBJECTIVES/ENDPOINTS
The exploratory objectives for this study would be to evaluate the effects of RO7234292 
compared on the basis of the following endpoints:

Change from baseline in exploratory biomarkers in CSF (e.g. neurofilament light 
chain [NfL])

Relationship between exploratory fluid biomarkers in CSF and blood (e.g. CSF and 
plasma NfL)

Relationship between biomarkers, safety (including Holter monitoring), PK, and 
immunogenicity

Relationship of biomarkers to clinical severity at baseline using the UHDRS and 
Clinical Global Impression


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to 
generate more granular time course data on PK, PD, and the PK/PD relationship after IT 
administration of RO7234292 to patients with manifest HD.  
Up to a maximum of 20 patients will be enrolled in the study. Prospective patients will 
undergo screening assessments during a 4-week screening period. A maximum of 
one re-screening will be allowed within 4 weeks of the initial screening failure for patients 
who fail the initial screening (see Section 4.5).
Patients will undergo safety and tolerability evaluations that include physical and 
neurological examinations, vital signs, ECGs, magnetic resonance imaging (MRI) scans, 
clinical laboratory safety tests, C-SSRS, and adverse event monitoring including related 
concomitant medications, as detailed in Appendix 1.
The following tentative dose levels are planned for the study:

Dose level 1: 120 mg RO7234292 (n=4 patients)

Dose level 2: 60 mg RO7234292 (n=4 patients)

Dose level 3: 30 mg RO7234292 (n=4 patients)
Patients will be assigned to a dose level in the order in which they are enrolled into the 
study. The final number of dose levels and total number of patients assigned to a given 
dose level will be defined during the study. Up to a maximum of 20 patients may be 
enrolled in the study, in order to enable investigation of additional dose levels other than 
those planned, or to repeat a dose level if required to fully characterize the PK, PD, 
safety and tolerability, or other pharmacological responses.
The highest tested RO7234292 dose in this study will not exceed 120 mg, which is the 
highest test dose in the previous Phase I/IIa clinical study (ISIS 443139-CS1).
After ongoing review of all available medical data (including adverse events, ECGs, vital 
signs, laboratory safety data, PK, and biomarker data) of the initial three dose groups of 
120 mg, 60 mg, and 30 mg, the decision will be made if any should be repeated, 
adjusted downwards, or if intermediate doses should be investigated.
Patients who complete the treatment period will return to the clinic for the follow-up visit, 
at 6 months 2 weeks after last study drug administration. Patients will then be given 
the option, on an individual basis, of receiving RO7234292 in an OLE study 
(Study BN40955) upon completion of Study BP40410, provided they meet eligibility 
criteria, the data from the ongoing RO7234292 program support continued development,
and approval of the OLE study is granted by the relevant competent authority and EC
(see Section 4.3.4).


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Figure 1 presents an overview of the study design.  A schedule of activities is provided in Appendix 1.
Figure 1
Overview of Study Design
Screening
Treatment Period
Follow-up
In-House Periods
Out-Patient Visits
Day -28 to 
Day -3
Day -2 to Day 4*
Day 28 to Day 29*
Day 30
Day 43
Day 71
Day 127
6 months 
(2 weeks) 
after last study 
drug 
administration

1st dose of study drug on 
Day 1

CSF sampling from 
predose to 48 hours 
postdose

2nd dose of study drug 
on Day 29

Single predose CSF 
sample on Day 29

Single (equivalent to predose) CSF sample on 
Day 43, Day 71, Day 127, and FU
* Note: Patients will be admitted to the site in the afternoon/evening of Day -2 or in the morning of Day-1 to begin the first in-house period of the 
study; patients will be discharged on Day 4 after all assessments have been completed. Patients will return to the site for the second in-house 
period in the afternoon/evening of Day 28 or in the morning on Day 29 and will be discharged on Day 29 after all assessments have been 
completed. 
CSF=cerebrospinal fluid; FU=follow-up.  


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs.
The end of the study is expected to occur approximately 6 months (2 weeks) after the 
last study drug administration has occurred.  
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 2 years.  
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for RO7234292 Dose and Schedule
In order to characterize the concentration time profile of RO7234292 and mHTT in 
plasma and CSF and the influence of dose on the magnitude and duration of mHTT 
lowering in CSF, initially, two IT bolus doses ranging from 30 mg up to 120 mg given 
28 days apart will be investigated in the present study.  Data from the completed 
Phase I/IIa multiple ascending dose (MAD) study (ISIS 443139-CS1) showed doses up 
to 120 mg IT RO7234292 over four doses administered every 28 days were safe and 
well tolerated.  Dose-dependent reductions of CSF mHTT from baseline at the end of the 
dosing interval after IT administration of doses ranging from 10 mg to 120 mg were 
observed. 
In the chronic toxicology study in monkeys, the No Observed Adverse Effect Level was 
determined to be 35 mg dose.  Conservatively correcting for differences in CSF volume 
between 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 maximum dose of 120 mg, to be evaluated in the present study.
Further details on non-clinical and clinical studies can be found in the Roche 
Investigator’s Brochure.  
The target reduction for clinical efficacy based on a non-clinical PK/PD model is at least 
30% reduction in CSF mHTT.  The administration of two IT doses of RO7234292 lead to 
trough percentage change of CSF mHTT of -25%, -28%, and -30% on average for 
60 mg, 90 mg, and 120 mg of RO7234292 in the Phase I/IIa MAD study 
(ISIS 443139-CS1).  


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Using a model developed based on data from the completed Phase I/IIa study and the 
ongoing OLE Study BN40697, non-linear mixed-effects simulations predict two IT 
doses of 30 mg, 60 mg, 90 mg, and 120 mg of RO7234292 are to result in median
percentage change from baseline of CSF mHTT of -24%, -27%, -29%, and -30%, 
respectively, at the end of the dosing interval (29 days) after the second IT 
administration.  Therefore, in order to characterize a mHTT concentration-time curve in 
the relevant range of mHTT reduction (~30% reduction), two IT doses administered 
every 4 weeks will be studied in this study.
Once a clear concentration effect has been established (peak effect and time course of 
effect) the information may inform a different dose regimen, including the potential for 
less frequent dosing. 
3.3.2
Rationale for Patient Population
Adult patients (age 25 to 65 years) with manifest HD (DCL 4) who are ambulatory 
without assistance, verbal, possess a CAG age product (CAP) score of 400, and an
Independence Scale score of 70 or greater will be included in this study.  This population 
represents an early stage of manifest disease where disability might be more plausibly 
reversed or slowed in response to a therapeutic intervention versus more advanced 
patients at baseline (Penney et al. 1990).  This definition also corresponds to the stage 
of participants most commonly recruited at present for clinical studies aiming to slow 
clinical progression.  Such cohorts are known to have longitudinal decline of clinical 
measures (Paulsen et al. 2014) over a timeframe appropriate for clinical studies.
3.3.3
Rationale for Biomarker Assessments 
3.3.3.1
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 is 
widely considered to be the primary driver of disease pathophysiology in HD (Wild and 
Tabrizi 2017).  mHTT protein in human CSF is associated with disease stage and 
severity and with markers of neuronal damage, including CSF NfL and CSF tau levels 
(Wild et al. 2015).  NfL levels in CSF predict progressive magnetic resonance imaging 
measures of brain atrophy, as well as progressive clinical decline in patients (Wild and 
Tabrizi 2017).  Longitudinal analysis of CSF mHTT, NfL, and other biomarkers related to 
HD, neurodegeneration, and inflammation may extend the current understanding of HD 
pathophysiology and progression and provide further data on how these putatively 
prognostic and potentially predictive biomarkers will respond to disease-modifying 
treatment.


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3.3.3.2
Blood-Derived Biomarkers
NfL levels in blood correlate with NfL levels in CSF and could serve as prognostic blood 
biomarkers of disease onset and progression in HD (Wild and Tabrizi 2017; 
Johnson et al. 2018).  Longitudinal analysis of NfL and other biomarkers related to HD, 
neurodegeneration, and inflammation in blood will facilitate the understanding of HD 
pathophysiology and progression.  
3.3.3.3
Genetic Testing to Determine CAG Repeat Length
HD is caused by mutation in the first exon of the HTT gene located on CAG expansion in 
the huntingtin protein.  Above 35 CAG repeats, the age of HD onset is inversely 
correlated with the length of the expansion (Duyao et al. 1993).  The CAG repeat length 
will be determined by direct DNA testing.  The results of the CAG repeat length testing 
will be used to confirm eligibility for enrollment into this study. 
3.3.3.4
Clinical Genotyping
Although CAG repeat length is inversely correlated to age of onset in HD, it only 
accounts for approximately 50% of the variance.  Identification of other genetic modifiers 
of disease severity and disease progression in HD could provide important insights, as 
has been recently shown in the Genetic Modifiers of Huntington's Disease Consortium 
(2015), where relatively common single nucleotide polymorphisms in the HD population 
were found to be associated with either an accelerated or delayed age of motor onset.  A 
blood sample will be collected to detect individual single nucleotide polymorphisms to 
explore, for example, their influence on progression rates, age of onset, severity, or 
response to treatment.  
3.3.3.5
Magnetic Resonance Imaging
MRI is a non-invasive method to assess structure and function of the human brain and 
can provide insights into the pathophysiological mechanisms of neurologic and 
neuropsychiatric diseases.  Several MRI techniques have shown sensitivity to detect 
abnormal structure and function within brains of individuals suffering from HD.  
Structural MRI (mandatory) will be used to assess brain volume.  As clinically 
indicated (and if patient gives specific consent), optional diffusion-weighted MRI may 
also be employed to examine structural brain connectivity, and optional resting-state 
functional MRI may be employed to identify functional connectivity.  All of the 
measures will be assessed at the whole-brain and regional levels.  These MRI 
assessments performed at screening and follow-up visits will serve as a safety measure 
to exclude any contraindication to IT catheter insertion and lumbar puncture and any 
overall contraindication to participation in the study.  In addition, MRI assessments 
will serve as a baseline assessment to enable ongoing safety monitoring for those 
patients who enroll in the OLE study (Study BN40955) upon completion of Study 
BP40410.
The acquisition parameters of the sequence, structure, and length of each MRI session 
and image-processing algorithms will be outlined in a separate MRI manual.


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Structural Magnetic Resonance Imaging
Numerous structural MRI studies have demonstrated wide-spread brain atrophy, 
including whole-brain, caudate, and ventricular changes in patients with premanifest 
and manifest HD (Douaud et al. 2006; Harrington et al. 2016).  Brain volume 
correlates with cognitive function (Peinemann et al. 2005).  Further, whole-brain, 
caudate, and ventricular volumes can predict and track progressive clinical decline in 
patients with HD and can also be associated with molecular biomarkers of 
neurodegeneration, such as NfL (Tabrizi et al. 2012).
Diffusion Magnetic Resonance Imaging (Optional)
Widespread changes in basal ganglia-cortical structural connectivity have also been 
observed in patients with HD (Novak et al. 2015), including associations between 
striatum-sensorimotor cortex connections and UHDRS motor scale and Total Motor 
Scale (TMS) (Bohanna et al. 2011), suggesting that the clinical phenotype in manifest 
HD may be a result of altered structural connectivity.
Resting-State Functional Magnetic Resonance Imaging (Optional)
Resting-state functional MRI studies have generated evidence for functional 
connectivity alterations and their correlation to several clinical and cognitive measures 
in patients with HD (Werner et al. 2014; Dogan et al. 2015; Liu et al. 2016; Espinoza 
et al. 2018), implying that disrupted functional integrity of distinct brain networks 
may underlie clinical progression in HD.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Up to 20 patients with manifest HD, aged 25 to 65 years (inclusive) may be enrolled in 
this study.  Due to the exploratory nature of this study, the actual number of patients will 
be determined during the study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form.

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form.

Manifest HD diagnosis, defined as a DCL score of 4 (see Appendix 3 and
Appendix 5).

Independence Scale score of 70.

Genetically confirmed disease by direct DNA testing with a CAP score > 400
(Zhang et al. 2011), calculated as follows:
CAP = Age × (CAG repeat length 33.66).

Ability to read the words “red,” “blue,” and “green” in the patient’s native language.


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
Ability to walk unassisted without a cane or walker and move about without a 
wheelchair on a daily basis as reviewed at screening and baseline visit.
Long distance use of wheelchairs for convenience (e.g., greater than 50 meters) for 
transfer is permitted.

Body mass index 16 and 32 kg/m2; total body weight 40 kg.

Ability to tolerate blood draws and lumbar punctures.

Estimated glomerular filtration rate 60 mL/min/1.73 m2 (Cockcroft-Gault formula).

Ability and willingness, in the Investigator's judgment, to comply with all aspects of 
the protocol including completion of interviews and assessments 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.

Signed study companion consent for participation if a study companion is available 
and fulfills the following criteria:
–
Age 18 years.
–
Reliable and competent, in the Investigator’s judgment.
–
Sufficiently knowledgeable of the patient’s condition to complete study 
companion assessments of the patient, and likely to remain sufficiently 
knowledgeable throughout the study, in the Investigator’s judgment.
–
Able to comment on the study participant’s symptoms and functioning 
experience, as required per Appendix 1.
Note: Companions with genetic confirmation of the mutant gene can only 
participate if they do not have confirmation of motor symptoms onset and, in the 
opinion of the Investigator, do not display any disease symptoms (i.e., the 
companion must have a DCL of < 4, as well as no cognitive or behavioral 
change that would question the validity of the acquired observer-reported data).
All effort should be made to retain the study companion; however, should this 
not be possible, a study companion can be replaced and new consent obtained.

For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods, and agreement 
to refrain from donating eggs, as defined below:
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. Women must refrain from 
donating eggs during this same period.
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).


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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.
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 study 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 female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
5 months after the last 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 study 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.

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).
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of attempted suicide or suicidal ideation with plan (i.e., active suicidal 
ideation) that required hospital visit and/or change in level of care within 12 months 
prior to screening.
Current suicidal ideation is demonstrated by the C-SSRS per judgment of the 
Investigator.  If suicidal ideation is present, a risk assessment should be done 
by an appropriately qualified mental health professional to assess whether it is 
safe for the patient to participate in the study.  Mild passive suicidal ideation 
(i.e., occasional thoughts that life is not worth living or is hard) without history of 
attempts or hospitalization over the past 12 months is generally acceptable for 
study participation, but final decision on participation should be made carefully 
and in consultation with appropriately qualified mental health professional.

Current active psychosis, confusional state, or violent behavior.

Any serious medical condition or clinically significant laboratory, vital signs, or ECG 
abnormalities at screening that, in the Investigator's judgment, precludes the 
patient's safe participation in and completion of the study.


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
Increased QTc interval (QT interval corrected through use of Fridericia's formula 
[QTcF] > 470 ms), baseline resting bradycardia < 45 bpm, or baseline resting
tachycardia > 100 bpm.

Family history of long QT syndrome or other risk factors for torsades de pointes.

History known to the Investigator or presence of an abnormal ECG that is clinically 
significant in the Investigator’s opinion, including complete left bundle branch block, 
second- or third-degree atrioventricular heart block, or evidence of prior myocardial 
infarction.

Clinical diagnosis of chronic migraines or history of low pressure headache after 
lumbar puncture requiring hospitalization or blood patch.

Pregnant or breastfeeding, or intending to become pregnant during the study or until 
the follow-up visit (6 months 2 weeks after the last dose of study drug).
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study drug.

Presence of implanted shunt for the drainage of CSF or an implanted CNS catheter.

Positive for hepatitis C virus antibody or hepatitis B surface antigen at screening.

Positive for human immunodeficiency virus (HIV)-1 or HIV-2 at screening.

Current or previous use of an ASO (including small interfering ribonucleic acid 
[RNA]).

Current or previous use of antipsychotics 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 of enrollment.

Current use of antipsychotics for motor symptoms or mood stabilization 
(i.e., irritability or aggressive behavior) at a dose that has not been stable for at least 
12 weeks prior to screening or is anticipated to change between screening and 
treatment initiation.

Current use of tetrabenazine, valbenazine, or deutetrabenazine within 2 weeks prior 
to screening or within 6 the elimination half-life of the medication prior to screening 
(whichever is longer) or anticipated use during the study.

Current use of supplements (e.g., coenzyme Q10, vitamins, creatine) at a dose that 
has not been stable for at least 6 weeks prior to screening or is anticipated to 
change during the study.

Current use of antidepressant or benzodiazepine at a dose that has not been stable
for at least 12 weeks prior to screening or is anticipated to change between 
screening and treatment initiation.

Treatment with investigational therapy within 4 weeks prior to screening or 5 drug 
elimination half-lives of investigational therapy, whichever is longer.


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
Antiplatelet or anticoagulant therapy within the 14 days prior to screening or 
anticipated use during the study, including, but not limited to, aspirin (unless 
81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and 
apixaban.

History of bleeding diathesis or coagulopathy.

Platelet count less than the lower limit of normal.
Platelet counts between 125,000 and 150,000 mm3 are permissible as long as 
the Investigator confirms there is no evidence of current bleeding diathesis or 
coagulopathy.

History of gene therapy or cell transplantation or any other experimental brain 
surgery.

Concurrent or planned concurrent participation in any interventional clinical study, 
including explicit pharmacological and non-pharmacological interventions. 
Observational studies (e.g., ENROLL-HD prospective study) are acceptable.

Drug (i.e., cannabis, opioid, stimulant, hallucinogen, designer) and/or alcohol abuse 
or psychological or physiological dependency within 12 months prior to screening, 
as per the Investigator's judgment.
Abuse is defined as a maladaptive pattern of use that leads to failure to fulfill 
major work or social obligations or use in situations where it leads to physical 
danger or legal problems, and may be the focus of clinical attention.

Unable or unsafe to perform lumbar puncture on the patient.

Previous lumbar surgery that is likely, in the opinion of the Investigator or surgical 
team, to make IT catheter insertion or IT injection unduly difficult or hazardous.

Poor peripheral venous access.

Scoliosis or spinal deformity making IT injection not feasible in the outpatient setting.

