A Multi-Site, Prospective, Longitudinal, Cohort Study Measuring Cerebrospinal Fluid-Mutant Huntingtin Protein in Patients With Huntington's Disease
Phase: PHASE1
Conditions: Huntington's Disease
Sponsor: Hoffmann-La Roche

 
Official Title: 
 
A Multi-Site, Prospective, Longitudinal, Cohort Study Measuring 
Cerebrospinal Fluid-Mutant Huntingtin Protein in Patients With 
Huntington's Disease 
NCT Number: NCT03664804 
Document Date: Protocol Version 3: 18-Dec-2019 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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.
F. Hoffmann-La Roche Ltd
Protocol BN40422, Version 3
PROTOCOL
TITLE:
A MULTI-SITE, PROSPECTIVE, LONGITUDINAL,
COHORT STUDY MEASURING 
CEREBROSPINAL FLUID-MUTANT HUNTINGTIN 
PROTEIN IN PATIENTS WITH HUNTINGTON'S
DISEASE
PROTOCOL NUMBER:
BN40422
VERSION NUMBER:
3
TEST PRODUCT
None
MEDICAL MONITOR:
, M.D., M.Sc.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic data stamp below
18-Dec-2019 13:36:49
Title
Approver's Name
Company Signatory
Date and Time (UTC)

F. Hoffmann-La Roche Ltd
Protocol BN40422, Version 3
2
PROTOCOL HISTORY
Protocol
Version
Date Final
1
3 July 2018
1 (Germany)
2 August 2018
2 (Germany)
18 October 2018

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3/ Protocol BN40422, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Changes to the protocol are summarized below.  Please note that version 1 (Germany) 
and version 2 (Germany) of the protocol were specific to Germany, and changes in 
those versions relative to version 1 (global) are noted below.  This version 3 (global) of 
the protocol replaces the current version 1 (global) and all German-specific versions.

The EudraCT number has been removed from the main cover page, from the 
protocol amendment acceptance form, and from the protocol synopsis cover page
as it is not required in studies without an investigational medicinal product (the 
EudraCT number was removed previously in the Germany-specific protocol 
version 2).

The protocol has been updated to included additional information that is applicable 
to the open-label extension study (Sections 3.1 and 4.3).

The protocol has been updated to provide clarification as to when a second lumbar 
puncture/cerebrospinal fluid (CSF) collection attempt is permitted and now specifies 
that all mandatory assessments should be completed and reviewed prior to the 
second attempt (Sections 3.1, 4.5.6, and Appendix 1); this will ensure that the 
primary endpoints are evaluated in the majority of the patients at this visit.

The protocol has been updated to allow the use of local CAG results for enrollment-
matching purposes, although centrally-assessed CAG results will be used for the 
final analysis (Section 4.2).

The protocol has been updated to allow a maximum of one re-screening for each 
patient and to clarify when this is permitted; it now notes the assessments that may 
be exempted at re-screening (CAG repeat length testing, screening MRI, and viral 
serology) (Section 4.5.2 and Appendix 1).

The protocol has been updated to allow for the collection of each patient’s 
Huntington's Disease Identification Number (HDID) so that data from this study can 
be linked to data from other studies and registries (Sections 4.5.3 and 8.4).

The guidance for lumbar puncture has been updated in Section 4.5.6 to state that 
fluoroscopy is allowed if it is required by local/institutional standards and to clarify 
that sedation must not be used; references to fluoroscopy were removed previously 
in the Germany-specific protocol version 1.

Section 4.5.7 has been updated to reflect local or central laboratory practices and to 
require the assessment of red blood cell (RBC) count and white blood cell (WBC)
count in CSF samples.

Because knowledge about biomarkers and biomarker assays continues to evolve, 
Section 4.5.7 now states that blood samples for clinical genotyping, CSF, and 
plasma samples collected for biomarker research will be destroyed no later than 
10 years (rather than 5 years) after the final Clinical Study Report has been 
completed.

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
Section 4.5.8 has been updated to state that if an MRI scan is unusable, 
re-scanning should be conducted more than 3 days after the lumbar puncture and 
within one week of the original scan if at all possible.

Section 4.5.9 has been updated to state that ECGs should not be obtained within 
30 minutes (rather than not within 3 hours) after a meal.