Serious infection requiring oral or intravenous antibiotics within 14 days prior to 
screening.

Antiretroviral medications.

Malignancy within 5 years prior to screening, except basal or squamous cell 
carcinoma of the skin or carcinoma in situ of the cervix that has been successfully 
treated.

Preexisting intra-axial or extra-axial lesions (e.g., tumor, arterio-venous 
malformation, meningiomas) as assessed by a centrally read MRI scan during the 
screening period.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study, therefore no blinding will be used.
Patients will be assigned to a dose level in the order in which they are enrolled into the 
study. Treatment assignment across clinical sites will be managed manually.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is RO7234292.
Patients will receive two IT doses of the same dose strength of RO7234292 at an 
interval of 28 days during the treatment period (Day 1 and Day 29).  Each dose of 
RO7234292 will be administered as a single IT bolus injection.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
RO7234292
RO7234292 drug product is provided as 6.0 mg/mL RO7234292 for IT injection.  The 
drug product is supplied as sterile, preservative-free liquid in a 20-mL single-use vial 
containing 10 mL of 6.0 mg/mL RO7234292 drug product having a pH of approximately 
7.2.  In addition to the active drug substance, the liquid is also composed of sodium 
dihydrogen phosphate dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, 
potassium chloride, calcium chloride dihydrate, and magnesium chloride hexahydrate.  
RO7234292 should be prepared by a pharmacist using aseptic technique.  RO7234292 
vials do not contain antimicrobial preservatives.  Therefore, care must be taken to 
ensure that the solution for infusion is not microbiologically compromised during 
preparation.  All transfer procedures require strict adherence to aseptic techniques.  Do 
not use RO7234292 beyond the use by date stamped on the carton.
The study drug must be stored according to the details on the product label.  The 
recommended storage conditions for RO7234292 drug product is between 2C to 8C 
(36F to 46F), protected from light. 
RO7234292 will be provided by Roche to investigational centers on a regular basis.  
Investigational product packaging will be overseen by the Roche Global Clinical Trial 
Supplies department.  The supply will be packed bearing labels with the identification 
required by local regulations and in accordance with Roche standards and local 
regulations.
Upon arrival of investigational products at the site, site personnel should check the 
investigational product for damage and verify proper identity, quantity, integrity of seals, 
and temperate conditions, and report any deviations or product complaints to the monitor 
upon discovery.
For information on the formulation, study drug preparation, and handling of RO7234292,
see the pharmacy manual.


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4.3.1.2
Diluent
RO7234292 diluent for IT injection is provided as a sterile, preservative-free liquid in a 
20-mL single-use vial containing 10 mL of RO7234292 diluent having a pH of 
approximately 7.2.  The liquid is also composed of sodium dihydrogen phosphate 
dihydrate, sodium phosphate dibasic anhydrous, sodium chloride, potassium chloride, 
calcium chloride dihydrate, and magnesium chloride hexahydrate.  
RO7234292 diluent must be stored according to the details on the product label.  The 
recommended storage conditions for RO7234292 drug product is between 2C to 8C 
(36F to 46F), protected from light.
RO7234292 diluent will be provided by Roche to investigational centers on a regular 
basis.  Investigational product packaging will be overseen by the Roche Global Clinical 
Trial Supplies department.  The supply will be packed bearing labels with the 
identification required by local regulations and in accordance with Roche standards and 
local regulations.
Upon arrival of RO7234292 diluent at the site, site personnel should check the 
investigational product for damage and verify proper identity, quantity, integrity of seals, 
and temperate conditions, and report any deviations or product complaints to the monitor 
upon discovery.
For information on the formulation, study drug preparation, and handling of RO7234292 
diluent, see the pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Each dose of RO7234292 will be administered as a single IT bolus injection of 20 mL.
Administration of the first dose will occur via an IT catheter inserted at baseline and also 
used for CSF sampling.  Administration of the second dose will occur via a lumbar 
puncture using a needle inserted into the L3/L4 space, although placement at a different 
level (either in the space above or the space below) is allowed if patient anatomy or 
clinical judgment dictates.  
For details on the lumbar puncture and IT bolus dosing procedure, please refer to the 
lumbar puncture manual and instructional video.  Of note, Investigators will perform a 
predose neurological examination, including fundoscopy, to rule out increased 
intracranial pressure prior to performing the lumbar puncture, which is a contraindication 
to the procedure. 
Patients will be discouraged from resting supine after the lumbar puncture procedure 
and will be encouraged to mobilize immediately by walking around at a minimum and, if 
feasible, walking briskly.
Patients may receive doses, which have previously been investigated in the Phase I/IIa 
MAD study (ISIS 443139-CS1) or OLE study (ISIS 443139-CS2), ranging from 30 to 


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120 mg of RO7234292.  The decision to determine which doses will be explored after 
the initial three dose levels of 120 mg, 60 mg, and 30 mg will be made following review 
of all relevant safety, tolerability, PK, and biomarker data collected from all previous 
patients.
The patient’s bladder must be completely emptied at the time of study drug 
administration.
No dosage adjustment from planned treatment is permitted in this study. If a patient 
misses a dose visit, the Investigator should contact the Medical Monitor to determine 
appropriate continuation of the patient in the study.
Cases of accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Section 5.4.4.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.3.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (RO7234292) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor to confirm the shipment condition 
and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to RO7234292
It is intended that patients will be eligible to receive RO7234292 as part of an OLE study 
(Study BN40955) as described in Section 3.1.
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 
IMP, as outlined below.


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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 IMP is available at the following 
website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, and nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 
screening to the study completion/discontinuation visit.  All such medications should be 
reported to the Investigator and recorded on the Concomitant Medications electronic 
Case Report Form (eCRF) at each clinical visit.  
4.4.1
Permitted Therapy 
Patients are permitted to use the following therapies during the study:

Contraceptive agents.

Supplements (e.g., coenzyme Q10, vitamins, creatine) if the dose has been stable
for at least 6 weeks prior to screening, and the dose is not anticipated to change 
during the study.


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
Antipsychotics only if prescribed for motor symptoms or mood stabilization
(i.e., irritability or aggressive behavior) if the does has been stable for at least 
12 weeks prior to screening, and the dose is not anticipated to change between 
screening and the start of treatment initiation.  
If clinically indicated, dose changes or medication starting and stopping can 
occur as per Investigator judgment during the course of the study. 

Antidepressants or benzodiazepines if the dose has been stable for at least 
12 weeks prior to screening, and the dose is not anticipated to change between 
screening and the start of study treatment.   
If clinically indicated, dose changes or medication starting or stopping can occur 
as per Investigator judgment during the course of the study.

Anti-epileptics if given for mood stabilization and/or pain.

Aspirin at doses 81 mg/day.

Local anesthesia for the lumbar puncture procedure, depending on institutional 
guidelines.
Sedation may not be used for lumbar puncture.
4.4.2
Prohibited Therapy
Use of the following concomitant therapies is prohibited:

Current use of tetrabenazine, valbenazine, or deutetrabenazine.

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/or riluzole.

Antiplatelet or anticoagulation therapy, including, but not limited to, aspirin, (unless 
81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, and 
apixaban.

Sedation for lumbar puncture or IT bolus procedures in the study.

Use of anti-anxiety medication is prohibited during scheduled MRI scans. 
Anti-anxiety medication used to prevent movement disorder to allow successful 
MRI scan is not permitted in this study, as movement disorder too severe to scan 
under drug-free conditions is an overall study exclusion criterion.
4.5
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in Appendix 1
and Appendix 2.  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.


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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 screening evaluations). Informed 
Consent Forms for patients and study companions (if available) will be maintained at the 
study site, regardless of whether the patient is subsequently enrolled.  If a patient`s 
capacity to consent is in question, the Investigator should consult an appropriately 
qualified colleague who will independently assess capacity.  This additional assessment 
should also be documented.  If the patient’s capacity is confirmed, the Investigator may 
proceed with signing of the Informed Consent Form. 
If applicable, the Informed Consent Form will contain a separate consent for optional 
procedures.  The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent for optional procedures at any time and 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 in optional procedures will not be 
required to provide a separate signature.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
A maximum of one re-screening will be allowed within 4 weeks of the initial screening 
failure for patients who fail the initial screening (e.g., as a consequence of abnormal 
laboratory values or general medical status not meeting inclusion or exclusion criteria).
If re-screening is required, CAG repeat length testing does not need to be repeated 
(historical values will not be accepted); MRI and viral serology from the initial screening 
may be acceptable as part of the re-screening assessments, if performed within 4 weeks 
of the baseline visit.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, HD history (including 
past hospitalizations [i.e., number, duration, and reason]) over the last 2 years, 
reproductive status, smoking history, and use of alcohol and drugs of abuse, will be 
recorded at baseline.  Alcohol and/or drug abuse is defined as a maladaptive pattern of 
use that leads to failure to fulfill major work or social obligations or use in situations 
where it leads to physical danger or legal problems, and may be the focus of clinical 
attention. Daily use of any drug (i.e., cannabinoid, opioid, stimulant, hallucinogen, 
designer) or daily alcohol use that meets criteria for either abuse or psychological or 
physiological dependence is not permitted and is exclusionary. Occasional use that 
does not meet the criteria for abuse is permissible in this study. In addition, all 


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medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, and nutritional supplements) used by the patient from screening 
to study completion/discontinuation will be recorded.  At the time of each study drug 
administration, an interval medical history should be obtained and any changes in 
medication, smoking, or allergies 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.  Race/ethnicity 
will be recorded because of the potential contribution of this variable to differences in 
observed PK, PD, toxicity, and/or response to treatment.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits
(see Appendix 1), should include an evaluation of the head, eyes, ears, nose, and throat, 
and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems (including fundoscopy); genitourinary examinations may be 
performed as clinically indicated.  The physical examinations should be conducted in the 
same manner on each occasion to ensure comparability to previous examinations.  
Height will be measured at screening only.
A neurologic examination should be performed at screening and other specified visits 
(see Appendix 1), and includes assessment of mental status, level of consciousness, 
cranial nerve function, motor function, sensory function, reflexes, and coordination.  The 
neurologic examination should be conducted in the same manner on each occasion to 
ensure comparability to previous examinations.  Neurologic examinations should be 
performed before and after treatment on each dosing day. Weight should also be 
measured at each neurologic examination.
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.
4.5.4
Vital Signs 
Vital signs will be collected at screening and other specified visits (see Appendix 1). 
Vital signs will include measurements of respiratory rate, pulse, systolic and diastolic 
blood pressure, and temperature while the patient is in a seated position after resting for 
approximately 5 minutes.
Abnormalities observed at baseline should be recorded on the General Medical History 
and Baseline Conditions eCRF.


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4.5.5
Collection of Cerebrospinal Fluid (Lumbar Puncture Procedure)
Skin (groin area) and nose swabs will be taken during screening to test for Methicillin-
resistant Staphylococcus aureus (MRSA).  If the MRSA screening result is positive, 
treatment for decolonization (as per local standard procedure) should be administered
for 5 days prior to catheter insertion. 
In preparation for the catheter insertion, patients will be required to remove all body 
piercings, make up, and nail polish and to cleanse the entire body (including hair) with 
antibacterial soap on Day -2 or Day -1. 
Within 72 hours prior to performing each scheduled lumbar puncture or IT catheter 
insertion, local laboratory analysis of coagulation factors (international normalized ratio 
[INR], activated partial thromboplastin time [aPTT], prothrombin time [PT]) and platelets 
must be conducted and the results reviewed.  Each lumbar puncture should be 
performed at approximately the same time at each visit (ideally in the morning between 
8:00 a.m. and 12:00 noon or in the early afternoon between 12:00 noon and 3:00 p.m.) 
to minimize potential diurnal variation of CSF parameters. A 20 mL sample will be taken 
at predose after the IT catheter has been inserted. Subsequently, during the CSF 
sampling period until 48 hours postdose, a maximum 5 mL of CSF fluid will be collected 
(via the IT catheter) at each timepoint indicated in Appendix 2. In addition, up to 2 mL 
CSF sample will be collected for daily CSF safety testing, including culture, during the 
indwelling-catheter period at the timepoints indicated in Appendix 1 and Appendix 2. 
Upon removal, the catheter tip should be sent for culture.
For all other lumbar punctures, CSF fluid (20 mL) will be collected by needle using a 
lumbar puncture collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a 
minimum of 5 mL should be collected over a maximum of 60 minutes.  The operator 
must confirm CSF flow is present prior to any injection of study drug.  A 24G (atraumatic) 
needle should be used to minimize risk of post-lumbar puncture syndrome.  Depending 
on institutional guidelines, local anesthesia should be used for the procedure.  Sedation 
may not be used.  Spinal ultrasound may be used for the lumbar puncture procedure if 
deemed necessary, but ultrasound is not required.  Ultrasound guidance may be used if 
attempts at lumbar puncture without imaging are unsuccessful, if it is local practice to 
use ultrasound, or if institutional guidelines dictate use of ultrasound with each lumbar 
puncture.  For details on the lumbar puncture and IT bolus dosing procedure, please 
refer to the lumbar puncture manual and instructional video.  
Lumbar punctures will be performed as specified in Appendix 1 and Appendix 2.  


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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, aPTT, and PT.

Platelet count.

Pregnancy test.
All women of childbearing potential will have a serum pregnancy test at screening
(central laboratory).  Urine pregnancy tests (local laboratory) will be performed at 
specified subsequent visits.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test (analyzed at a central laboratory).

CSF safety sample: cell count (red blood cell [RBC] and white blood cell [WBC]), 
glucose, protein, and culture.

Blood for C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)

Hematology: WBC count, RBC count, platelet count, hemoglobin, hematocrit, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes). 

Skin and nasal swab for MRSA screening.
Samples for the following laboratory tests will be sent to a central laboratory for analysis:

Serum chemistry panel: bicarbonate, sodium, potassium, chloride, glucose, blood 
urea nitrogen, creatinine, total protein, albumin, phosphorus, calcium, total and 
direct bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), uric acid, gamma-glutamyl transferase, and creatine 
phosphokinase.  

Hormone panel (female subjects only): follicle-stimulating hormone and Estradiol.

Thyroid panel: thyroid-stimulating hormone and free thyroxine (also known as T4) 
levels.

Viral serology: hepatitis B virus surface antigen, hepatitis C virus antibody, HIV-1 
antibody, HIV-2 antibody.

Serum pregnancy test.
Serum pregnancy tests will be performed on women of childbearing potential at 
screening and subsequent visits to confirm a positive urine pregnancy test (if 
applicable).

Urinalysis including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, and bacteria).

CSF, urine, and plasma samples for PK analyses and metabolite identification.

Blood samples for immunogenicity analysis.

Blood sample for determination of CAG repeat length in HTT for patient eligibility.


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
Blood sample for clinical genotyping for DNA extraction to enable exploratory 
analysis and assay development with respect to genes related to HTT function and 
severity of the disease.

CSF samples to perform biomarker analysis, including mHTT and NfL, and other 
exploratory biomarkers related to HD, neurodegeneration, inflammation, and drug 
response.

Plasma samples, which may be used to evaluate biomarkers such as NfL and tau, 
as well as other exploratory blood-based biomarkers related to HD, 
neurodegeneration, inflammation, and drug response.

Blood, plasma, and CSF samples for exploratory research on biomarkers may also 
be used to support the development of additional biomarker assays.
Exploratory biomarker research may include, but will not be limited to, total HTT, tau, 
and other substances related to HD, neurodegeneration, and inflammation.  Research 
may involve extraction of DNA and analysis of mutations, single nucleotide 
polymorphisms, and other genetic variations.  Research will not be aimed at 
distinguishing germline mutations from somatic mutations.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research in the Research Biosample Repository (RBR) (see 
Section 4.5.10), biological samples will be destroyed when the final Clinical Study Report 
has been completed, with the following exception:

Blood, plasma, and CSF samples collected for biomarker research will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.

CSF, plasma, and urine samples collected for PK or immunogenicity analysis may 
be needed for additional immunogenicity characterization and for PK or 
immunogenicity assay development and validation and will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.  
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.


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Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study Investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.7
Electrocardiograms
Single 12-lead ECGs will be obtained at specific timepoints, as outlined in the schedule 
of activities (see Appendix 1 and Appendix 2), 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.  Electrocardiograms for each patient should be obtained from the same 
machine whenever possible.  Lead placement should be as consistent as possible.  
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes.  All ECGs are to be obtained prior to other invasive 
procedures scheduled at that same time (e.g., blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, and conversation), should be 
avoided during the pre-ECG resting period and during ECG recording.  In some cases, it 
may be appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator must review, sign, and date all ECG 
tracings.  Paper copies will be kept as part of the patient’s permanent study file at the 
site. 
ECG characteristics, including heart rate, QRS duration, and PR and QT intervals, will 
be recorded on the eCRF.  QTcF and RR will be calculated.  Changes in T-wave and 
U-wave morphology and overall ECG interpretation will be documented on the eCRF.  
T-wave information will be captured as normal or abnormal. U-wave information will be 
captured in two categories: absent/normal or abnormal.
4.5.7.1
Holter ECG Monitoring
From Day -1 to Day 3, patients will wear a digital Holter monitoring device for continuous 
recordings of 12-lead ECG traces over 72 hours (starting 24 hours before first study drug 
administration until 48 hours postdose), as specified in the schedules of activities. On
Day 29, patients will again wear a digital Holter ECG device for recordings of data over 4 
hours, starting at predose until 4 hours postdose. See Appendix 1 and Appendix 2.
Holter recordings will be sent to a central ECG analysis laboratory for ECG extraction 
and retrospective expert review with estimation of ECG intervals.  Triplicate ECG 
tracings will be extracted from the continuous recording at the period of verified stability 
of the heart rate for 1 minute as close as possible to the scheduled PK (plasma) 


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sampling timepoint.  Triplicate estimates of uncorrected QT intervals, QTcF, 
individual-specific QTc will be derived from the ECG traces at each nominal PK (plasma) 
sampling timepoint, along with other intervals (PR, RR, QRS) and information on T-wave 
and U-wave morphology, as appropriate.
Triplicate ECG tracings from the continuous recordings will be extracted within 
10 minutes of the nominal timepoints for PK (plasma) sampling as specified in the 
schedules of activities (see Appendix 1 and Appendix 2).  At these specific timepoints,
the patient should be at rest and in a supine position for at least 10 minutes prior to and 
remain in the supine position for at least 5 more minutes after the specified PK (plasma) 
sampling timepoint.
4.5.7.1.1
Holter monitoring conditions
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.
In order for the Holter recordings to be conducted under the same conditions, food 
consumption/intake must occur at the same time on Day -1, Day 1, and Day 29.  Food 
consumption/intake should be avoided (to the extent possible) when the Holter ECG 
data is collected. 
4.5.8
Performance Outcome and Clinician-Reported Outcomes
Performance outcome (PerfO) and clinician-reported outcome (ClinRO) data will be 
collected via assessments to document the treatment effect of RO7234292.  The 
assessments, translated into the local language as appropriate, will be completed in their 
entirety at specified timepoints during the study.  To ensure instrument validity and that 
data standards meet health authority requirements, assessments will be 
self-administered or interviewer-administered (as appropriate) before the patient or 
clinician receives any information on disease status, prior to the performance of 
non-PerfO/ClinRO assessments, and prior to the administration of study treatment, 
unless otherwise specified.
Patients and clinicians may use paper forms or electronic devices to capture PerfO and 
ClinRO data.  The paper forms, electronic devices, and/or instructions for completing the 
assessments will be provided by site staff.  The data will be entered into the eCRF.  The 
data will be available for access by appropriate study personnel.
The intent of the clinical measures (Huntington's disease-Daily Activities Scale [HD-DAS], 
TFC, Total Motor Scale [TMS], Independence Scale, Clinical Global Impression –
Severity [CGI-S], Clinical Global Impression – Change [CGI-C], Montreal Cognitive 
Assessment [MoCA], Symbol Digit Modalities Test [SDMT], Stroop Word Reading Test 
[SWRT], and C-SSRS) is to assess the relationship of baseline clinical variables to 
biomarkers, i.e., to explore the cross-sectional relationship of clinical severity to 


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biomarker abnormalities, and secondly, to collect baseline clinical data prior to study 
drug administration and prior to enrollment in the OLE study for longer treatment, such 
that the clinical status and change in clinical status can be known in these individuals 
over time; no efficacy analyses are planned to be performed on clinical measure data 
collected for this study. 
4.5.8.1
Total Functional Capacity Scale
The TFC Scale represents the Investigator's assessment of the patient's capacity to 
perform a range of activities of basic daily living, including working, chores, managing 
finances, eating, dressing, and bathing.  The 5-item assessment is based on a brief 
interview with the patient and the study companion (if available).  The TFC score ranges 
from 0 to 13, with a higher score representing better functioning.  The TFC takes 
approximately 10 minutes to administer and will be completed at clinic visits as indicated 
in Appendix 1.
4.5.8.2
Independence Scale
A patient's Independence Scale score is a measure of disease progression in functional 
disability.  The Independence Scale evaluates a patient's degree of independence, as 
assessed by the Investigator, and is a subscale of the UHDRS.  The scale consists of 
19 discrete levels ranging from 10 to 100 (by 5), in which a score of 100 indicates no 
special care is needed and a score of 10 indicates the patient is fed by tube and requires 
total bed care.
4.5.8.3
Huntington’s Disease Daily Activities Scale
The HD-DAS assesses patients’ daily function.  Following a semi-structured interview 
with the patient and/or study companion, the patient’s ability 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.
4.5.8.4
Total Motor Scale
The TMS is a holistic measure of motor function in HD that is linked to functional 
capacity based on the TFC score, independence, and driving status 
(Beglinger et al. 2012; Schobel et al. 2017).
The TMS score is the sum of the individual motor ratings obtained from administration of 
the 31-item motor assessment portion of the UHDRS by the Investigator.  The score 
ranges from 0 to 124, with a higher score representing more severe impairment.  The 
TMS takes approximately 15 minutes to administer and will be completed at clinic visits.


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4.5.8.5
Clinical Global Impression – Severity 
The CGI-S is a single-item measure of current global severity and is completed by the 
clinician at clinic visits (as indicated in Appendix 1).  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.
4.5.8.6
Clinical Global Impression – Change 
The CGI-C is a single-item measure of change in global status (since starting the study) 
and is completed by the clinician at the follow-up visit (as indicated in Appendix 1).  The 
CGI-C has seven response options:  "very much worse," "much worse," "minimally 
worse," "no change," "minimally improved," "much improved," and "very much 
improved."  The CGI-C can be completed in approximately 2 minutes.  To assess the 
relevance of this change, a follow up question with dichotomous response options ("yes" 
or "no") asks if the change has had a meaningful impact on the patient’s well-being.
4.5.8.7
Montreal Cognitive Assessment
The MoCA is a patient-completed assessment used to detect cognitive impairment.  The 
MoCA contains a series of basic assessments, including attention and visuospatial tasks.  
The total score ranges from 0 to 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.  The MoCA takes approximately 10 minutes to administer.
4.5.8.8
Symbol Digit Modalities Test
The SDMT is used to assess attention, visuoperceptual processing, working memory, 
and psychomotor speed.  It has been shown to have strong reliability and validity (Smith 
1982).  The patient pairs abstract symbols with specific numbers according to a 
translation key.  The test measures the number of items correctly paired (maximum of 
110 correct pairs) in 90 seconds.  The SDMT will be administered at clinic visits (as 
indicated in Appendix 1) 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).
4.5.8.9
Stroop Word Reading Test
The SWRT 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 clinic visits (as indicated in Appendix 1).   
4.5.8.10
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 
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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 studies
(FDA 2012).  The C-SSRS will be used to assess eligibility for the study (full version at 
baseline, requiring approximately 20 minutes to administer) and to monitor the patients 
throughout the study at clinic visits (as indicated in Appendix 1) (follow-up version, 
requiring approximately 5 minutes to administer, assuming absence of suicidal ideation 
and no change in clinical status from previous administration).
The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.9
Magnetic Resonance Imaging
MRI images of the brain will be acquired (standard safety sequences, as well as 
structural MRI) at screening and at the follow-up visit (or at early termination visit, if 
applicable). Structural MRI is mandatory and must be performed at screening and at 
the follow-up visit (or at early termination visit, if applicable).  As clinically indicated
(and if patient gives specific consent), optional diffusion-weighted MRI may also be 
employed to examine structural brain connectivity and resting-state functional MRI 
may be employed to identify functional connectivity.  All of the measures will be 
assessed at the whole-brain and regional levels. 
MRI should be performed using a 3-Tesla (3T) magnet.  The acquisition parameters of 
the sequence, structure, and length of each MRI session, as well as image-processing 
algorithms, will be outlined in a separate MRI manual.  MRI scans will be managed by 
a central laboratory to monitor and ensure the integrity and quality of the acquired 
data.  The screening MRI will be evaluated by the central laboratory to determine 
patient eligibility.  During central review, the Sponsor and/or site staff will be notified 
of any unexpected findings requiring clinical follow up.  Local neuroradiologists will be 
responsible for assessing MRI-related ongoing safety monitoring.  
MRI should take place as early as possible within the screening window but may take 
place at any time during screening. The screening MRI scan should be performed at 
least 7 days prior to the IT catheter insertion to allow time for re-scanning if the 
quality of the initial MRI is inadequate.  The screening MRI scan must pass central 
laboratory image quality control review and results must be available before the patient 
can be enrolled in the study. 
The follow-up (or early termination, if applicable) MRI should take place within the 
14-day window allowed for the follow-up visit (or early termination visit, if 
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who enrolled under protocol Version 3 cannot undergo and tolerate MRI scans, no MRI 
scans will be performed at the follow-up visit (or early termination visit, if applicable).
Anti-anxiety medication is prohibited during scheduled scans, as described in 
Section 4.4.2.
4.5.10
Optional Samples for Research Biosample Repository 
4.5.10.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board (IRB) or EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RBR sampling, this section 
of the protocol (Section 4.5.10) will not be applicable at that site.
4.5.10.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7234292, the HTT 
protein, HD or other diseases, or drug safety:

Leftover blood, CSF, and plasma biomarker samples, and any derivatives thereof 
(e.g., proteins, peptides)

Blood (for RBR DNA and RBR RNA) at Day 1 and RBR serum samples collected at 
Days 1, 28, 43, 71, and 127


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


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4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The Investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  However, if RBR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall research 
data.  If a patient wishes to withdraw consent to the testing of his or her RBR samples 
during the study, the Investigator must inform the Medical Monitor in writing of the 
patient's wishes through use of the appropriate RBR Subject Withdrawal Form and must 
enter the date of withdrawal on the RBR Research Sample Withdrawal of Informed 
Consent eCRF.  If a patient wishes to withdraw consent to the testing of his or her RBR 
samples after closure of the site, the Investigator must inform the Sponsor by emailing 
the study number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study.
4.5.10.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, EC review, and 
health authority inspections by providing direct access to source data and documents 
related to the RBR samples.


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4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
An excessive rate of withdrawals (either study treatment discontinuation or withdraw 
from the study) can render the study non-interpretable.  Therefore, all efforts should be 
taken to motivate patients to comply with all study-specific procedures and to be 
followed until the end of the study.  
Investigators should explore all possible options to reach patients for visits, especially 
end-of-treatment visits.  The site must document all attempts to try to contact the patient
in the patient’s medical records and source documents.
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Any event that meets stopping criteria defined in Section 5.1.3
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
All patients who withdraw or discontinue from study treatment early will be asked to 
return to the clinic for the early termination visit within 28 days 14 days after the last 
dose of study drug.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the Investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the Investigator.  Patients who withdraw from the study will not be 
replaced.


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4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
RO7234292 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with RO7234292 in completed and 
ongoing studies.  The anticipated important safety risks for RO7234292 are outlined 
below.  Please refer to the RO7234292 Investigator's Brochure for a complete summary 
of safety information.  
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  Specific procedures for sterile 
preparation and microbiologcal testing are required to lower the risk of catheter infection 
and provide more rapid recognition of catheter associated infection, as described in 
Section 4.5.5.  In addition, guidelines for managing adverse events, including criteria for 
treatment interruption or discontinuation, are provided below.


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5.1.1
Known Risks Associated with Lumbar Puncture
In the completed Phase I/IIa study, 46 patients were randomized to receive RO7234292 
(n=34) or placebo (n=12).  The most commonly reported adverse events across all 
treatment groups included procedural pain (54%) and post-lumbar puncture syndrome 
(37%).  One patient who received placebo reported a serious adverse event of 
post-dural-puncture headache.
In the ongoing Phase II OLE Study BN40967 (15-month data cut), potential post-lumbar 
puncture adverse events (including procedural pain, post-lumbar puncture syndrome, 
post-procedural discomfort, puncture site pain, headache, migraine, nausea, dyspepsia, 
backpain, malaise, and paraesthesia) occurring within 72 hours of drug administration 
were summarized per cohort. For the Q4W cohort (n23), 35 events were reported in 
14 (60.9%) patients; for the Q8W cohort (n23), 36 events were reported in 
12 (65.2%) patients.
Many of the complications associated with lumbar puncture can be avoided by the 
mandatory use of a 24G atraumatic needle with a stylet, adherence to procedural 
guidelines (see lumbar puncture manual and instructional video), and careful 
assessment of the patient, including neurologic examination with fundoscopy both prior 
and post the lumbar puncture procedure.  Lumbar puncture should be avoided when 
contraindication is present.
CSF leakage is more likely with larger bore needles.  To minimize this risk, a 24G 
atraumatic needle will be used.  Training for use of the 24G atraumatic needle will be 
provided prior to initiation of lumbar puncture in the study, as will a review of extension 
tubing use and the need to gently aspirate CSF for timely collection.  If headache with 
characteristics of low-pressure syndrome is present after the procedure and persists 
despite standard-of-care treatment, a blood patch should be considered.  Formation of a 
subarachnoid epidermal cyst (i.e., when a skin plug is introduced into the arachnoid 
space) can be avoided by use of a needle with stylet, which is mandatory. Rarely, brain 
herniation can occur in the setting of lumbar puncture and increased intracranial 
pressure.
There are specific contraindications to performing lumbar puncture.  These include 
unstable cardiorespiratory status, where positioning the patient for lumbar puncture may 
not be tolerated, signs of cerebral herniation or incipient cerebral herniation, signs of 
increased intracranial pressure, or focal neurological findings on examination.  In those 
patients, lumbar puncture (and IT treatment administration) should not be performed and 
appropriate diagnostic work-up should be initiated.  On a case-by-case basis and 
following discussion with the Medical Monitor, such patients may be able to resume 
treatment.  Previous lumbar surgery, that is likely, in the opinion of the Investigator or 
surgical team, to make IT catheter insertion or IT injection unduly difficult or hazardous,
is an exclusion criterion for this study.


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In the setting of HD, for the purposes of lumbar puncture and IT bolus injection of 
RO7234292, moderate to severe truncal chorea may also be prohibitive.  
5.1.1.1
Post-Lumbar Puncture Syndrome
RO7234292 will be delivered directly to the CNS by IT lumbar puncture injection.  
Post-lumbar puncture syndrome (e.g., headaches, nausea, vomiting, infection, 
hemorrhage, and/or nerve irritation pain) can occur with IT administration.
Experience to date with post-lumbar puncture syndrome, as reported in the completed
Phase I/IIa study, includes headache, which occurred after 10% of procedures and was 
transient and mild in the vast majority of patients. In the ongoing Phase II OLE 
Study BN40967 (15-month data cut), 13 events of potential post-lumbar puncture 
syndrome events (post-lumbar puncture syndrome, headache and nausea) were reported 
in the Q4W cohort and 12 events in the Q8W cohort.
Patients should walk post-lumbar procedure to assist drug distribution (see 
Section 4.5.5); however, if a patient develops a headache after the lumbar puncture with 
characteristic features, which makes walking intolerable, the patient should be 
encouraged to first sit down, and if the headache persists, then lie in a comfortable 
position, which is most likely in the supine position owing to the postural nature of the 
symptoms.  Supportive treatment may include rehydration, consumption of caffeinated 
drinks, simple analgesics, opioids, and antiemetics.  If these conservative measures fail, 
more specific measures may be indicated.
5.1.1.2
Spinal Hematoma
Post-lumbar puncture spinal hematoma is a very rare but important potential risk that 
can present as persistent back pain, radicular pain, new sensory or motor symptoms, 
sphincter disturbance, or meningism.  Prompt magnetic resonance imaging 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 this study (see
Section 4.1.2).  Management of spinal hematomas should be in consultation with 
neurosurgical colleagues.
5.1.1.3
Meningitis
Meningitis is a rare potential risk of lumbar puncture.  Patients may present with 
headache, meningism, photophobia, neck stiffness, and pyrexia.  Guidelines for the 
management of patients with suspected meningitis are provided in Table 1.


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5.1.1.4
Known Risks Associated with an Indwelling Catheter
Insertion of an intrathecal catheter carries the same risks as a lumbar puncture, with 
additional risks of catheter blockage, disconnection or retraction.
Of note, in the current study, 2 out of 6 patients developed a lumbar abscess after 
having had the catheter implanted for 4 days.
5.1.2
Potential Risks Associated with RO7234292
The potential risks identified below have been considered in relation to clinical data 
available as of 18 July 2019, including the completed Phase I/IIa study and ongoing 
Phase II OLE study (15-month data cut).
5.1.2.1
Neurological Changes
In cynomolgus monkeys, acute, transient deficits in lower spinal reflexes (patellar reflex 
in particular) were typically observed 2 to 8 hours following dosing in the 13-week and 
the chronic toxicity studies. The transient changes in patellar reflex were observed in all 
treatment groups, including controls, with a slightly higher incidence in the high-dose 
groups. These findings were fully reversible within 24 hours following dosing. No other 
treatment-related changes in general sensory and motor function parameters nor 
changes in the cerebral reflexes were observed.
In the Phase I/IIa MAD study (ISIS 443139-CS1), no adverse trends in neurological 
examinations were detected and only a few drug-related neurological adverse events 
were observed in 2 patients. See the RO7234292 Investigator’s Brochure for more 
information.
In the ongoing Phase II OLE Study BN40697, 2 cases of asymptomatic lumbar 
radiculopathy that were characterized by loss of ankle reflexes, without changes in 
motor or sensory function, have been observed in the Q4W cohort. In the same cohort, 
central nervous system effects have been reported, including 2 suspected unexpected 
serious adverse reaction (SUSAR) cases (hemiparesis, hyporeflexia, myelitis, neuritis, 
and radiculopathy in 1 patient and hydrocephalus following chemical meningitis in 
another patient who also experienced speech and coordination difficulties), which the 
investigator considered to be unrelated to the study drug (for details see the 
RO7234292 Investigator’s Brochure).
Full neurological examinations will be conducted as indicated in Appendix 1. In addition, 
patients should be observed in clinic for any complications or complaints post-LP and 
IT administration of RO7234292.
5.1.2.2
Elevations in CSF WBCs and Protein
Mild elevations in CSF WBCs have been observed during the Phase I/IIa, dose 
escalation study (Study ISIS 443139-CS1) and its respective OLE study (Study ISIS 
443139-CS2 [Study BN40697]) at various timepoints that are sometimes associated with 


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changes in CSF protein without signs of inflammation.  The majority of patients have 
counts under 10/L WBCs, with several patients with higher elevations observed to date 
in the OLE study.  Patients with CSF WBC elevations have generally been 
asymptomatic.  One case, with elevations in CSF WBCs and CSF protein presented with 
ankle hyporeflexia after the seventh dose of 120 mg monthly with enhancement of the 
cauda equina noted on an MRI of the spine, with no other clinical sequelae noted and 
follow-up ongoing.
The CSF WBC elevations were also observed in the chronic non-human primate study 
with slight increases over time.  Increases were mild, and there was no apparent dose 
dependency.
5.1.2.3
Thrombocytopenia
Reductions in platelet count have been observed after systemic administration of some 
2'-methoxyethyl (MOE) chimeric ASOs to clinical study subjects.  However, no clinically 
significant reduction in platelet counts has been observed in clinical studies for
RO7234292 to date.
In one 13-week and one 9-month IT toxicity studies of RO7234292 in the cynomolgus 
monkey, there were no effects on hematology or coagulation parameters.
No clinically significant reduction in platelet counts was observed in the completed 
RO7234292 Phase I/IIa study. In the ongoing Phase II OLE Study BN40697, no adverse
events of thrombocytopenia have been reported to date.
Platelet counts will be monitored as indicated in Appendix 1.  Guidelines for the 
management of patients who develop reductions in platelet counts are provided in 
Table 1.
5.1.2.4
Kidney Effects
Reductions in renal function have been observed after administration of some 2'-MOE 
containing chimeric ASOs to clinical study subjects. In a 13-week and 9-month IT 
toxicity study of RO7234292 in the cynomolgus monkey, there were no test article-
related histologic findings in the visceral organs or effects on clinical chemistries.
No clinically significant reduction in kidney function was observed in the completed 
RO7234292 Phase l/IIa study. In the ongoing Phase II OLE Study BN40697, 1 case of 
moderate proteinuria considered related to the study drug has been reported in the Q4W 
cohort (resolved without any intervention and continued study drug administration); no 
other clinically significant kidney abnormality has been observed.
Kidney function will be monitored as indicated in Appendix 1.  Guidelines for the 
management of patients who develop decreased renal function are provided in Table 1.