Section 4.5.10 has been updated to prohibit the use of paper scales to capture 
Clinical Outcomes except for performance outcome measures (e.g., SWR, SDMT, 
and MoCA).

Section 4.5.10.16 has been updated to clarify which visits will require the use of the 
full Columbia-Suicide Severity Rating Scale and which visits will require the use of 
the follow-up scale; the protocol now states that this scale must be administered by 
a study-qualified physician.

The primary and secondary medical monitor information has been updated 
(Section 5.4.1).

Section 8.2 has been updated to mandate a signature on the companion informed 
consent form (when applicable).

Appendix 4 has been updated to specify the study site personnel who are 
responsible for each assessment at clinic visits.
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.

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5/ Protocol BN40422, Version 3
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 11
PROTOCOL SYNOPSIS .................................................................................... 12
1.
BACKGROUND .......................................................................................... 19
1.1
Background on Huntington's Disease.................................... 19
1.2
Study Rationale ..................................................................... 19
2.
OBJECTIVES AND ENDPOINTS ............................................................... 20
2.1
Primary Objective .................................................................. 20
2.2
Secondary Objective ............................................................. 20
2.3
Exploratory Objectives........................................................... 21
3.
STUDY DESIGN......................................................................................... 21
3.1
Description of the Study......................................................... 21
3.2
End of Study and Length of Study......................................... 22
3.3
Rationale for Study Design.................................................... 22
3.3.1
Rationale for Patient Population ............................................ 22
3.3.2
Rationale for Clinical Assessments ....................................... 23
3.3.2.1
Patient-Reported, Clinician-Reported, Observer-
Reported, and Performance Outcome 
Questionnaires ...................................................................... 23
3.3.2.2
Roche Huntington's Disease Mobile App............................... 24
3.3.3
Rationale for Biomarker Assessments................................... 24
3.3.3.1
Cerebrospinal Fluid Biomarkers ............................................ 24
3.3.3.2
Blood-Derived Biomarkers..................................................... 25
3.3.3.3
Genetic Testing to Determine CAG Repeat 
Length.................................................................................... 25
3.3.3.4
Clinical Genotyping................................................................ 25
3.3.3.5
Magnetic Resonance Imaging ............................................... 25
4.
MATERIALS AND METHODS .................................................................... 26
4.1
Patients.................................................................................. 26
4.1.1
Inclusion Criteria.................................................................... 26

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4.1.2
Exclusion Criteria................................................................... 27
4.2
Method and Strategy of Enrollment ....................................... 29
4.3
Access to Treatment after Study Completion ........................ 29
4.4
Concomitant Therapy ............................................................ 30
4.4.1
Permitted Therapy................................................................. 31
4.4.2
Prohibited Therapy ................................................................ 31
4.5
Study Assessments ............................................................... 31
4.5.1
Capacity to Consent .............................................................. 31
4.5.2
Informed Consent Forms and Screening Log........................ 31
4.5.3
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 32
4.5.4
Physical/Neurological Examinations...................................... 32
4.5.5
Vital Signs.............................................................................. 33
4.5.6
Collection of Cerebrospinal Fluid (Lumbar 
Puncture Procedure) ............................................................. 33
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 34
4.5.8
Neuroimaging Assessments.................................................. 35
4.5.9
Electrocardiograms................................................................ 36
4.5.10
Patient-Reported, Clinician-Reported, Observer-
Reported, and Performance Outcomes ................................. 36
4.5.10.1
Total Functional Capacity Scale ............................................ 37
4.5.10.2
Total Motor Scale .................................................................. 37
4.5.10.3
Symbol Digit Modalities Test ................................................. 37
4.5.10.4
Stroop Word Reading Test .................................................... 37
4.5.10.5
Independence Scale.............................................................. 37
4.5.10.6
Clinical Global ImpressionSeverity and Clinical 
Global ImpressionChange ................................................... 37
4.5.10.7
Patient Global ImpressionSeverity and Patient 
Global ImpressionChange ................................................... 38
4.5.10.8
Montreal Cognitive Assessment ............................................ 38
4.5.10.9
WHO Disability Assessment Schedule 2.0 ............................ 38
4.5.10.10
Work Productivity and Activity Impairment............................. 39
4.5.10.11
Apathy Evaluation Scale........................................................ 39