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5.1.2.5
Liver Effects
Elevations in liver enzymes have been observed after administration of some 2’-MOE 
chimeric ASOs to clinical study subjects.  However, no clinically significant elevations in 
liver enzymes have been observed in the clinical studies for RO7234292 to date.
In a 13-week and 9-month IT toxicity study of RO7234292 in the cynomolgus monkey, 
there were no test article-related histologic findings in the visceral organs including the 
liver or effects on clinical chemistries. No clinically significant elevations in liver 
enzymes were observed in the completed RO7234292 Phase I/IIa study.  In the ongoing 
Phase II OLE Study BN40697, no drug-related clinically significant hepatic abnormality 
has been observed to date.
Liver enzymes will be monitored as indicated in Appendix 1.  Guidelines for the 
management of patients who develop decreased hepatic function are provided in 
Table 1.
5.1.2.6
Hydrocephalus
Hydrocephalus is included as a warning in the labelling of one marketed IT-administered 
2'-MOE chimeric ASO. No hydrocephalus was observed in the completed RO7234292 
Phase I/IIa MAD study (ISIS 443139-CS2). A single case of hydrocephalus following 
chemical meningitis has been observed in the Q4W cohort of the ongoing Phase II OLE 
Study BN40697 to date. For details please see the RO7234292 Investigator’s Brochure; 
for management guidelines, see Section 5.1.3.3.
5.1.2.7
Neuropsychiatric Changes
Nonclinical studies in animals did not show any adverse effects on the CNS. Though a 
single case of completed suicide has occurred in the ongoing Phase II OLE Study 
BN40697, when weighing all available details of the case, the Investigator has 
concluded that this event was not related to RO7234292.
In consideration that RO7234292 is being administered directly to the CNS, and that 
there is limited clinical experience with RO7234292, patients should be closely 
monitored for signs and symptoms of neuropsychiatric changes in addition to routine 
monitoring with the C-SSRS.  
5.1.2.8
Potential Risk due to Reduction of Target Protein HTT
By specifically targeting mRNA from both HTT alleles, RO7234292 can lower levels of 
both mHTT and normal "wild-type" huntingtin (wtHTT) protein in all patients, regardless 
of other 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 in non-clinical studies 
or in the completed Phase I/IIa study of RO7234292 in adults with HD (see RO7234292 
Investigator’s Brochure), in which partial lowering was achieved.


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Transgenic mice expressing human mHTT develop progressive HD-like phenotypes that 
recapitulate many aspects of HD in humans.  ASO-mediated mHTT lowering provides 
therapeutic benefits and often restores normal functioning in transgenic and fully 
humanized animal models of HD, with generally similar results regardless of whether 
wtHTT is also lowered.  Moreover, no detrimental effects of partial wtHTT lowering in 
animal models have been reported in multiple studies using ASOs and non-reversible 
approaches.
Still, the current understanding of the diverse cellular functions of HTT suggests potential 
theoretical risks associated with reducing total HTT levels in people with HD.  More than 
2 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 expression ameliorate disease and increases in mHTT 
exacerbate disease in animal models of HD, regardless of concomitant changes in 
wtHTT levels.
No clinically significant new neurologic events were observed in the completed 
Phase l/IIa study.
As a precaution a full neurological examination will be conducted as indicated in 
Appendix 1.
5.1.3
Management of Patients Who Experience Adverse Events
5.1.3.1
Dose Modifications
No dose adjustment from the planned treatment is permitted in this study, whether by 
varying the amount of study drug volume injected or the frequency of procedure per 
protocol (i.e., all participants will receive 20 mL of study drug per injection at the 
prespecified dose level).
5.1.3.2
Treatment Interruption
RO7234292 treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study drug.  If RO7234292 has been withheld for 
3 days because of toxicity, the patient should be discontinued from RO7234292, unless 


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resumption of treatment is approved following Investigator discussion with the Medical 
Monitor.  RO7234292 treatment may be suspended for reasons other than toxicity 
(e.g., surgical procedures) with Medical Monitor approval.  The Investigator and the 
Medical Monitor will determine the acceptable length of treatment interruption.
5.1.3.3
Management Guidelines
Guidelines for management of specific adverse events are outlined in Table 1.  
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 1
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 
consciousness/ cognition, changes in continence, or a 
combination of all three signs) are required for diagnosis of 
suspected hydrocephalus.

Clinical signs and symptoms of meningitis (e.g., headache, 
stiff neck, and 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 to
50/µL WBC count) elevations in CSF WBC count without 
clinical symptoms do not meet criteria for diagnosis of 
suspected meningitis.

In the event of persistent back pain or fever, promptly 
consider imaging investigation to exclude spinal abscess and 
discuss with Medical Monitor.

The Medical Monitor should be consulted in all cases of WBC
count CSF elevations, or a change from baseline in CSF 
proteins greater than twice baseline, or where there is 
uncertainty to discuss next steps of patient management in the 
study.

If a diagnosis of suspected meningitis, radiculitis, arachnoiditis,
hydrocephalus or 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.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; 
CSF=cerebrospinal fluid; eGFR=estimated glomerular filtration rate; INR=international 
normalized ratio; ULN=upper limit of normal; WBC=white blood cell.


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Table 1
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.  
Monitor platelet counts daily until two successive values 
show improvement.  Then monitor every 2 to 3 days until 
platelet count is stable, and at least weekly until platelet 
count returns to normal.
Administration of steroids may be considered for patients 
whose platelet count is 25,000/mm3.
Decreased renal function

Withhold study drug in the event of a persistent (> 2 weeks) 
decrease of eGFR or CrCl or increase in creatinine, as defined 
below:
1.
eGFR or CrCl 60 mL/min/1.73 m2.
2.
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.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; 
CSF=cerebrospinal fluid; eGFR=estimated glomerular filtration rate; INR=international 
normalized ratio; ULN=upper limit of normal; WBC=white blood cell.


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Table 1
Guidelines for Management of Patients Who Experience Adverse 
Events (cont.)
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.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; 
CSF=cerebrospinal fluid; eGFR=estimated glomerular filtration rate; INR=international 
normalized ratio; ULN=upper limit of normal; WBC=white blood cell.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 and 
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death).

Is life threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death).
This does not include any adverse event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11).

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions).

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug.

Is a significant medical event in the Investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above).
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe; see Section 5.3.3); the event 
itself may be of relatively minor medical significance (such as severe headache without 
any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the Investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7).

Suspected transmission of an infectious agent by the study drug, as defined below.
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product. This term applies only when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The Investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 to Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, all adverse 
events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
catheter insertion, biopsies, discontinuation of medications) should be reported.  If the 
adverse event meets the criteria for serious adverse event, it should be reported 
immediately (see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until the follow-up visit or 
until the patient receives his or her first dose of study drug in the OLE study 
(Study BN40955), at which time reporting will occur per the new study requirements.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale indicated in Table 2 will be used for assessing 
adverse event severity.  Laboratory values determined as an adverse event should be 
graded as per Appendix 7, which is based on National Cancer Institute Common 
Terminology Criteria for Adverse Events (v5.0).
Table 2
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
Regardless of severity, some events may also meet seriousness criteria.  Refer to the definition 
of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence,
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse 
event and administration of the study drug, and the adverse event cannot be 
readily explained by the patient's clinical state, intercurrent illness, or 
concomitant therapies; and/or the adverse event follows a known pattern of 
response to the study drug; and/or the adverse event abates or resolves upon 
discontinuation of the study drug or dose reduction and, if applicable, 
reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria 
specified below.  Evidence exists that the adverse event has an etiology other 
than the study drug (e.g., preexisting medical condition, underlying disease, 
intercurrent illness, or concomitant medication); and/or the adverse event has 
no plausible temporal relationship to administration of the study drug 
(e.g., cancer diagnosed 2 days after first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
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 [see Section 4.5.5]).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.4) a diagnosis (if 
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.


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5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all 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 adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).


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


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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, Investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of HD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of HD, “Huntington’s Disease progression"
should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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


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5.3.5.12
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this study.  
In addition, safety biomarker data will not inform decisions on patient management.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical study.  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)

Accidental overdoses or medication errors (see Section 5.4.4 for details on reporting 
requirements)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
(Primary)
Telephone No.:
 Ext. 
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 Medical 


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Responsible (listed above and/or on the Medical Emergency List), and track all calls. 
The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days a week.  Toll-free numbers for the Help Desk, as well as the Medical Monitor and 
Medical Responsible contact information, will be distributed to all Investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, any
serious adverse events caused by a protocol-mandated intervention should be reported.
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to Investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to Investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the follow-up visit.  Investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after learning of the event) 
on the Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to Investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to Investigators. Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur after the follow-up visit are 
provided in Section 5.6.


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


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If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication errors (hereafter collectively referred to as "special 
situations") are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose.

Medication error:  accidental deviation in the administration of a drug.
In some cases, a medication error may be intercepted prior to administration of the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
RO7234292, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.


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In addition, all special situations associated with RO7234292, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event).  
Special situations should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The Investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the Investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or study-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.


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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the Investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
until the follow-up visit), if the event is believed to be related to prior study drug treatment.  
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the Investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the paper 
Clinical Trial Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to Investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to Investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the information in this protocol and 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
DETERMINATION OF SAMPLE SIZE
Up to 20 patients with HD may be enrolled in this study.  Due to the exploratory nature of 
this study, the actual number of patients will be determined during the study.
While there is no formal statistical basis for the sample size of 20 patients (at maximum), 
it has been selected based on prior experience with second generation 2 ASOs given by 
IT injection to ensure that the PK and PD will be adequately assessed while minimizing 
patient exposure.  However, the number of patients may be adapted during the study to 
sufficiently characterize the PK/PD relationship in CSF of RO7234292, while not 
exceeding 20.


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6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results.
6.3
ANALYSIS POPULATIONS
6.3.1
Safety Analysis Population
All patients who have received at least 1 dose of the study drug, whether prematurely 
withdrawn from the study or not, will be included in the safety analyses.
6.3.2
Pharmacokinetic Analysis Population 
Patients will be excluded from the PK analysis population if they did not receive 
treatment or otherwise significantly deviated from the protocol, violated inclusion or 
exclusion criteria, or if data are unavailable or incomplete which may influence the PK
analysis.  Excluded cases will be documented together with the reason for exclusion.
6.3.3
Pharmacodynamic Analysis Population 
Patients will be excluded from the PD analysis population if they did not receive 
treatment or otherwise significantly deviated from the protocol, violated inclusion or 
exclusion criteria, or if data are unavailable or incomplete which may influence the PD
analysis.  Excluded cases will be documented together with the reason for exclusion.
6.4
SAFETY ANALYSES
All safety analyses will be based on the safety analysis population.  The safety data, 
including adverse events, reasons for withdrawal from study, laboratory data, ECG, 
concomitant medications, vital signs, physical and neurological examinations, and 
C-SSRS, will be reported in individual listings and summarized by treatment for each 
assessment time using descriptive statistics. 
The incidence of adverse events will be summarized on the basis of body systems and 
Medical Dictionary for Regulatory Affairs preferred terms.  The incidence of adverse 
events by severity and relationship to study drug or study procedure and incidence of 
marked abnormal laboratory test results will be provided.
6.4.1
Adverse Events 
All safety analyses will be based on the safety analysis population. 
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor.  Adverse events will be listed and summarized by body 
system and preferred term using the most recent Medical Dictionary for Regulatory
Affairs version available.


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6.4.2
Clinical Laboratory Test Results
All clinical laboratory data will be stored on the database in the units in which they were 
reported.  Listings and summary statistics at each assessment time will be presented 
using the International System of Units (SI units; Système International d’Unités).  
Laboratory data not reported in SI units will be converted to SI units before processing.
Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges.
6.4.2.1
Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters.  For most parameters, the measured laboratory test 
result will be assessed directly using the Roche standard reference range.  Certain 
laboratory parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, alkaline phosphatase, and total bilirubin.  Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
6.4.2.2
Definition of Laboratory Abnormalities
A Roche predefined standard reference range exists for all laboratory parameters 
included.  Laboratory values falling outside of this standard reference range will be 
labeled “H” for high or “L” for low in patient listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter.  The marked reference range is 
broader than the standard reference range.  Values falling outside of the marked 
reference range that also represent a defined change from baseline will be considered 
marked laboratory abnormalities (i.e., potentially clinically relevant).  If a baseline value 
is not available for a patient, the midpoint of the standard reference range will be used 
as the patient’s baseline value for the purposes of determining marked laboratory 
abnormalities.  Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low.
6.4.3
Vital Signs
Vital signs data will be presented by individual listings and tabular summaries, as 
appropriate.
6.4.4
12-lead ECG  
ECG data will be presented by individual listings with both values outside the normal 
ranges and marked abnormalities flagged.  In addition, tabular summaries will be used, 
as appropriate.


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12-lead Holter ECG recordings may be used for concentration-QT modeling using linear 
or non-linear mixed-effects models that relate individual PK concentrations to the 
QT interval or its change from baseline.  Results of this will be provided in a separate 
report.
6.4.5
Concomitant Medications 
The original terms recorded on the patients’ eCRF by the Investigator for concomitant 
medications will be standardized by the Sponsor by assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
6.5
PHARMACOKINETIC ANALYSES
All PK analyses will be based on the PK analysis population.
PK parameters will be read directly from the (plasma and CSF) concentration-time 
profiles, or calculated using standard non-compartmental methods.  The following 
PK parameters will be computed for RO7234292 and its metabolite(s), as appropriate.  
However, other PK parameters might be computed in addition as appropriate:

Time to maximum (or peak) serum concentration, maximum (or peak) serum 
concentration

Area under the plasma concentration-time curve (AUC) from time zero to the last 
measurable concentration, AUC from time zero to a timepoint, AUC from time zero 
to infinity, extrapolated AUC, AUC for a dosing interval

Lambda(z), half-life; apparent total clearance

Cumulative amount of unchanged drug excreted in urine, fraction of IT administered 
drug excreted in urine, renal clearance of the drug from plasma
Individual and mean PK concentration data at each sampling timepoint of RO7234292 
(and its metabolite[s] as appropriate) in plasma, CSF, and urine, and calculated PK 
parameters thereof, will be presented by listings and descriptive summary statistics 
including arithmetic means, geometric means, ranges, standard deviations, and 
coefficients of variation.  Individual and mean concentration versus time of RO7234292 
(and its metabolite[s] as appropriate) will be plotted on linear or semi-logarithmic scales 
as appropriate.
All PK parameters will be presented by individual listings and summary statistics 
including arithmetic means, geometric means, medians, ranges, standard deviations, 
and coefficients of variation.
In addition, data from the present study may be pooled with data from other studies to 
analyze the concentration-time data for RO7234292 in CSF and plasma following IT 
administration using non-linear mixed-effects modeling.  A covariate analysis may also 
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., AUC and average trough 


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plasma concentration) will be computed and used to describe the relationship between 
plasma and/or CSF exposure and biomarker measures (mHTT in CSF) as well as safety 
measures.  The data from this study may be pooled with data from other studies 
conducted with RO7234292 to support 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.
6.6
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least 1 ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) will be summarized by treatment group.  For those who 
are ADA-positive, titers will be estimated as well as antibody subtype.  In addition, the 
numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized for patients on active treatment only.  When determining 
post-baseline incidence, patients are considered to be ADA positive if they are ADA 
negative or have missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of 1 or more post-baseline samples is at least 4-fold greater than 
the titer of the baseline sample (treatment-enhanced ADA response).  Patients are 
considered to be ADA negative if they are ADA negative or have missing data at 
baseline and all post-baseline samples are negative, or if they are ADA positive at 
baseline but do not have any post-baseline samples with a titer that is at least 4-fold 
greater than the titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be explored.
6.7
BIOMARKER ANALYSES
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.  
Individual and mean exploratory biomarker data and parameters will be presented by 
listings and descriptive summary statistics including means, geometric means, medians, 
ranges, standard deviations, and coefficients of variation, as appropriate.
The data from this study may be pooled with data from other studies conducted with 
RO7234292 to support the biomarker analysis.


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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 will be sent 
directly to the Sponsor, using the Sponsor's standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.
PerfO and ClinRO data will be collected on paper forms or electronic devices.  The data 
from the assessments will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee.
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
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, PerfOs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 


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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 study.
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 7.5.
To facilitate source data verification and review, the Investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
study-related monitoring, Sponsor audits, and EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PerfO and ClinRO data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study or for the length of time required by relevant national or local 
health authorities, whichever is longer.  After that period of time, the documents may be 
destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.


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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 laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child's Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before EC submission.  The final ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient 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.
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 EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
EC policy) during their participation in the study.  For any updated or revised Consent 


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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.
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.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the EC by the Principal 
Investigator and reviewed and approved by the EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the EC.  Investigators are also responsible for 
promptly informing the EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and EC.  Investigators may receive written Investigational New 
Drug safety reports or other safety-related communications from the Sponsor.  
Investigators are responsible for ensuring that such reports are reviewed and processed 
in accordance with health authority requirements and the policies and procedures 
established by their EC, and archived in the site's study file.  
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.


RO7234292—F. Hoffmann-La Roche Ltd
90/Protocol BP40410, Version 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 on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of 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 EC in accordance with established EC policies 
and procedures.  The Sponsor will review all protocol deviations and assess whether 
any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 


RO7234292—F. Hoffmann-La Roche Ltd
91/Protocol BP40410, Version 4
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The Investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, safety, and biostatistical 
management.
A contract research organization will be contracted to manage the study site(s) and 
perform monitoring activities. 
A minimum of 1 site globally will participate to enroll approximately 20 patients.  
However, additional clinical sites may participate in order to facilitate patient enrollment. 
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.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE
SECRETS
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical study registries of the U.S. National Institutes of Health and the 
European Medicines Agency, 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, and redacted Clinical Study Reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
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 studies 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 study results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical studies in 


RO7234292—F. Hoffmann-La Roche Ltd
92/Protocol BP40410, Version 4
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 studies only in their entirety and not as individual 
center data.  In this case, a coordinating Investigator will be designated by mutual 
agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the EC and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the 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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93/Protocol BP40410, Version 4
10.
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systemic review and discussion. Neurodegener Dis Manage 2016;6:33143. 
Beglinger LJ, Prest L, Mills JA, et al. Clinical predictors of driving status in Huntington's 
disease. Mov Disord 2012;27:114652.
Bohanna I, Georgiou-Karistianis N, Sritharan A, et al. Diffusion tensor imaging in 
Huntington's disease reveals distinct patterns of white matter degeneration associated 
with motor and cognitive deficits. Brain Imaging Behav 2011;5:17180.
Cerritelli SM and Crouch RJ. Ribonuclease H: the enzymes in eukaryotes. FEBS J 
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Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu 
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Dogan I, Eickhoff CR, Fox PT, et al. Functional connectivity modeling of consistent 
cortico striatal degeneration in Huntington's disease. Neuroimage Clin 2015;7:64052.
Douaud G, Gaura V, Ribeiro MJ, et al. Distribution of grey matter atrophy in 
Huntington's disease patients: a combined ROI-based and voxel-based morphometric 
study. Neuroimage 2006;32:156275.
Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of 
onset in Huntington's disease. Nat Genet 1993;4:38792.
Espinoza FA, Turner JA, Vergara VM, et al. Whole-brain connectivity in a large study 
of Huntington's disease gene mutation carriers and healthy controls. Brain Connect 
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[FDA] Food and Drug Administration. Guidance for industry: suicidal ideation and 
behavior: prospective assessment of occurrence in clinical studies [resource on the 
Internet] 2012 [cited 28 February 2018]. Available from: 
https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm315
156.htm
Harrington DL, Long JD, Durgerian S, et al. Cross-sectional and longitudinal 
multimodal structural imaging in prodromal Huntington's disease. Cross-sectional and 
longitudinal multimodal structural imaging in prodromal Huntington's disease. Mov 
Disord 2016;31:166475.


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Hogarth P, Kayson E, Kieburtz K, et al; and the United States-Venezuela Huntington’s 
Disease Collaborative Research Group, and the Huntington Study Group. Interrater 
agreement in the assessment of motor manifestations of Huntington’s disease. Mov 
Disord 2005;20:2937.
Huntington Study Group. Unified Huntington’s disease rating scale: reliability and
consistency. Mov Disord 1996;11(2):13642.
Investigator’s Brochure for RO7234292. Version 4. July 2018.
Johnson EB, Byrne LM, Gregory S, et al. Neurofilament light protein in blood predicts 
regional atrophy in Huntington disease. Neurology 2018;90:e71723.
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of
Huntington’s disease by transient repression of huntingtin synthesis. Neuron
2012;74:103144.
Liu JP and Zeitlin SO. Is Huntingtin dispensable in the adult brain? J Huntingtons Dis 
2017;6(1):117.
Liu W, Yang J, Chen K, et al. Resting-state fMRI reveals potential neural correlates of 
impaired cognition in Huntington's disease. Parkinsonism Relat Disord 2016;27:416.
Moumné L, Betuing S, Caboche J. Multiple aspects of gene dysregulation in 
Huntington's disease. Front Neurol 2013;4:127. 
Nance M, Paulsen JS, Rosenblatt A, Wheelock V. A physician’s guide to the 
management of Huntington’s disease. 3rd Edition, Huntington’s Disease Society of 
America 2011. 
Novak MJ, Seunarine KK, Gibbard CR, et al. Basal ganglia-cortical structural 
connectivity in Huntington's disease. Hum Brain Mapp 2015;36:172840.
Paulsen JS, Long JD, Johnson HJ, et al. Clinical and biomarker changes in premanifest 
huntington disease show study feasibility: a decade of the PREDICT-HD study. Front 
Aging Neurosci 2014;6:78.
Paulson HL and Albin RL. Huntington’s Disease. Clinical features and routes to therapy. 
In: Lo DC, Hughes, RE, editors. Neurobiology of Huntington’s disease: applications to 
drug discovery. Boca Raton, FL. CRC Press 2011. Chapter 1.
Peinemann A, Schuller S, Pohl C, et al. Executive dysfunction in early stages of 
Huntington's disease is associated with striatal and insular atrophy: a 
neuropsychological and voxel-based morphometric study. J Neurol Sci 2005;239:119.


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Penney JB, Young AB, Shoulson I, et al. Huntington’s disease in Venezuela: 7 years of 
follow-up on symptomatic and asymptomatic individuals. Mov Disord 1990;5:939.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults.  Am J Psychiatry 2011;168:126677.
Ross CA, Aylward EH, Wild EJ, et al. Huntington’s disease: natural history, biomarkers
and prospects for therapeutics. Nat Rev Neurol 2014;10(4):20416.
Schobel SA, Palermo G, Auinger P, et al. Motor, cognitive, and functional declines 
contribute to a single progressive factor in early HD. Neurology 2017;89:24952502.
Shoulson I and Fahn S. Huntington disease: clinical care and evaluation. Neurology 
1979;29:13.
Smith, A.  Symbol Digit Modalities Test (SDMT). Manual (rev.). Los Angeles: Western 
Psychological Services, 1982.
Sorensen SA and Fenger K. Causes of death in patients with Huntington's disease and 
in unaffected first degree relatives. J Med Genet 1992;29:9114.
Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of 
transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse 
model of Huntington’s disease. J Huntingtons Dis 2013;21728. 
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. Lancet Neurol 2012;11:4253.
Van Raamsdonk JM, Pearson J, Rogers DA, et al. Loss of wild-type huntingtin 
influences motor dysfunction and survival in the YAC128 mouse model of Huntington 
disease. Hum Mol Genet 2005;14(10):137992.
Walker FO. Huntington's disease. Lancet 2007;369:21828. 
Werner CJ, Dogan I, Saß C, et al. Altered resting-state connectivity in Huntington's 
disease. Hum Brain Mapp 2014;35(6):258293.
Wexler NS, Young AB, Tanzi RE, et al. Homozygote for huntington’s disease. 
Nature1987;326:1947. 
Wild EJ and Tabrizi SJ.  Therapies targeting DNA and RNA in Huntington's disease.  
Lancet Neurol 2017;16:83747.


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Zhang Y, Long JD, Mills JA, et al. Indexing disease progression at study entry with 
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Appendix 1
Schedule of Activities
Assessment
Screeninga)
Treatment
Period
Follow-upb)
Early 
Terminationc)
Visits
-28 to -3 
days before 
1st study 
drug admin
Day
-2
Day 
-1d)
Day 
1d)
Day 
2
Day 
3
Day
4
Day 
28
Day 
29d)
Day 
30
Day 
43
Day 
71
Day 
127
6 months 
after last 
study drug 
admin
up to 28 days 
after last study 
drug admin
Window
NA
NA
NA
NA
NA
NA
NA
2 
days
2 
days
2 
days
7 
days
14 
days
14 
days
14 days
14 days
Month
-1
1
1
1
1
1
1
2
2
2
2
3-4
5-6
7-8
NA
Week
-4 to -1
1
1
1
1
1
1
5
5
5
6-7
8-12
16-20
27-31
NA
Hour
NA
NA
-24
0
24
48
72
NA
NA
NA
NA
NA
NA
NA
NA
Signed informed 
consente)
x
Review of inclusion 
and exclusion criteria
x
Demographic data
x
Medical history and 
baseline conditionsf)
x
x
Blood sample for CAG 
repeat length
x
Skin and nose swab 
for MRSAg)
x
Viral serologyh)
x
Thyroid paneli)
x
MRIj)
x
x
x
Vital signsk)
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical 
examinationl)
x
x
x
x
x
x
x
x
Neurological 
examinationm)
x
x
x
x
x
x
x
x
x
x
12-lead (single) ECGn)
x
x
x
x
x
x
x
x
x
x
x
x
x
12-lead Holter 
ECGd), o)
x
x
x
x
x
Hematology (local)p)
x
x
x
x
x
x
x
x
x
x
x
x
x
Chemistryq)
x
x
x
x
x
x
x
x
x
x
Pregnancy testr)
x
x
x
x
x
x
x
x
Hormone panels)
x
x
Local PT, INR, aPTT, 
platelet count
x
x
x
x
x
x
x
x
Urinalysist)
x
x
x
x
x
x
x
x
x
x


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
98/Protocol BP40410, Version 4
Assessment
Screeninga)
Treatment
Period
Follow-upb)
Early 
Terminationc)
Visits
-28 to -3 
days before 
1st study 
drug admin
Day
-2
Day 
-1d)
Day 
1d)
Day 
2
Day 
3
Day
4
Day 
28
Day 
29d)
Day 
30
Day 
43
Day 
71
Day 
127
6 months 
after last 
study drug 
admin
up to 28 days 
after last study 
drug admin
Window
NA
NA
NA
NA
NA
NA
NA
2 
days
2 
days
2 
days
7 
days
14 
days
14 
days
14 days
14 days
Month
-1
1
1
1
1
1
1
2
2
2
2
3-4
5-6
7-8
NA
Week
-4 to -1
1
1
1
1
1
1
5
5
5
6-7
8-12
16-20
27-31
NA
Hour
NA
NA
-24
0
24
48
72
NA
NA
NA
NA
NA
NA
NA
NA
RO7234292 PK 
sampling (plasma)u)
x
x
x
x
x
x
x
x
x
x
x
x
RO7234292 PK 
sampling (urine)v)
x
x
x
x
RO7234292 PK 
sampling (CSF)w)
x
x
x
x
x
x
x
x
x
Plasma sampling for 
immunogenicity 
testing
x
x
x
x
CSF sample for 
safetyw)
x
x
x
x
x
x
x
x
x
CSF sample for 
biomarkersw)
x
x
x
x
x
x
x
x
x
Blood sample for 
CRP and ESR (local)
x
x
x
x
x
x
x
x
x
x
x
Plasma sample for 
biomarkersx)
x
x
x
x
x
x
x
x
x
x
x
Treatment assignment
x
Admission to sitey)
x
x
x
x
x
x
x
x
Overnight stay at site
x
x
x
x
x
x
Discharge from site
x
x
x
x
x
x
x
x
Insertion of IT 
catheterz)
x
Removal of IT 
catheter
x
Catheter tip for 
culture
x
Study drug 
administration 
x
x


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
99/Protocol BP40410, Version 4
Assessment
Screeninga)
Treatment
Period
Follow-upb)
Early 
Terminationc)
Visits
-28 to -3 
days before 
1st study 
drug admin
Day
-2
Day 
-1d)
Day 
1d)
Day 
2
Day 
3
Day
4
Day 
28
Day 
29d)
Day 
30
Day 
43
Day 
71
Day 
127
6 months 
after last 
study drug 
admin
up to 28 days 
after last study 
drug admin
Window
NA
NA
NA
NA
NA
NA
NA
2 
days
2 
days
2 
days
7 
days
14 
days
14 
days
14 days
14 days
Month
-1
1
1
1
1
1
1
2
2
2
2
3-4
5-6
7-8
NA
Week
-4 to -1
1
1
1
1
1
1
5
5
5
6-7
8-12
16-20
27-31
NA
Hour
NA
NA
-24
0
24
48
72
NA
NA
NA
NA
NA
NA
NA
NA
Lumbar punctureaa)
CSF sampling from
predose until (and 
including) 48 hours 
postdose
x
x
x
x
x
x
C-SSRSbb)
x
x
x
x
x
x
x
Independence Scale
x
x
x
HD-DAS
x
x
MoCA
x
x
TMS
x
x
CGI-S
x
x
CGI-C
x
SDMT
x
x
SWRT
x
x
TFC
x
x
x
Blood sample for RBR 
DNA (optional)cc)  
x
Blood sample for RBR 
RNA (optional)cc)  
x
Serum sample for 
RBR (optional)cc)  
x
x
x
x
x
Clinical genotyping
x
Adverse eventsdd)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Change in medical 
information since 
previous visitsee)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
medicationsff)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Note: At timepoints where more than one assessment is required, the sequence noted in Appendix 6 should be followed as 
applicable. 


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
100/Protocol BP40410, Version 4
a)
A maximum of one re-screening will be allowed within 4 weeks of the initial screening failure for patients who fail the initial 
screening (e.g., as a consequence of abnormal laboratory values or general medical status not meeting inclusion or exclusion 
criteria).  If re-screening is required, CAG repeat length testing does not need to be repeated (historical values will not be 
accepted), and the viral serology from the initial screening may be acceptable as part of the re-screening assessments, if 
performed within 4 weeks of the baseline visit.
b)
Patients who complete the treatment period will return to the clinic for the follow-up visit 6 months (2 weeks) after last study 
drug administration. Study visits should be planned as per the study schedule; however, under exceptional circumstances, time 
windows as indicated in the schedule of activities can be utilized.
c)
All patients who withdraw or discontinue from study treatment early will be asked to return to the clinic for the early termination 
visit within 28 days 14 days after the last dose of study drug.
d)
In order for the Holter recordings to be conducted in the same conditions, food consumption/intake must occur at the same time 
on Day -1, Day 1, and Day 29.  Food consumption/intake should be avoided (to the extent possible) when the Holter ECG data is 
collected. 
e)
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.
f)
Medical history, including clinically significant diseases, surgeries, HD history (including past hospitalizations [i.e., number, 
duration, and reason]) over the last 2 years, reproductive status, smoking history, and use of alcohol and drugs of abuse will be 
recorded at baseline.
g)
Skin (groin area) and nose swabs will be taken during screening to test for Methicillin-resistant Staphylococcus aureus (MRSA).  
If the MRSA screening result is positive, treatment for decolonization (as per local standard procedure) should be administered 
for 5 days prior to catheter insertion.
h)
Viral serology: HbsAg, HCV antibody, HIV-1 antibody, and HIV-2 antibody.
i)
Thyroid panel: thyroid-stimulating hormone and free thyroxine (also known as T4).


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
101/Protocol BP40410, Version 4
j)
Structural MRI is mandatory; diffusion-weighted and resting-state functional MRIs are optional, as clinically indicated (and if 
patient gives specific consent).  MRIs should take place as early as possible within the screening window but may take place at 
any time during screening.  The screening MRI scan should be performed at least 7 days prior to the IT catheter insertion to 
allow time for re-scanning if the quality of the initial MRI is inadequate.  The screening MRI scan must pass central laboratory 
image quality control review and results must be available before the patient can be enrolled in the study.  The follow-up (or 
early termination, if applicable) MRI should take place within the 14-day window allowed for the follow-up visit (or early 
termination visit, if applicable) and prior to the lumbar puncture scheduled at follow-up (or early termination, if applicable).  If 
patient who enrolled under protocol Version 3 cannot undergo and tolerate MRI scans, no MRI scans will be performed at the 
follow-up visit (or early termination visit, if applicable).
k)
Includes respiratory rate, pulse, temperature, and systolic and diastolic blood pressure while the patient is in a seated position for 
approximately 5 minutes. Record abnormalities observed at baseline (Day -1) on the General Medical History and Baseline 
Conditions eCRF. At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
l)
A complete physical examination, performed at screening and at other visits as specified in the schedule of activities, should 
include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems (including fundoscopy); genitourinary examinations may be performed if 
clinically indicated.  The physical examinations should be conducted in the same manner on each occasion to ensure 
comparability to previous examinations.  Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.  Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities (i.e., beyond expected variation or normal age-related change) should be recorded as 
adverse events on the Adverse Event eCRF.  Height will be measured at screening only. 
m) A neurologic examination, performed at screening and at other visits as specified in the schedule of activities, should include 
assessment of mental status, level of consciousness, cranial nerve function, motor function, sensory function, reflexes, and 
coordination. The neurologic examination should be conducted in the same manner on each occasion to ensure comparability to 
previous examinations. Neurologic examinations should be performed before and after treatment on each dosing day. Weight 
should also be measured at each neurologic examination. Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  Changes from baseline abnormalities should be recorded in patient 


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
102/Protocol BP40410, Version 4
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.  
n)
Single 12-lead ECGs are to be recorded after the patient has been in a supine position for approximately 10 minutes.  ECGs for 
each patient should be obtained from the same machine whenever possible. At screening, baseline (Day -1), and other visits, 
pre-dose ECGs are to be recorded prior to any blood draws and before the lumbar puncture. 
o)
From Day -1 to Day 3, patients will wear a digital Holter monitoring device for continuous recordings of 12-lead ECG traces over 
72 hours (starting 24 hours before first study drug administration until 48 hours postdose).  On Day 29, patients will again wear a 
digital Holter device for recordings of data over 4 hours, starting from predose until 4 hours postdose.  Collection of 12-lead ECG 
traces from Holter recordings will be done at pre-defined timepoints (See Appendix 2).  Extraction times on Day -1 must match 
the times of extraction on Day 1 and Day 29.  The Day 29 Holter ECG recording data will be extracted at predose (~0 hour), 1, 2, 
and 4 hours postdose.  Triplicate ECG tracings from the continuous recordings will be extracted within 10 minutes of the nominal 
timepoints for PK (plasma) sampling.  At these specific timepoints the patient should be at rest and in a supine position for at least 
10 minutes prior to and remain in the supine position for at least 5 more minutes after the specified PK (plasma) sampling 
timepoint.
p)
Hematology includes WBC count, RBC count, platelet count, hemoglobin, hematocrit, differential count (neutrophils, eosinophils, 
basophils, monocytes, and lymphocytes).
q)
Serum chemistry panel: bicarbonate, sodium, potassium, chloride, glucose, blood urea nitrogen, creatinine, total protein, albumin, 
phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, gamma-glutamyl transferase, and 
creatine phosphokinase.
r)
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.
s)
Females only to confirm post-menopausal status. Includes measurement of follicle-stimulating hormone and Estradiol. 
t)
Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, and bacteria).