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4.5.10.12
Neuro-Qol Cognition Function Short Form, 
Version 2 ............................................................................... 39
4.5.10.13
Huntington's DiseaseSpeaking Difficulty Item.................... 39
4.5.10.14
Symptoms of Major Depressive Disorder Scale .................... 39
4.5.10.15
EuroQol 5-Dimension, 5-Level Questionnaire ....................... 40
4.5.10.16
Columbia-Suicide Severity Rating Scale ............................... 40
4.5.11
Roche HD Mobile App (Smartphone and 
Wrist-Worn Wearable) ........................................................... 40
4.5.11.1
Roche HD Mobile App Remote Monitoring............................ 41
4.5.11.2
Roche HD Mobile App In-Clinic Assessments....................... 41
4.5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 41
4.5.12.1
Overview of the Research Biosample Repository.................. 41
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 42
4.5.12.3
Sample Collection.................................................................. 42
4.5.12.4
Confidentiality........................................................................ 42
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 43
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 43
4.5.12.7
Monitoring and Oversight....................................................... 44
4.6
Patient, Study, and Site Discontinuation................................ 44
4.6.1
Patient Discontinuation.......................................................... 44
4.6.2
Study Discontinuation............................................................ 44
4.6.3
Site Discontinuation............................................................... 44
5.
ASSESSMENT OF SAFETY....................................................................... 45
5.1
Safety Plan ............................................................................ 45
5.2
Safety Parameters................................................................. 45
5.2.1
Adverse Events ..................................................................... 45
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 45
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 46

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5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 46
5.3.1
Adverse Event Reporting Period ........................................... 46
5.3.2
Eliciting Adverse Event Information....................................... 47
5.3.3
Assessment of Severity of Adverse Events ........................... 47
5.3.4
Assessment of Causality of Adverse Events ......................... 47
5.3.5
Procedures for Recording Adverse Events............................ 47
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 48
5.3.5.2
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 48
5.3.5.3
Persistent or Recurrent Adverse Events................................ 48
5.3.5.4
Abnormal Vital Sign Values ................................................... 49
5.3.5.5
Abnormal Liver Function Tests.............................................. 49
5.3.5.6
Deaths ................................................................................... 49
5.3.5.7
Preexisting Medical Conditions.............................................. 49
5.3.5.8
Hospitalization or Prolonged Hospitalization.......................... 50
5.3.6
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 50
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 51
5.4.1
Emergency Medical Contacts................................................ 51
5.4.2
Reporting Requirements for Serious Adverse 
Events.................................................................................... 52
5.4.3
Reporting Requirements for Pregnancies.............................. 52
5.4.3.1
Pregnancies in Female Patients............................................ 52
5.5
Follow-Up of Patients after Adverse Events .......................... 52
5.5.1
Investigator Follow-Up........................................................... 52
5.5.2
Sponsor Follow-Up ................................................................ 53
5.6
Adverse Events that Occur after the Adverse 
Event Reporting Period.......................................................... 53
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 53
6.
STATISTICAL CONSIDERATION AND ANALYSIS PLAN ......................... 53
6.1
Determination of Sample Size ............................................... 54

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6.2
Analysis Population ............................................................... 54
6.3
Primary Analyses................................................................... 54
6.4
Secondary Analyses.............................................................. 54
6.5
Safety Analyses..................................................................... 55
6.6
Exploratory Analyses............................................................. 55
6.7
Interim Analyses .................................................................... 55
7.
DATA COLLECTION AND MANAGEMENT ............................................... 55
7.1
Data Quality Assurance......................................................... 55
7.2
Electronic Case Report Forms............................................... 56
7.3
Electronic Patient-Reported, Clinician-Reported, 
Observer-Reported, and Performance Outcome 
Data....................................................................................... 56
7.4
Electronic Data Obtained by the Roche HD 
Mobile App............................................................................. 56
7.5
Source Data Documentation.................................................. 57
7.6
Use of Computerized Systems .............................................. 57
7.7
Retention of Records............................................................. 58
8.
ETHICAL CONSIDERATIONS.................................................................... 58
8.1
Compliance with Laws and Regulations ................................ 58
8.2
Informed Consent.................................................................. 58
8.3
Institutional Review Board or Ethics Committee.................... 59
8.4
Confidentiality........................................................................ 60
8.5
Financial Disclosure .............................................................. 61
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 61
9.1
Study Documentation ............................................................ 61
9.2
Protocol Deviations................................................................ 61
9.3
Site Inspections ..................................................................... 61
9.4
Administrative Structure......................................................... 62
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 62
9.6
Protocol Amendments ........................................................... 63
10. REFERENCES ........................................................................................... 64