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
103/Protocol BP40410, Version 4
u)
Plasma PK sampling will be collected as follows: at Day 1 (0 [predose], 1, 2, 4, 6, 8, 12, and 16 hours postdose), Day 2 (24 and 
36 hours postdose), Day 3 (48 and 60 hours postdose), Day 4 (72 hours postdose), Day 28 (at a timepoint equivalent to Day 1 
predose sample), Day 29 (0 [predose], 1, 2, and 4 hours postdose), Day 30, 43, 71, and 127 (at a timepoint equivalent to Day 29 
predose sample), and the follow-up visit (early termination visit if applicable).
v)
Bladder must be completely emptied at the time of study drug administration. Quantitative urine will be collected in the following 
intervals: 0 to 24 hours, 24 to 48 hours, and 48 to 72 hours following first study drug administration. 
w)
Cerebrospinal fluid sampling will be performed from predose to (and including) 48 hours postdose via the IT catheter, at all other 
visits CSF sampling will be done by single lumbar puncture. Pharmacokinetic CSF sampling will be collected as follows: at Day 1 
(0 [predose], 2, 4, 8, 12, and 16 hours postdose), Day 2 (24 and 36 hours postdose), Day 3 (48 hours), Day 29 (predose), Day 43, 
71, and 127, and the follow-up visit (early termination visit if applicable). Sampling for CSF biomarkers will be collected as follows: 
Day 1 (0 [predose], 4, 8, 12, and 16 hours postdose), Day 2 (24 and 36 hours postdose), Day 3 (48 hours postdose), Day 29 
(predose), Day 43, 71, and 127, and the follow-up visit (early termination visit if applicable). In addition, up to 2 mL CSF sample 
will be collected for daily CSF safety testing, including culture, during the indwelling-catheter period.
x)
Sampling for plasma biomarkers will be collected as follows: at Day -1 (-24, -20, -16, -12, and -8 hours), Day 1 (0 [predose], 1, 2, 
4, 6, 8, 12, and 16 hours postdose), Day 2 (24 and 36 hours postdose), Day 3 (48 and 60 hours postdose), Day 4 (72 hours 
postdose), Day 29 (predose), Day 43, 71, and 127, and the follow-up visit (early termination visit if applicable).
y)
Admission to the clinical unit may occur either on the evening/afternoon of Day -2 or the morning of Day -1. Assessments for 
Day -2 should be conducted on Day -2, but it is not mandatory for the patient to remain at the clinic overnight on Day -2 if it is 
more convenient to stay at a hotel or return home.
z)
In preparation for the catheter insertion, patients will be required to remove all body piercings, make up, and nail polish and to 
cleanse the entire body (including hair) with antibacterial soap on Day -2 or Day -1.
aa) Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR, aPTT, PT) and 
platelets must be conducted and the results reviewed. Collection of these local laboratory tests may occur at any time in the 
72 hours prior to the lumbar puncture (with the exception of CSF collection during the CSF sampling period from predose prior to 
first study drug administration until 48 hours postdose).  The lumbar puncture (with the exception of the CSF sampling around the 
first dose) should be performed at approximately the same time at each visit (ideally in the morning between 8:00 a.m. and 12:00 


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
104/Protocol BP40410, Version 4
noon or in the early afternoon between 12:00 noon and 3:00 p.m.) to minimize potential diurnal variation of CSF parameters. A 
20 mL CSF sample will be collected at predose after the IT catheter has been inserted and before the study drug administration. 
Subsequently, during the CSF sampling period from predose until 48 hours postdose approximately 5 mL of CSF fluid will be 
collected (via the IT catheter) at the timepoints indicated in Appendix 2. In addition, up to 2 mL CSF sample will be collected for 
daily CSF safety testing, including culture, during the indwelling-catheter period. For all other lumbar punctures, CSF fluid (20 
mL) is to be collected for analyses using a lumbar puncture collection kit. If there are difficulties in collecting 20 mL of CSF fluid, a 
minimum of 5 mL should be collected over a maximum of 60 minutes. The operator must confirm CSF flow is present prior to 
injecting study drug. A 24G (atraumatic) needle should be used to minimize risk of post-lumbar puncture syndrome.  Depending 
on institutional guidelines, local anesthesia should be used for the procedure. Sedation may not be used. Spinal ultrasound may 
be used for the lumbar puncture procedure if deemed necessary, but ultrasound is not required. Spinal ultrasound guidance may
be used if attempts at lumbar puncture without imaging are unsuccessful, if it is local practice to use ultrasound, or if institutional 
guidelines dictate use of ultrasound with each lumbar puncture. Patients will be discouraged from resting supine after the lumbar 
puncture procedure and will be encouraged to mobilize immediately by walking around at a minimum and, if feasible, walking 
briskly.
bb) The C-SSRS will be used to assess eligibility for the study (full version at baseline, requiring approximately 20 minutes to 
administer) and to monitor the patients throughout the study at clinic visits (follow-up version, requiring approximately 5 minutes to 
administer, assuming absence of suicidal ideation and no change in clinical status from previous administration).
cc) Performed only for patients at participating sites who have provided written informed consent to participate.
dd) After informed consent has been obtained but prior to initiation of study drug, any serious adverse events caused by a 
protocol-mandated intervention should be reported. After initiation of study drug, all adverse events will be reported until 
6 months after the last 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.
ee) At the time of each study drug administration, an interval medical history should be obtained and any changes in medications, any 
major procedures or hospitalizations, and any physician visits for HD or general medical care should be recorded.


Appendix 1: Schedule of Activities
RO7234292—F. Hoffmann-La Roche Ltd
105/Protocol BP40410, Version 4
ff)
Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated treatment from screening to the follow-up visit.
Admin=administration; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
CAG=cytosine, adenine, guanine base sequence found in DNA which is translated into glutamine; CGI-C=Clinical Global Impression–Change; 
CGI-S=Clinical Global Impression–Severity; CRPC-reactive protein; CSF=cerebrospinal fluid; C-SSRS=Columbia-Suicide Severity Rating Scale; 
DNA=deoxyribonucleic acid; ECG=electrocardiogram; eCRF=electronic Case Report Form; ESRerythrocyte sedimentation rate; HbsAg=hepatitis 
B virus surface antigen; HCV=hepatitis C virus; HD=Huntington’s disease; HD-DAS=Huntington’s Disease Daily Activity Scale; HIV=human 
immunodeficiency virus; INR=international normalized ratio; IT=intrathecal; MoCA=Montreal Cognitive Assessment; MRSA Methicillin-resistant 
Staphylococcus aureus; MRI magnetic resonance imaging; NA=not applicable; PK=pharmacokinetic; PT=prothrombin time; RBC=red blood cell; 
RBR=Research Biosample Repository; RNA=ribonucleic acid; SDMT=Symbol Digit Modalities Test; SWRT=Stroop Word Reading Test; TFC=Total 
Functional Capacity; TMS=Total Motor Score; WBC=white blood cell.


RO7234292—F. Hoffmann-La Roche Ltd
106/Protocol BP40410, Version 4
Appendix 2
Schedule of Detailed Assessments During the In-house Periods
Assessment
Treatment Period
Day
-1
-1
-1
-1
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
28
29
29
29
29
Month
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
Week
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
5
5
Hour
-24
-20
-16
-12
-8
0
1
2
4
6
8
12
16
24
36
48
60
72
0
0
1
2
4
Medical history 
and baseline 
conditionsf)
x
Vital signsk)
x
x
x
x
x
x
x
x
x
Complete 
physical 
examinationl)
x
Neurological 
examinationm)
x
x
x
12-lead (single) 
ECGn)
x
x
x
x
x
x
x
x
x
12-lead Holter 
ECGd), o)
-24 hours to 48 hours postdose
0 to 4 hours postdose
Holter ECG 
timepoints for 
extractiono)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hematology
(local)p)
x
x
x
x
x
x
Chemistryq)
x
x
x
x
Pregnancy testr)
x
Local PT, INR, 
aPTT, platelet 
count
x
Urinalysist)
x
x
x
x


Appendix 2: Schedule of Detailed Assessments During the In-House Periods
RO7234292—F. Hoffmann-La Roche Ltd
107/Protocol BP40410, Version 4
Assessment
Treatment Period
Day
-1
-1
-1
-1
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
28
29
29
29
29
Month
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
Week
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
5
5
Hour
-24
-20
-16
-12
-8
0
1
2
4
6
8
12
16
24
36
48
60
72
0
0
1
2
4
RO7234292 PK 
sampling 
(plasma)u)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
RO7234292 PK 
sampling (urine)v)
0 to 24 hours
24 to 48 hrs
48 to 72 hrs
RO7234292 PK 
sampling (CSF)w)
x
x
x
x
x
x
x
x
x
x
Plasma sampling 
for 
immunogenicity 
testing
x
x
CSF sample for 
safetyw)
x
x
x
x
CSF sample for 
biomarkersw)
x
x
x
x
x
x
x
x
x
Blood for CRP
and ESR (local)
x
x
x
x
x
x
Plasma sample 
for biomarkersx)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Insertion of IT 
catheterz)
x
Removal of IT 
catheter
x
Catheter tip for 
culture
x


Appendix 2: Schedule of Detailed Assessments During the In-House Periods
RO7234292—F. Hoffmann-La Roche Ltd
108/Protocol BP40410, Version 4
Assessment
Treatment Period
Day
-1
-1
-1
-1
-1
1
1
1
1
1
1
1
1
2
2
3
3
4
28
29
29
29
29
Month
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
Week
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
5
5
Hour
-24
-20
-16
-12
-8
0
1
2
4
6
8
12
16
24
36
48
60
72
0
0
1
2
4
Study drug 
administration
x
x
Lumbar 
punctureaa)
CSF sampling from predose until (and including) 48 hours postdose
x
C-SSRSbb)
x
x
Blood sample for 
RBR DNA 
(optional)cc)  
x
Blood sample for 
RBR RNA 
(optional)cc)  
x
Serum sample for 
RBR (optional)cc)  
x
x
Clinical 
genotyping
x
Adverse eventsdd)
x
Change in 
medical 
information since 
previous visitsee)
x
Concomitant 
medicationsff)
x
Note: Patients will be admitted to the site in the afternoon/evening of Day -2 or the morning of Day -1 to begin the first in-house period of the study; 
patients will be discharged on Day 4 after all assessments have been completed. Patients will return to the site for the second in-house period in
the afternoon/evening of Day 28 or in the morning on Day 29 and will be discharged on Day 29 after all assessments have been completed. 
See corresponding footnotes in Appendix 1.


RO7234292—F. Hoffmann-La Roche Ltd
109/Protocol BP40410, Version 4
Appendix 3 Clinician-Reported Outcomes
Assessment
Name
Items
Concepts
Approx. Duration
Timing
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10 min
Screening and 
Follow-up visits
HD-DAS
Huntington’s 
Disease Daily 
Activities Scale
25
Daily function
25 min
Screening and 
Follow-up visits
IS
Independence Scale
1
Functional 
disability/independence
3 min
Screening and 
Follow-up visits
TFC
Total Functional 
Capacity Scale
5
Overall function
10 min
Screening and 
Follow-up visits
TMS
Total Motor Score
31
Motor function
15 min
Screening and 
Follow-up visits
C-SSRS
Columbia-Suicide 
Severity Scale
5
Suicidal ideation and 
behavior
20 min full version; 
5 min follow-up 
version
Full version at 
Screening and 
follow-up version at 
Follow-up visit
CGI-S
Clinical Global 
Impression–Severity
1
Overall severity of 
patient status
2 min
Screening and 
Follow-up visits
CGI-C
Clinical Global 
Impression–Change
1
Overall change in 
patient status
2 min
Follow-up visit
Approx.=approximately.


RO7234292—F. Hoffmann-La Roche Ltd
110/Protocol BP40410, Version 4
Appendix 4 Performance Outcomes
Assessment
Name
Items
Concepts
Approx. Duration
Timing
SDMT
Symbol Digit 
Modalities Test
Max no. in 90 sec
Cognitive
5
Screening and 
Follow-up visits
SWRT
Stroop Wording 
Reading Test
Max no. in 45 sec
Cognitive
5
Screening and 
Follow-up visits
Approx.=approximately; No.=number; Max=maximum.


RO7234292—F. Hoffmann-La Roche Ltd
111/Protocol BP40410, Version 4
Appendix 5 Diagnostic Confidence Level
The diagnostic confidence level is calculated as shown below (from the Unified 
Huntington’s Disease Rating Scale Total Motor Score Scale, Item 17):
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, or rigidity) in a subject at risk for Huntington’s 
disease (HD)?
0=normal (no abnormalities)
1= non-specific motor abnormalities (less than 50% confidence)
2=motor abnormalities that may be signs of HD (50% to 89% confidence)
3=motor abnormalities that are likely signs of HD (90% to 98% confidence)
4=motor abnormalities that are unequivocal signs of HD (>99% confidence)
Copyright 1999
Huntington Study Group. Unified Huntington’s Disease rating scale: reliability and 
consistency. Mov Disord 1996:11:13642.


RO7234292—F. Hoffmann-La Roche Ltd
112/Protocol BP40410, Version 4
Appendix 6 Order of Assessments
At timepoints where more than one assessment is required, the following sequence 
should be followed as applicable, and priority will be given to the CSF PK sample being 
taken at the scheduled time:

Obtain resting single 12-lead ECGs and Holter ECGs collection.

Collect resting vital signs.

Collect CSF sample for CSF PK determination.

Collect CSF sample for CSF PD determination and CSF biomarker determination.

Collect CSF safety sample.

Collect blood sample for plasma PK determination.

Collect blood sample for plasma PD determination and blood/plasma/serum 
biomarker determination.

Collect blood samples for blood chemistry, hematology, viral serology and 
coagulation.

Collect urine sample for urinalysis.

Collect urine sample for urine PK determination.

Collect blood sample for clinical genotyping.

Administer study drug.


RO7234292—F. Hoffmann-La Roche Ltd
113/Protocol BP40410, Version 4
Appendix 7 Grading Scale for Adverse Events Related to 
Laboratory Abnormalities
The following grading recommendations for adverse events related to clinical laboratory 
test abnormalities are based on the Common Terminology Criteria for Adverse Events, 
Version 5.
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
  
  
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
  
  
  
 
 
  
 
  
 
 
 
 
  
  
  
  
  
  
  
 
 
 
  
 
  
 
 
 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 7: Grading Scale for Adverse Events Related to Laboratory Abnormalities
RO7234292—F. Hoffmann-La Roche Ltd
114/Protocol BP40410, Version 4
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
   
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
  
 
  
  
 
 
  
 
 
  
  
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
  
 
  
 
  
  
 


Appendix 7: Grading Scale for Adverse Events Related to Laboratory Abnormalities
RO7234292—F. Hoffmann-La Roche Ltd
115/Protocol BP40410, Version 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
  
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
Official Title: 
An Open-Label Adaptive Multiple-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 
NCT Number: 
NCT04000594 
Document Date: 
SAP Version 1: 15-Jun-2020 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
RO7234292—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BP40410
STATISTICAL ANALYSIS PLAN
TITLE:
AN OPEN-LABEL, ADAPTIVE MULTIPLE-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
PROTOCOL NUMBER:
BP40410
STUDY DRUG:
RO7234292 (ISIS 443139 or RG6042)
VERSION NUMBER:
1
EUDRACT NUMBER:
2018-003010-40
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
15-Jun-2020 08:54:30
Company Signatory


RO7234292—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BP40410
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 1
2.
STUDY DESIGN........................................................................................... 1
2.1
OBJECTIVES .......................................................................... 4
2.1.1
Primary Objectives .................................................................. 4
2.1.2
Secondary Objectives.............................................................. 4
2.2
Exploratory Objectives/Endpoints............................................ 4
2.3
Endpoints................................................................................. 5
2.3.1
Safety and Tolerability Endpoints ............................................ 5
2.3.2
Pharmacokinetic Endpoints ..................................................... 5
2.3.3
Pharmacodynamic and Clinical Outcomes .............................. 5
2.4
Determination of Sample Size ................................................. 6
2.5
Analysis Timing ....................................................................... 6
3.
STUDY CONDUCT....................................................................................... 6
3.1
PATIENT ENROLLMENT........................................................ 7
4.
STATISTICAL METHODS ............................................................................ 7
4.1
Analysis Populations ............................................................... 7
4.1.1
Safety Population .................................................................... 7
4.1.2
Immunogenicity Population...................................................... 7
4.1.3
Pharmacokinetic Population .................................................... 7
4.1.4
Pharmacodynamic Population................................................. 8
4.2
Baseline definitions.................................................................. 8
4.3
Analysis of Study Conduct....................................................... 8
4.4
Analysis of Treatment Group Comparability ............................ 8
4.5
Data Handling Rules................................................................ 8
4.6
Missing Data............................................................................ 9
4.7
Safety Analyses....................................................................... 9
4.7.1
Exposure of Study Medication................................................. 9
4.7.2
Adverse Events ....................................................................... 9
4.7.3
Laboratory Data..................................................................... 10
4.7.4
Vital Signs.............................................................................. 11