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LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale ....................................... 47
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 22
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 68
Appendix 2
Clinician-Reported Outcomes ..................................................... 73
Appendix 3
Patient-Reported, Observer-Reported, and Performance 
Outcomes and Roche HD Mobile Application ............................. 74
Appendix 4
Order and Approximate Timing  of Assessments at Clinic 
Visits ........................................................................................... 76

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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A MULTI-SITE, PROSPECTIVE, LONGITUDINAL, 
COHORT STUDY MEASURING 
CEREBROSPINAL FLUID-MUTANT HUNTINGTIN 
PROTEIN IN PATIENTS WITH HUNTINGTON'S 
DISEASE
PROTOCOL NUMBER:
BN40422
VERSION NUMBER:
3
TEST PRODUCT
None
MEDICAL MONITOR:
, M.D., M.Sc.
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 the CRO.

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PROTOCOL SYNOPSIS
TITLE:
A MULTI-SITE, PROSPECTIVE, LONGITUDINAL, COHORT 
STUDY MEASURING CEREBROSPINAL FLUID-MUTANT 
HUNTINGTIN PROTEIN IN PATIENTS WITH HUNTINGTON'S 
DISEASE
PROTOCOL NUMBER:
BN40422
VERSION NUMBER:
3
TEST PRODUCT:
None
INDICATION:
Huntington's disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This longitudinal study in patients with early Huntington's disease (HD) will explore the 
prognostic value of baseline cerebrospinal fluid (CSF) mutant huntingtin protein (mHTT); the 
relationship of CSF mHTT to other key biological markers in the putative causal pathway; rate 
and variability of CSF mHTT increase in untreated patients; and the utility of recording clinical 
outcome measures via sensors contained in the Roche HD mobile app.  Since no study 
medication will be given to the patients, safety assessments will consist of monitoring and 
recording adverse events, including serious adverse events, related to study procedures.  
Specific objectives are outlined below.
Primary Objective
The primary objective of this study is to examine the predictive value of baseline CSF mHTT 
levels on measures of disease progression using the following endpoints:

Change from baseline in the following clinical endpoints at 3, 9, and 15 months: composite 
Unified Huntington's Disease Rating Scale (cUHDRS), Total Functional Capacity Scale
(TFC), Total Motor Scale (TMS), Symbol Digit Modalities Test (SDMT), Stroop Word 
Reading (SWR) Test, and Independence Scale (IS)

Change from baseline in biomarkers of neuronal injury (e.g., CSF NfL and tau) at 3, 9, and 
15 months

Change from baseline in brain atrophy endpoints (e.g., whole brain volume decline, caudate 
volume decline) as determined by brain MRI, at 3, 9, and 15 months
Secondary Objective
The secondary objective of this study is to investigate the temporal profile of longitudinal CSF 
mHTT changes within patient, and the association of these changes with corresponding 
changes in biomarkers of neuronal injury (e.g., CSF NfL and tau) and clinical outcomes using 
the following endpoints:

Within-patient change from baseline in CSF mHTT levels at 3, 9, and 15 months

Association of change from baseline in CSF mHTT levels at 3, 9, and 15 months and:
-
Change from baseline in clinical measures (cUHDRS, TFC, TMS, SDMT, SWR, and IS) 
at 3, 9, and 15 months
-
Change from baseline in biomarkers of neuronal injury (e.g., CSF NfL and tau) at 3, 9, 
and 15 months
-
Change from baseline in brain atrophy endpoints, as determined by brain MRI at 3, 9, 
and 15 months

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Exploratory Objectives
The exploratory objectives of this study are:

To examine the association of the Roche HD mobile app and standard clinical assessments 
at baseline and at 3, 9, and 15 months 

To examine the association of the Roche HD mobile app and biological markers under 
study at baseline and at 3, 9, and 15 months

To examine the utility of Roche HD mobile app and patient-reported outcomes (PROs) in 
monitoring disease progression in early HD 