RO7234292—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BP40410
4.7.5
Electrocardiogram ................................................................. 11
4.7.6
Anti-drug Antibodies .............................................................. 12
4.7.7
Physical/Neurological Examination........................................ 13
4.7.8
Columbia-Suicide Severity Rating Scale ............................... 14
4.8
Clinical Outcomes and pharmacodynamics........................... 16
4.8.1
Describing Parameters over Time ......................................... 16
4.8.1.1
Unified Huntington’s Disease rating Scale............................. 16
4.8.1.2
Huntington’s Disease Daily Activities Scale........................... 18
4.8.1.3
Clinical Global Impression-Severity ....................................... 18
4.8.1.4
Clinical Global Impression-Change ....................................... 18
4.8.1.5
Montreal Cognitive Assessment ............................................ 18
4.8.1.6
Summary of outputs for describing the 
parameters over time............................................................. 19
4.8.2
Relationship between selected parameters........................... 19
4.9
Pharmacokinetic and PKPD Analyses................................... 21
4.10
Interim Analyses .................................................................... 22
REFERENCES................................................................................................... 23


RO7234292—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BP40410
LIST OF TABLES
Table 1. CSF Safety Labs Standard (Marked) Reference Ranges..................... 11
Table 2. Vital Signs (Supine) Abnormality Ranges............................................. 11
Table 3. ECG Parameters Abnormality Ranges ................................................. 12
Table 4. Criteria for abnormal absolute QTc and change in QTcF interval......... 12
Table 5. Overview of planned outputs to describe parameter evolution over 
time............................................................................................. 19
Table 6. Overview of planned outputs to describe the association between 
selected pairs of parameters....................................................... 20
LIST OF FIGURES
Figure 1. Diagram of study design........................................................................ 3


RO7234292—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan BP40410
STUDY GLOSSARY
Abbreviation
Definition
ADA
Anti-drug antibody
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
BLQ
Below the limit of quantification 
CAG
Cytosine, adenine, guanine base sequence found in DNA which is 
translated into glutamine 
CAP
CAG age product
CGI-C
Clinical Global Impression – Change
CGI-S
Clinical Global Impression – Severity
ClinRO
Clinician-reported outcome
CNS
Central nervous system
CSF
Cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic data capture
FDA
Food and Drug Administration
HA
Health Authorities
HD
Huntington's disease
HD-DAS
Huntington's Disease -Daily Activities Scale
HTT
Huntingtin gene
IMP
Investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IT
Intrathecal
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities 
mHTT
Mutant Huntingtin 
MoCA
Montreal Cognitive Assessment


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Statistical Analysis Plan BP40410
MOE
Methoxyethyl
mRNA
Messenger ribonucleic acid
NfL
Neurofilament light chain 
OLE
Open-label extension
PD
Pharmacodynamics(s)
PerfO
Performance outcome
PK
Pharmacokinetic(s)
PT
Prothrombin time
QTc
Corrected QT interval
QTcF
QT interval corrected through use of Fridericia's formula
RBC
Red blood cell
RBR
Research Biosample Repository
RNA
Ribonucleic acid
SAP
Statistical Analysis Plan
SDMT
Symbol Digit Modalities Test
SI
Système International d’Unités
SPA
Statistical Programming & Analysis
SWRT
Stroop Word Reading Test
Study Day 1
Defined as the first day Study Drug is administered to the patient
Study Drug
RO7234292 (previously known as ISIS 443139)
TEAE
Treatment-emergent adverse event
TFC
Total Functional Capacity 
TMS
Total Motor Scale
UHDRS
Unified Huntington's Disease Rating Scale
ULN
Upper limit of normal
WBC
White blood cell
WES
Whole exome sequencing
WGS
Whole genome sequencing
wtHTT
Wild-type huntingtin


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1/Statistical Analysis Plan BP40410
1.
BACKGROUND
This Statistical Analysis Plan describes all planned methods of summarizing and analyzing 
data to be collected in study BP40410. Study BP40410 is an open-label, adaptive multiple-
dose clinical study designed to generate time course data on PK, PD, and the PK/PD
relationship after intrathecal (IT) administration of RO7234292 to patients with manifest 
HD (males and females aged 25-65 years, inclusive). 
Huntington’s disease is an autosomal dominant neurodegenerative disease caused by a 
CAG repeat expansion in the first exon of the HTT gene located on Chromosome 4 
resulting in a polyglutamine expansion in the huntingtin protein (Htt). Based upon non-
clinical and clinical evidence, mHTT protein is considered the primary driver of HD 
pathophysiology [1]. 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 to 20 years, with pneumonia, heart failure, or other complications frequently cited as 
the cause of death [2].
2.
STUDY DESIGN
Eligible subjects will receive dose assigned to the cohort they are allocated to. Three dose 
levels are tentatively planned as follows:

Dose level 1: 120 mg RO7234292 (n=4 patients)

Dose level 2: 60 mg RO7234292 (n=4 patients)

Dose level 3: 30 mg RO7234292 (n=4 patients)
This is not a randomization study Patients are allocated to a cohort and hereby dose level 
according to the way they are sequentially enrolled into the study. Thus, the first 4 subjects 
will be assigned to 120mg, the next 4 subjects to 60mg and the next 4 subjects to 90mg.
After a review of medical data from the initial 3 dose levels and initial set of patients, a 
decision will be made whether to enroll additional patients and, in this case, whether to 
repeat a dose level, or to evaluate a lower or intermediate dose levels. The final number 
of dose levels and total number of patients assigned to a given dose level will be defined 
during the study.  Up to a maximum of 20 patients will be enrolled in the whole study and 
the highest tested RO7234292 dose in this study will not exceed 120 mg, which is the 
highest test dose in the previous Phase I/IIa clinical study (ISIS 443139-CS1).


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2/Statistical Analysis Plan BP40410
Study day is calculated relative to the date of first dose administration in Study BP40410. 
Study Day 1 will be the first treatment dose administration date. There is no day zero, 
hence the study day for patients who took at least one dose will be computed as follows:
Study Day = assessment date – treatment start date + 1, 
if the assessment date is on or after the treatment date; or 
Study Day = assessment date – treatment start date, 
if the assessment date is earlier than the treatment date. 
The end of this study is defined as the date when the last patient, last visit occurs. The 
end of the study is expected to occur approximately 6 months after the last study drug 
administration for the last patient has occurred.  The total length of the study, from 
screening of the first patient to the end of the study, is expected to be approximately 1.5
years.  
After completing study treatment in the current study, the patient will be eligible to enroll 
in an open label extension (OLE) study (BN40955) with active RO7234292 compound, 
provided the data from the ongoing RO7234292 program support continued development, 
the patient meets the inclusion and exclusion criteria for the OLE, and the OLE meets
approval by the relevant competent authorities, IRBs, and ECs.
The SAP language supersedes the language in the protocol and protocol synopsis.
A schematic overview of the study design is presented in Figure 1. For additional details, 
refer to the Schedule of Assessments in the study protocol (Appendices 1 and 2).


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3/Statistical Analysis Plan BP40410
* Note:  Patients will be admitted to the site in the afternoon/evening of Day -2 or in the morning of Day-1 to begin the first in-house period of the study; patients will 
be discharged on Day 4 after all assessments have been completed.  Patients will return to the site for the second in-house period in the afternoon/evening of 
Day 28 or in the morning on Day 29 and will be discharged on Day 29 after all assessments have been completed. 
CSF=cerebrospinal fluid; FU=follow-up.  
Figure 1. Diagram of study design


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2.1
OBJECTIVES 
This study will evaluate the PK, PD, and safety of RO7234292 in patients with HD.
2.1.1
Primary Objectives

To characterize the PK of RO7234292 in CSF and plasma following administration 
of multiple (2) IT doses of RO7234292

To characterize mHTT CSF protein time course following administration of multiple 
(2) IT doses of RO7234292 in patients with HD

To investigate the PK/PD relationship of multiple (2) IT doses of RO7234292 on 
mHTT in CSF
2.1.2
Secondary Objectives

To assess the safety and tolerability of multiple (2) IT doses of RO7234292 in 
patients with HD

To evaluate the immunogenicity of RO7234292

To characterize the PK of RO7234292 in urine following administration of an IT dose 
of RO7234292
2.2
EXPLORATORY OBJECTIVES/ENDPOINTS
The exploratory objectives for this study would be to evaluate the effects of RO7234292 
compared on the basis of the following endpoints:

Change from baseline in exploratory biomarkers in CSF (e.g. neurofilament light 
chain [NfL])

Relationship between exploratory fluid biomarkers in CSF and blood (e.g. CSF and 
plasma NfL)

Relationship between biomarkers, safety (including Holter monitoring), PK, and 
immunogenicity

Relationship of biomarkers to clinical severity at baseline using the UHDRS and 
Clinical Global Impression
Safety, PK, PD and clinical individual endpoints are outlined in the following sub-
sections.


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2.3
ENDPOINTS
2.3.1
Safety and Tolerability Endpoints

Adverse events (AEs)

Vital signs 

Electrocardiograms (ECGs)

Clinical laboratory results

Columbia - Suicide Severity Rating Scale (C-SSRS)

Anti-drug antibodies (ADAs)
2.3.2
Pharmacokinetic Endpoints
PK parameters will be read directly from the (plasma, CSF) concentration-time profiles
or calculated using standard non-compartmental methods. These parameters include but 
not limited to:  

Time to maximum (or peak) plasma concentration, maximum (or peak) plasma
concentration

Area under the plasma concentration-time curve (AUC) from time zero to the last 
measurable concentration, AUC from time zero to a timepoint, AUC from time zero to 
infinity, extrapolated AUC, AUC for a dosing interval

Lambda(z), half-life; apparent total clearance

Cumulative amount of unchanged drug excreted in urine, fraction of IT administered 
drug excreted in urine, renal clearance of the drug from plasma
2.3.3
Pharmacodynamic and Clinical Outcomes

Biomarkers

CSF levels, including but not limited to:

mHtt

NFfL

Plasma NfL

MRI


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
Clinical-Reported Outcomes
o
Montreal Cognitive Assessment (MoCA)
o
Huntington’s Disease Daily Activities Scale (HD-DAS)
o
Independence Scale (IS)
o
Total Motor Scale (TMS)
o
Total Functional Capacity Scale (TFC)
o
Clinical Global Impression-Severity (CGI-S)
o
Clinical Global Impression-Change (CGI-C)
o
Symbol Digit Modalities Test (SDMT)
o
Stroop Wording Reading Test (SWRT)
2.4
DETERMINATION OF SAMPLE SIZE
Up to 20 patients with HD may be enrolled in this study.  Due to the exploratory nature of 
this study, the actual number of patients will be determined during the study.
The sample size of 20 patients (at maximum) has been selected based on prior experience 
with second generation 2 ASOs given by IT injection to ensure that the PK and PD will be 
adequately assessed while minimizing patient exposure.  The number of patients may be 
adapted during the study to sufficiently characterize the PK/PD relationship in CSF of 
RO7234292, while not exceeding 20.
2.5
ANALYSIS TIMING
Despite the tentative safety analyses performed in order to determine the subsequent 
dose levels, the final analysis will be conducted once all recruited patients have completed 
the study as defined in the protocol or withdrawn early from the study and data have been 
cleaned and verified and the database has been locked.
Given the adaptive nature of this study, data may be reviewed at any time by the Sponsor, 
to inform the decision of eventually enrolling more than the initial planned 12 patients. 
Additionally, data may be used before the final analysis to support interactions with health 
authorities (HA).
3.
STUDY CONDUCT
The Guidelines of the World Medical Association Declaration of Helsinki dated October 
2002, the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable 
regulatory requirements will be strictly followed.


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3.1
PATIENT ENROLLMENT
This is a non-randomization study as patients are assigned to a dose level in the order 
they are enrolled after successfully completing all screening evaluations and after the 
Investigator has verified that the patient is eligible per inclusion and exclusion criteria 
outlined in the Protocol.
In the event of a screen-failure, a maximum of 1 re-screening will be allowed within 4 
weeks of the initial screening failure (e.g., as a consequence of abnormal laboratory 
values or general medical status not meeting inclusion or exclusion criteria).  If re-
screening is required, CAG repeat length testing does not need to be repeated (historical 
values will not be accepted), MRI and viral serology from the initial screening may be 
acceptable as part of the re-screening assessments, if performed within 4 weeks of the 
baseline visit.
4.
STATISTICAL METHODS
Descriptive summary statistics including but not limited to n, mean, median, standard 
deviation, range (minimum, maximum) for continuous variables, and counts and 
percentages for categorical variables will be used to summarize data by dose level and 
visit. Where applicable, statistical tests will be conducted using 2-sided tests and 95% 
confidence intervals will reported.
4.1
ANALYSIS POPULATIONS
4.1.1
Safety Population
All patients who are enrolled and received any dose of RO7234292, whether 
prematurely withdrawn from the study or not, will be included in the safety analyses.
The Safety Population will be the primary population for all safety analyses and patients 
will be analyzed by dose received.
4.1.2
Immunogenicity Population
All patients who received any dose of RO7234292 and with at least one post-dose 
ADA assessment.
4.1.3
Pharmacokinetic Population
All patients who are enrolled and receive at least 1 dose of RO7234292, have not 
significantly deviated from the protocol, violated inclusion or exclusion criteria. Patients 
with incomplete data may be excluded if this would undermine the interpretability of the
the PK analysis. Excluded cases will be documented together with the reason for 
exclusion.


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4.1.4
Pharmacodynamic Population
All patients who are enrolled and receive at least 1 dose of RO7234292, have not 
significantly deviated from the protocol, violated inclusion or exclusion criteria. Patients 
with incomplete dattta may be excluded of this would undermine the interpretability of 
the PD analysis. Excluded cases will be documented together with the reason for 
exclusion.
4.2
BASELINE DEFINITIONS
For all assessments, baseline will be defined as the last non-missing measure prior to the 
first dose administration. For fluid biomarkers, if appropriate time-matched baseline may 
also be considered to assess diurnal effects.
4.3
ANALYSIS OF STUDY CONDUCT
The number of patients who enroll in the study, discontinue from the study, and complete 
the study will be summarized overall and by dose level. Reasons for premature study 
withdrawal will be listed and summarized. All major protocol deviations will be listed and 
summarized.
Additional analyses will be performed to assess and describe the impact of COVID-19 on 
the study conduct.
4.4
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics will be summarized by dose level using but not 
limited to n, mean, standard deviation, median and range for continuous variables and 
proportion for categorical variables, as appropriate.  Summaries will be presented overall 
and by dose level.
4.5
DATA HANDLING RULES
For safety laboratory and measurements that are reported as ‘<x’ or ‘>x’, the analysis 
value will be replaced by ‘x’. For biomarkers (e.g. CSF mHtt, CSF NfL, etc) where entries 
will be indicated as ‘BLQ’, the analysis value will be set to BLQ divided by 2 (BLQ*0.5). 
No imputation will be performed on missing entries without a corresponding BLQ limit. In 
case of listing, however, the original data entries will be presented.
A summary table for subjects with imputed values by dose level and visit will be presented 
for each parameter.
For CSF/plasma biomarkers (e.g. NfL, mHtt) and CSF protein, scatter plots to assess
relationships will be based on the natural log-transformed parameter.
For PK concentrations, BLQ values will be set to zero if corresponding time was prior to 
Tmax and set to missing after Tmax.


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4.6
MISSING DATA
Incomplete dates for AEs and laboratory data will be handled as described in the Roche 
data analysis standards (GDSR). Missing values will not be imputed unless otherwise 
specified (e.g. for BLQs).
4.7
SAFETY ANALYSES
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee 
in accordance with the Safety Management Plan throughout the conduct of the clinical 
trial. Data will be summarized using descriptive statistics. Only scheduled visits will be 
presented in summary tables and both scheduled and unscheduled visits will be included 
in listings. 
4.7.1
Exposure of Study Medication
Duration of treatment exposure (in days) to study drug will be calculated as: 
Date of last dose – Date of first dose +1
Summary tables for treatment exposure will be presented by dosing level. Number of 
doses received will also be reported.
4.7.2
Adverse Events
All treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) will 
be summarized for each dose level and for all patients using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding by system organ class, preferred term, 
relationship to Study Drug, and severity. Missing data will be handled as described in
Section 4.6. Percentages presented in AE tables will display the percentage of patients 
within a treatment dose level experiencing the AE at least once. 
For frequency counts by preferred term, multiple occurrences of the same AE in an 
individual are counted only once. For overall total number of events, multiple occurrences 
of the same AE in an individual are counted separately.
An adverse event will be regarded as treatment emergent adverse event (TEAE) if the 
event occurs after the first dose of treatment or worsened after treatment.
Adverse events that occur before first dose administration and are not related to study 
procedure will be included in data listings only. SAEs and non-serious AEs that lead to 
treatment discontinuation or treatment interruption will be listed separately. Selected AEs,
for instance procedure related AEs, will be summarized and listed separately. 
Additional analyses will be considered to describe the impact of COVID-19 on patient 
safety.