To examine the association of potential prognostic biomarkers and genetic modifiers with 
disease status and disease progression
Study Design
Description of Study
The study is designed as a multi-site, prospective, 15-month longitudinal, cohort study 
measuring CSF mHTT in patients with early manifest Stage I or Stage II HD.  After completion
of the observational period, participants will have the option of receiving the active compound 
RO7234292 in an OLE study (Study BN40955, ClincalTrials.gov Identifier NCT03842969), pro-
vided they meet eligibility criteria, the data from the ongoing RO7234292 program supports 
continued development, and subject to approval by the relevant competent authorities and Insti-
tutional Review Boards/Ethics Committees (IRBs/ECs).
This study will enroll up to approximately 100 patients at approximately 20 sites.  After a 28-day 
screening period, patients will return to the clinic at baseline and at Months 3, 9, and 15.  During 
these visits, patients will receive clinical, MRI, and Roche HD mobile app assessments; they will 
also provide CSF and blood samples. Patients who will not enter the OLE study (Study 
BN40955, ClinicalTrials.gov Identifier NCT03842969) will have a post-observational
follow-up visit 2 weeks after the 15-month longitudinal period that may occur by telephone or in 
the clinic.  Early termination visits should take place via clinic visit, where possible. If there is
the occurrence of a failed CSF collection procedure due to inadequate establishment of access
to the IT space, there may be a second attempt up to 14 days after the original attempt.  For 
this additional visit, local laboratory analysis of coagulation factors (INR and/or PT, aPTT) 
and platelets must be conducted and the results reviewed within 72 hours prior to performing 
the LP.  In addition, neurological examination, vital signs, and a review of AEs and 
concomitant medication should occur as part of the safety and tolerability evaluations on the 
day of LP.
The final study visit will be Study Day 421 (Month 15) for patients who enter the OLE Study 
(Study BN40955, ClinicalTrials.gov Identifier NCT03842969), and the follow-up visit will be 
the final study visit for those patients who do not enter the OLE.
Number of Patients
The study will enroll up to approximately 100 patients with early manifest Stage I or II HD.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Capacity to consent to participate in the study as assessed using the Evaluation to Sign
Consent tool and investigator judgment

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form

Early manifest, Stage I or Stage II HD (defined as TFC of 713, inclusive)

Genetically confirmed disease (CAG repeat length 36 in huntingtin gene by direct DNA
testing)

Body mass index 18 and 32 kg/m2; total body weight 50 kg

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
Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no metal implants 
including MRI-incompatible intrauterine devices or metal dental braces, chorea of a severity 
that precludes MRI scans, or any condition that renders testing intolerable for the patient)

Ability to tolerate blood draws and lumbar puncture 

Ability and willingness to comply with all aspects of the protocol, including completion of 
interviews and questionnaires and carrying/wearing of a digital monitoring device

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to screening 
and at the time of enrollment  
Patients may be managed according to clinical judgment during study observational 
period.

Signed study companion consent for participation, if a study companion is available
A study companion should be reliable, competent, and at least 18 years of age; willing 
to accompany the patient to clinic visits and to be available to the study site by 
telephone if needed; and (in the opinion of the investigator) a person who is and will 
remain sufficiently knowledgeable of the patient's ongoing condition to respond to 
study site enquiries about the patient.  The study companion will complete study 
companion assessments and will provide demographic and social status data 
(e.g, relationship to patient and employment status).

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the 
observational 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).
The following are acceptable contraceptive methods:  bilateral tubal ligation; male 
sterilization; hormonal contraceptives; hormone-releasing intrauterine devices; copper 
intrauterine devices; male or female condom with or without spermicide; and cap, 
diaphragm, or sponge with spermicide.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the observational 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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Any condition, including severe chorea, that would prevent either writing or performing pen-
and-paper or smartphone-based tasks 

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 active suicidal ideation is demonstrated by the Columbia-Suicide Severity 
Rating Scale.  If suicidal ideation is generally 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 per judgment of the 
investigator.

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, vital sign, or 
electrocardiogram abnormalities at screening that, in the investigator's judgement, 
precludes the patient's safe participation in and completion of the study

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
Pregnant or breastfeeding, or intending to become pregnant during the study 

Positive for hepatitis C virus antibody or hepatitis B surface antigen at screening

Known HIV infection

Current or previous use of an antisense oligonucleotide (including small interfering RNA)

Current use of antipsychotics prescribed for psychosis, cholinesterase inhibitors, 
memantine, amantadine, or riluzole including use within 12 weeks of enrollment
Use of antipsychotics for motor symptoms and/or tetrabenazine or deutetrabenazine is 
not permitted unless on stable dose for at least 12 weeks prior to screening.

Treatment with an investigational drug within 30 days prior to screening or 5 half-lives of the 
investigational drug, 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 81mg/day), clopidogrel, 
dipyridamole, warfarin, dabigatran, rivaroxaban, and apixaban

History of bleeding diathesis or coagulopathy; platelet count lower limit of normal unless 
stable and assessed by the Investigator and Sponsor Medical Monitor to be not clinically 
significant

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

History of gene therapy or cell transplantation or any other experimental brain surgery

Concurrent or planned concurrent participation in any clinical study without approval of the 
Medical Monitor

Presence of implanted shunt for the drainage of CSF or an implanted CNS catheter

Prexisting structural brain lesion (e.g., tumor, arterio-venous malformation) as assessed by 
MRI scan
End of Study
The end of the study will be the date from which the last patient, last visit is recorded in the 
study database.  The end of the study is expected to occur 15.5 months after the last patient is 
enrolled. 
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 27 months.  
Statistical Methods
Primary Analysis
The primary objective of this study is to investigate whether baseline CSF mHTT is a predictor 
of the change from baseline to 15 months for the following variables:

Clinical endpoints (cUHDRS, TFC, TMS, SDMT, SWR, and IS) 

CSF and blood biomarkers

Brain imaging (MRI)
Initially, a linear model will be used to evaluate the association between each response variable 
(e.g., change from baseline to 15 months in cUHDRS) and baseline CSF mHTT without 
adjustment for any baseline characteristics. 
The same model will then be considered again, adjusting for baseline level of the response 
variable (e.g., baseline cUHDRS), baseline CSF mHTT levels, CAG, and baseline CAP (the 
latter defined as the product of age at baseline by [CAG33.66]. A sensitivity analysis to 
evaluate the impact of additional baseline characteristics (e.g., gender, education level) may be 
performed.
Other approaches may be used in the case of severe multicollinearity, which would results in 
model instability.

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Determination of Sample Size  
In this study, up to approximately 100 patients are expected to be enrolled across approximately 
20 sites.  
Interim Analyses 
The Sponsor may choose to conduct one or more interim analyses.  The decision to conduct 
such an optional interim analysis and the timing of the analysis will be documented in the 
Sponsor’s study master file prior to the conduct of the interim analysis.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AES
Apathy Evaluation Scale
CGI-C
Clinical Global ImpressionChange
CGI-S
Clinical Global ImpressionSeverity
ClinRO
clinician-reported outcome
CSF
cerebrospinal fluid 
C-SSRS
Columbia-Suicide Severity Rating Scale
cUHDRS
composite Unified Huntington's Disease Rating
Scale
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D-5L
EuroQol 5-Dimension, 5-Level Questionnaire
FDA
Food and Drug Administration
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HD
Huntington's disease
HDID
Huntington's Disease Identification Number
HD-SDI
Huntington's DiseaseSpeaking Difficulty Item
HIPAA
Health Insurance Portability and Accountability 
Act
HRQoL
health-related quality of life
ICH
International Council for Harmonisation
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IS
Independence Scale
IxRS 
interactive voice or web-based response system 
mHTT
mutant huntingtin protein
MRI
magnetic resonance imaging
Neuro-Qol
Quality of Life in Neurological Disorders
NfL
neurofilament light chain
NRS
numeric rating scale
ObsRO
observer-reported outcome
OLE
open-label extension
PerfO
performance outcome
PGI-C
Patient Global ImpressionChange
PGI-S
Patient Global ImpressionSeverity

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Abbreviation
Definition
PRO
patient-reported outcome
RBR
Research Biosample Repository
SDMT
Symbol Digit Modalities Test
SMDDS
Symptoms of Major Depressive Disorder Scale
SWR
Stroop Word Reading
TFC
Total Functional Capacity Scale
TMS
Total Motor Scale
UHDRS
Unified Huntington's Disease Rating Scale
VAS
visual analog scale
WES
whole exome sequencing
WGS
whole genome sequencing
WHODAS 2.0
WHO Disability Assessment Schedule 2.0
WPAI
Work Productivity and Activity Impairment