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4.7.3
Laboratory Data
Laboratory data including chemistry, hematology, CSF safety labs and urinalysis, will be 
collected throughout the study. 
Summary statistics at each assessment time will be presented using the International 
System of Units (SI units; Système International d’Unités). Laboratory data not reported 
in SI units will be converted to SI units before processing.
Descriptive tables will be used to summarize absolute, change and percentage change 
from baseline by dose level and study day. Measurements reported as ‘>x’ or ‘<x’ will be 
handled as outlined in Section 4.5.
Spaghetti plots (with overlaid median) for absolute and change and percentage change
from baseline values will be presented for all parameters by dose level on the numeric 
time scale.
In addition, the shifts (relative to the normal range) from baseline to the minimum and 
maximum post-baseline values will be presented. If a subject is missing a baseline value 
but had a post-baseline value, then the baseline assessment is labeled as "unknown". 
Likewise, if a subject had a baseline value but had no post-baseline values, then the 
minimum and maximum are labeled as "unknown". For each parameter, the incidence of 
shift to low (below the normal range) will be summarized using the minimum post-baseline 
values; the incidence of shift to high (above the normal range) will be summarized using 
the maximum post-baseline values.
Finally, the number of patients with abnormal absolute values for the CSF safety labs, 
according to the parameter ranges presented in Table 1 will be summarized by dose level
and visit and also as a listing. Red blood and white blood counts cannot be negative and 
the lower normal range limit is 0, hence no abnormal low values. Roche standard 
reference ranges, rather than the reference ranges of the Investigator will be used for all 
parameters.
For most parameters, the measured laboratory test result will be assessed directly using 
the Roche standard reference range.  Certain laboratory parameters will be transformed 
to Roche’s standard reference ranges. A transformation will be performed on certain 
laboratory tests that lack sufficiently common procedures and have a wide range of 
Investigator ranges, e.g., enzyme tests that include AST, ALT, alkaline phosphatase, and 
total bilirubin.  Since the standard reference ranges for these parameters have a lower 
limit of zero, only the upper limits of the ranges will be used in transforming the data.
Standard and marked reference range for CSF laboratory parameters are presented in 
Table 1, given that there were no internal standards for those parameters..  There is no 
difference in the standard and marked reference ranges for protein and Leukocytes except 
for Glucose and Erythrocytes upper limits.




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abnormal. RR and QT corrected according to Frederica’s (QTcF) formulas used at sites
are defined as following: 

 = 60 
	
and  


 = 
 
 
	
⁄
The absolute values as well the changes from baseline will be summarized with 
descriptive statistics by dose level and study day. All ECG data will be listed. 
In addition, abnormal findings for ECG parameters (according to Table 3, Roche Standard 
ranges) will be listed. If a patient has an abnormal finding, all parameters will be reported. 
Abnormal absolute QTc and change in QTc interval, as presented in Table 4 will also be 
summarized. Abnormal ECG Interpretation, U-wave and T-wave will also be listed.
Spaghetti plots (with overlaid median) for absolute and change from baseline values will 
be presented for all parameters by dose level on the numeric time scale.
Holter ECG recordings will also be recorded. Details on their collection and analysis will 
be detailed and provided in a separate document. In addition, details on QTc-
concentration analysis will be detailed and provided in a separate document.
      Table 3. ECG Parameters Abnormality Ranges
Parameter
Low
Normal
High
HR (beats/min)
<40
40-100
>100
PR Interval (msec)
<120
120-200
>200
RR Interval (msec)
<600
600-1500
>1500
QRS Duration (msec)
<40
40-120
>120
QT Interval (msec)
<200
200-500
>500
QTcF interval (ms)
<350
350-450
>450
                      Table 4. Criteria for abnormal absolute QTc and change in QTcF interval
Parameter
Criteria
QTcF interval (ms)
>450
>480
>500
QTcF change from baseline (ms)
>30
>60
4.7.6
Anti-drug Antibodies
For patients under treatment, there is a potential for them to develop anti-drug antibodies 
(ADA) over time. The plasma sampling for anti-drug antibody assessment data will be 
available for baseline and pre-dose at each time point post-baseline and follow-up visit 6 


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13/Statistical Analysis Plan BP40410
months after the last dose (or early termination visit). Data will be presented in summary 
tables (proportions of baseline prevalence and incidence of ADA by dose level and a listing 
of patients who tested positive for ADA.
The following definitions based on [3]  as well as a Sponsor’s definition for ADA with 
neutralizing potential will be used to describe patients’ immunogenicity:

ADA Positive
- Treatment induced: ADA developed de novo (seroconversion) following drug 
administration. Patients who have no pre-existing ADA or are missing ADA data 
before drug administration and who have at least one ADA positive sample 
following drug administration.
-
Treatment boosted: Patients who have pre-existing ADA and have a ≥4 fold 
increase in ADA titer following drug administration compared to baseline 
measurement.

ADA Negative
-
ADA negative all samples: Patients who have no pre-existing ADA (i.e. 
antibodies reactive with the drug that are present in patients before treatment) 
or are missing ADA data before drug administration and who have all negative 
ADA results following drug administration, and treatment unaffected ADA-
negative patients.
-
Treatment unaffected ADA: Patients who had positive sample at baseline and 
post-baseline were either negative or positive but do not have a ≥4 fold increase 
in ADA titer following drug administration compared to baseline measurement.

Transient ADA 
-
Treatment-induced ADA detected only at one sampling time point during the 
treatment or follow-up observation period (excluding the last sampling time 
point).

Persistent ADA
-
Treatment-induced ADA detected at 2 or more sampling time points during the 
treatment or follow-up observation period, or detected on last sampling time 
point.
4.7.7
Physical/Neurological Examination
A complete physical and neurological examination will be performed at screening and at 
other visits as specified in the schedule of activities (refer to the study protocol Appendices 
1 and 2 for details). Unlike other assessments which will be pre-dose, neurological 
examination will be pre and post dose on each dosing day.


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Any abnormality identified at baseline will be recorded on the General Medical History and 
Baseline Conditions eCRF.  Changes from baseline abnormalities will be recorded in 
patient notes.  New or worsened clinically significant abnormalities (i.e., beyond expected 
variation or normal age-related change) will be recorded as adverse events on the 
Adverse Event eCRF.
Respective assessments will be summarized in their respective eCRF aforementioned 
category.
4.7.8
Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a structured tool to assess 
suicidal ideation and behavior. Four constructs will be assessed: severity of ideation, 
intensity of ideation, behavior and lethality of actual suicide attempts. 
The C-SSRS collects binary responses to 11 categories: five subtypes of suicidal ideation, 
five subtypes of suicidal behavior, and self-injurious behavior without suicidal intent. 
Specifically, the following outcomes are C-SSRS categories and have binary (Yes/No) 
responses. The categories have been re-ordered from the actual scale to facilitate the 
definitions of the composite endpoints and to enable clarity in the presentation of the 
results.
Suicidal Ideation:

Category 1 - Wish to Be Dead

Category 2 - Non-specific Active Suicidal Thoughts

Category 3 - Active Suicidal Ideation with Any Methods (Not Plan) without lntent 
to Act

Category 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan

Category 5 - Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior:

Category 6 - Preparatory Acts or Behavior

Category 7 - Aborted Attempt

Category 8 - Interrupted Attempt

Category 9 - Actual Attempt (non-fatal)

Category 10 - Completed Suicide
Other:

Category 11 - Non-suicidal Self-injurious Behavior
In addition, a numerical score, the Suicidal Ideation Score, will be defined as the highest 
suicide ideation category (1-5) at which the patient responded "Yes" for the given visit. If 
the patient did not respond “Yes” to any of these categories, the score will be set to zero.


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For each of the aforementioned 11 categories, the number and percent of patients with a 
“Yes” response at any time post-baseline (regardless of baseline response) will be 
summarized by dose level. Emergent suicidal ideation or behavior will be summarized. 
The listed binary categories and the Suicidal Ideation Score will be used to identify a 
number of composite suicidal endpoints. Note that "recent history" for these composite 
endpoints is defined as the 12 months prior to Screening and the Screening period. At the 
Screening visit, CSSRS data is collected for the prior 12 months. Therefore, analyses that 
utilize data from “recent history'” will include the historical 12-month data collected at 
Screening as well as all on-study C-SSRS data collected prior to first dose. The endpoints 
are defined as follows:
o
Suicidal Ideation: A “Yes" answer at any time post-first-dose to any one of the 
five   suicidal ideation questions (Categories 1-5), regardless of the pre-dose 
responses
o
Suicidal Behavior: A “Yes" answer at any time post-first-dose to any one of the 
five suicidal behavior questions (Categories 6-10), regardless of the pre-dose 
responses.
o
Suicidal Ideation or Behavior: A "Yes" answer at any time post-first-dose to any 
one of the ten suicidal ideation or behavior questions (Categories l-10), regardless 
of the pre-dose responses.
o
Treatment-Emergent Suicidal ldeation compared to recent history: A 
maximum post-first-dose suicidal ideation score that is increased from the 
maximum suicidal ideation score in recent history.
o
Treatment-Emergent Serious Suicidal ldeation compared to recent history: A 
maximum post-first-dose suicidal ideation score of 4 or 5 when the maximum 
suicidal ideation score during recent history was less than 4 (i.e., scores of 0-3). 
Only patients with a recent history score of 0-3 will be considered evaluable for this 
outcome.
o
Emergence of Serious Suicidal ldeation compared to recent history: A 
maximum post-first-dose suicidal ideation score of 4 or 5 when the maximum 
suicidal ideation score during recent history was 0. Only patients with a recent 
history score of 0 will be considered evaluable for this outcome.
o
Improvement in Suicidal ldeation compared to baseline: A decrease in the 
suicidal ideation score at the patient's Study Day 127 (last day for the Treatment 
Period) C-SSRS assessment compared to the baseline score, defined as the last 
measurement taken prior to first dose. Only patients with a baseline score >0 will 
be considered evaluable for these outcomes.
o
Emergence of Suicidal Behavior compared to all prior history: The occurrence 
of suicidal behavior (a "Yes" response to one or more of Categories 6-10) post-
first dose from not having suicidal behavior prior to first dose (includes the "lifetime" 
score collected at the Screening Visit as well as all C-SSRS assessments collected 
from the Screening Visit through pre-dose on Study Day 1).


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Each of the composite endpoints will be summarized by dose level and study day. For 
each treatment emergent outcome listed, only those patients with the specified screening 
condition will be considered evaluable. In addition, patients who discontinue from the study 
with no post-first dose C-SSRS assessment will be considered unevaluable for analyses 
of suicidality. Percentages will be based on the number of evaluable patients for each 
outcome.
In addition, a shift table will be created to demonstrate the change in suicidal ideation 
score from recent history to treatment period and/or post-treatment period. The maximum 
suicidal ideation score in each period will be used to create the shift table. If a patient's 
recent history suicidal ideation score is missing but has a post-first-dose score, then the 
recent history assessment will be labeled as "unknown". Likewise, if a patient's recent 
history suicidal ideation score is available but has no post-first-dose score, then the scores 
during the treatment and post-treatment period will be labeled as "unknown".
4.8
CLINICAL OUTCOMES AND PHARMACODYNAMICS
Clinical-reported outcomes and pharmacodynamic parameters considered for analysis 
are outlined in Section 2.3.3 and detailed information is presented in the following sub-
sections. Refer to the study protocol (Appendices 3 and 4) for a summary of all clinical 
endpoints with respect to number of items recorded and duration.
4.8.1
Describing Parameters over Time
All clinical outcomes will only be collected at Screening and follow-up visits, hence, 
descriptive tables (Table 5) will be presented at these two visits (including change from 
baseline at follow-up visit), while association analysis (Table 6) involving these parameters 
will only be presented at baseline.
As presented in Table 5, for PD biomarkers, descriptive tables will be presented per each 
time point and dose level. Additionally, for biomarkers, spaghetti plots (with overlaid
median) for absolute, change and percent change from baseline values using 
untransformed data will be presented for all parameters by treatment dose level. In 
addition, individual patient profiles for selected biomarkers on absolute, change and 
percent change from baseline will be presented on the same page.
4.8.1.1
Unified Huntington’s Disease rating Scale
The Composite Unified Huntington’s Disease Rating Scale (cUHDRS) [4] is defined as a 
combination of the following first 4 individual assessments:

Total Functional Capacity
The Total Functional Capacity (TFC) represents the Investigator’s assessment of 
the patient’s capacity to perform a wide range of activities of daily living including 
working, chores, managing finances, eating, dressing and bathing. The 5-item 
assessment is based on a brief interview with the patient and the study companion 


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(if available).  The TFC score ranges from 0 to 13, with a higher score representing 
better functioning.  

Total Motor Scale
The Total Motor Scale (TMS) is the sum of the individual motor ratings obtained 
during administration of the motor assessment portion of the UHDRS by the 
investigator. The score ranges from 0 to 124, with a higher score representing 
more severe impairment. 

Symbol Digit Modalities Test
The
Symbol Digit Modalities Test (SDMT) is used to assess attention, 
visuoperceptual processing, working memory and psychomotor speed. It has been 
shown to have strong reliability and validity [5] [6]. The patient must pair abstract 
symbols with specific numbers according to a translation key. The test measures 
the number of items correctly paired (maximum of 110) in 90 seconds.

Stroop Word Reading Test
The Stroop Word Reading Test (SWRT) is a measure of 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 (typically within 45 seconds). The number of words read correctly 
is counted and higher scores indicate better cognitive performance.
Based on the aforementioned assessments, the following formula is used to derive the 
cUHDRS;
 = TFC −8.8
2.8
 −TMS −34.4
17.4
 + SDMT −25.2
12.4
 + SWRT −58
21.2
 + 10.0

Independence Scale
The patient’s Independence Scale (IS) is the Investigator’s assessment of the 
patient’s degree of independence and is a subscale of the UHDRS. The scale 
consists of 19 discrete levels ranging from 10 to 100 (by 5), in which a score of 100 
indicates no special care is needed and a score of 10 indicates the patient is fed 
by tube and requires total bed care.
Descriptive tables will be provided as described in Section 4.8.1  and Table 5 for cUHDRS, 
its individual components and IS.


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4.8.1.2
Huntington’s Disease Daily Activities Scale
The Huntington’s Disease Daily Activities Scale (HD-DAS) assesses patients’ daily 
function. Following a semi-structured interview with the patient and/or study companion, 
the patient’s ability 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.  
Descriptive tables will be provided as described in Section 4.8.1  and Table 5.
4.8.1.3
Clinical Global Impression-Severity
The Clinical Global Impression-Severity (CGI-S) is a single-item measure of current global 
severity and is completed by the clinician at clinic visits. The CGI-S is assessed using an 
11-point numeric rating scale, where higher scores indicate greater severity.  
Descriptive tables will be provided as described in Section 4.8.1  and Table 5. 
4.8.1.4
Clinical Global Impression-Change
The Clinical Global Impression-Change (CGI-C) is a single-item measure of change in 
global status (since starting the study) and is completed by the clinician at the follow-up 
visit. The CGI-C has seven response options:  "very much worse," "much worse," 
"minimally worse," "no change," "minimally improved," "much improved," and "very much 
improved." To assess the relevance of this change, a follow up question with dichotomous 
response options ("yes" or "no") asks if the change has had a meaningful impact on the 
patient’s well-being.
Descriptive tables will be provided as described in Section 4.8.1  and Table 5.
4.8.1.5
Montreal Cognitive Assessment
The Montreal Cognitive Assessment (MoCA) is a patient-completed assessment used to 
detect cognitive impairment.  The MoCA contains a series of basic assessments, including 
attention and visuospatial tasks.  The total score ranges from 0 to 30, where lower scores 
indicate greater impairment.
Descriptive tables will be provided as described in Section 4.8.1  and Table 5.






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4.9
PHARMACOKINETIC AND PKPD ANALYSES
All PK analyses will be based on the PK analysis population described in Section 4.1.3.
PK parameters will be read directly from the (plasma and CSF) concentration-time profiles, 
or calculated using standard non-compartmental methods. PK parameters outlines in 
Section 2.3.2 will be computed for RO7234292 and its metabolite(s), as appropriate.  
However, other PK parameters might be computed in addition as appropriate.
Individual and mean PK concentration data at each sampling timepoint of RO7234292 
(and its metabolite[s] as appropriate) in plasma, CSF, and urine, and calculated PK 
parameters thereof, will be presented by listings and descriptive summary statistics 
including arithmetic means, geometric means, ranges, standard deviations, and 
coefficients of variation.  Individual and mean concentration versus time of RO7234292 
(and its metabolite[s] as appropriate) will be plotted on linear or semi-logarithmic scales 
as appropriate.
All PK parameters will be presented by individual listings and summary statistics including 
arithmetic means, geometric means, medians, ranges, standard deviations, and 
coefficients of variation.
Nonlinear mixed effects modeling will be used to analyze the plasma and CSF 
concentrations of RO7234292 and mHTT in CSF. If needed, the PK and PD data collected 
in this study may be pooled with data from other clinical studies. The influence of 
covariates, such as age, body weight, baseline mHTT on the PK and PD parameters will 
be investigated.
Population and individual estimates of primary PK parameters (e.g., clearance, distribution 
volume) and secondary PK parameters (e.g., AUC and average trough plasma 
concentration) will be computed and used to describe the relationship between plasma 
and/or CSF exposure and biomarker, clinical endpoints as well as safety measures.  The 
data from this study may be pooled with data from other studies conducted with 
RO7234292 to support 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 separate document from the Clinical Study 
Report.


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4.10
INTERIM ANALYSES
Given the adaptive nature of this study, data may be reviewed at any time by the Sponsor, 
to inform the decision of eventually enrolling more than the initial planned 12 patients. 
Additionally, data may be used before the final analysis to support interactions with Health 
Authorities.


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REFERENCES
[1] Wild EJ and Tabrizi SJ, "Therapies targeting DNA and RNA in Huntington's 
disease.," Lancet Neurol, no. 16, pp. 837-47, 2017. 
[2] Sorensen SA and Fenger K, " Causes of death in patients with Huntington's 
disease and in unaffected first degree relatives.," J Med Genet, no. 29, pp. 
911-4, 1992. 
[3] Shankar G, Arkin S, Cocea L, et al., "Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology 
and tactical recommendations," AAPS J, no. 16, pp. 658-73, 2014. 
[4] Schobel SA, Palermo G, Auinger P et al.,For the TRACK-HD, COHORT, 
CARE-HD, and 2CARE Huntington Study Group Investigators, "Motor, 
cognitive, and functional declines contribute to a single progressive factor in 
early HD," Neurology, pp. 2495-2502, 2017. 
[5] A. Smith, "Symbol digit modalities test: Manual," Los-Angeles: Western 
Psychological Services., 1982. 
[6] Hinton-Bayre AD, Geffen GM, Geffen LB, et al., "Concussion in contact 
sports: reliable change indices of impairment and recovery," Clin Exp 
Neuropsychol, pp. 70-86, 1999.