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1.
BACKGROUND
1.1
BACKGROUND ON HUNTINGTON'S DISEASE
Huntington's disease (HD) is an autosomal dominant genetic disease, with onset 
typically in adulthood, caused by expansion of CAG repeats on exon 1 of chromosome 4.
This mutation produces a toxic form of huntingtin protein (mHTT), which is, based upon 
preclinical and clinical evidence, the assumed primary disease-causing protein
(Wild and Tabrizi 2017).  Individuals who carry at least 40 CAG repeats experience 
progressive motor, cognitive, and functional decline usually in adult life, typically age 
4045 years, with an end stage of profound physical wasting.  Common causes of death 
include pneumonia, heart failure, and starvation (Sorensen and Fenger 1992).  Currently,
the only approved therapies (i.e., tetrabenazine and deutetrabenazine) target abnormal 
involuntary movements (i.e., chorea) associated with HD, and these symptomatic 
therapies have a challenging benefitrisk profile.
1.2
STUDY RATIONALE
With the advent of huntingtin proteinlowering therapies and the ability to measure the 
mutant protein in cerebrospinal fluid (CSF), there is a need to better understand the 
potential of CSF mHTT to serve as a biomarker for drug development and for predicting 
and measuring disease progression in HD.  In cross-sectional studies, CSF mHTT 
protein levels are specific to HD; correlate with severity of disease burden, motor, and 
cognitive symptoms; and are associated with markers of neuronal damage 
(e.g., neurofilament light chain [NfL]) (Wild et al. 2015). Yet, the relationship between
baseline mHTT levels and subsequent clinical progression and to longitudinal changes 
in other biomarkers is unknown. Longitudinal collection of CSF mHTT will allow 
evaluation of the prognostic value of mHTT protein levels; provide information on the 
rate and variability of increased levels over time in untreated patients; evaluate the 
relationship of this biomarker to other key putative biological markers over time (e.g., NfL 
levels in CSF or plasma, progressive brain atrophy as assessed by magnetic resonance 
imaging [MRI]); and help determine the role played by mHTT in the causal pathway.
Findings from this study will inform drug development and will aid in the interpretation of 
ongoing therapeutic studies, which use mHTT as a biomarker of disease state, an 
exploratory pharmacodynamic measure, a potential prognostic biomarker for likely 
disease progression, and a potential biomarker of progression and treatment efficacy.
The study will also explore the utility of clinical outcome measures collected via sensors 
in smartphones and wrist-worn wearables ("the Roche HD mobile app"). The data 
generated by the digital approach will be correlated with standard clinical assessments 
and with the other biological markers under study.
Study BN40422 is part of a broader development plan for RO7234292, an anti-sense 
oligonucleotide (originally developed by Ionis Pharmaceuticals, Inc. and formerly 
referred to as ISIS 443139 or IONIS-HTTRx). A Phase I/IIa study has been completed 
(Study ISIS 443139-CS1), and RO7234292 is now being investigated in an open-label 

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extension (OLE) study (BN40697; Clinicaltrials.gov Identifier NCT03342053) as the first 
potential therapy in clinical development to target the underlying cause of HD.
2.
OBJECTIVES AND ENDPOINTS
This longitudinal study in patients with early HD will explore the prognostic value of 
baseline CSF mHTT; the relationship of CSF mHTT to other key biological markers in 
the putative causal pathway; rate and variability of CSF mHTT increase in untreated 
patients; and the utility of recording clinical outcome measures via sensors contained in 
the Roche HD mobile app.  Since no study medication will be given to the patients, 
safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events, related to study procedures. Specific objectives are outlined 
below.
2.1
PRIMARY OBJECTIVE
The primary objective of this study is to examine the predictive value of baseline
CSF mHTT levels on measures of disease progression using the following endpoints:

Change from baseline in the following clinical endpoints at 3, 9, and 15 months: 
composite Unified Huntington's Disease Rating Scale (cUHDRS), Total Functional 
Capacity Scale (TFC), Total Motor Scale (TMS), Symbol Digit Modalities Test
(SDMT), Stroop Word Reading (SWR) Test, and Independence Scale (IS)

Change from baseline in biomarkers of neuronal injury (e.g., CSF NfL and tau) at 3, 
9, and 15 months

Change from baseline in brain atrophy endpoints (e.g., whole brain volume decline, 
caudate volume decline) as determined by brain MRI, at 3, 9, and 15 months
2.2
SECONDARY OBJECTIVE
The secondary objective of this study is to investigate the temporal profile of longitudinal 
CSF mHTT changes within patient, and the association of these changes with 
corresponding changes in biomarkers of neuronal injury (e.g., CSF NfL and tau) and 
clinical outcomes using the following endpoints:

Within-patient change from baseline in CSF mHTT levels at 3, 9, and 15 months

Association of change from baseline in CSF mHTT levels at 3, 9, and 15 months
and:
–
Change from baseline in clinical measures (cUHDRS, TFC, TMS, SDMT, SWR, 
and IS) at 3, 9, and 15 months
–
Change from baseline in biomarkers of neuronal injury (e.g., CSF NfL and tau) 
at 3, 9, and 15 months
–
Change from baseline in brain atrophy endpoints, as determined by brain MRI at 
3, 9, and 15 months

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2.3
EXPLORATORY OBJECTIVES
The exploratory objectives of this study are:

To examine the association of the Roche HD mobile app and standard clinical 
assessments at baseline and at 3, 9, and 15 months

To examine the association of the Roche HD mobile app and biological markers 
under study at baseline and at 3, 9, and 15 months

To examine the utility of Roche HD mobile app and patient-reported outcomes
(PROs) in monitoring disease progression in early HD 

To examine the association of potential prognostic biomarkers and genetic modifiers 
with disease status and disease progression
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
The study is designed as a multi-site, prospective, 15-month longitudinal, cohort study
measuring CSF mHTT in patients with early manifest Stage I or Stage II HD.  After 
completion of the observational period, participants will have the option of receiving the 
active compound RO7234292 in an OLE study (Study BN40955, ClinicalTrials.gov 
Identifier NCT03842969), provided they meet eligibility criteria, the data from the 
ongoing RO7234292 program supports continued development, and subject to approval 
by the relevant competent authorities and Institutional Review Boards/Ethics 
Committees (IRBs/ECs).  
This study will enroll up to approximately 100 patients at approximately 20 sites.  After a
28-day screening period, patients will return to the clinic at baseline and at Months 3, 9, 
and 15. During these visits, patients will receive clinical, MRI, and Roche HD mobile app 
assessments; they will also provide CSF and blood samples.  Patients who will not 
enter the OLE study (Study BN40955, ClinicalTrials.gov Identifier NCT03842969) 
will have a post-observational follow-up visit 2 weeks after the 15-month longitudinal 
period that may occur by telephone or in the clinic. Early termination visits should take 
place via clinic visit, where possible. If there is the occurrence of a failed CSF collection 
procedure due to inadequate establishment of access to the IT space, there may be a 
second attempt up to 14 days after the original attempt.  For this additional visit, local 
laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets must be 
conducted and the results reviewed within 72 hours prior to performing the LP.  In 
addition, neurological examination, vital signs, and a review of AEs and concomitant 
medication should occur as part of the safety and tolerability evaluations on the day of 
LP.
The final study visit will be Study Day 421 (Month 15) for patients who enter the OLE 
Study (Study BN40955, ClinicalTrials.gov Identifier NCT03842969), and the 
follow-up visit will be the final study visit for those patients who do not enter the OLE.

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Figure 1 presents an overview of the study design, with 1 month defined as one 28-day 
period.  A schedule of activities is provided in Appendix 1.
Figure 1
Study Schema
HDHuntington's disease.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study will be the date from which the last patient, last visit is recorded in 
the study database.  The end of the study is expected to occur 15.5 months after the last 
patient is enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 27 months.  In addition, the Sponsor may decide to 
terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
There are currently no longitudinal CSF mHTT data in patients with HD.  This study has 
been designed to collect data for CSF mHTT, other biomarkers, clinical assessments,
and the Roche HD mobile app assessments at four timepoints over 15 months. 
3.3.1
Rationale for Patient Population
Patients with early-stage HD, defined as Stage I or II by Shoulson and Fahn (1979), will 
be included in this study, as they are expected to show progressive decline in clinical 
parameters measurable over a 12-month timeframe (Huntington Study Group 1996; 
Schobel et al. 2017), and because they have measurable abnormalities in the key 
biomarkers in cross-sectional studies compared to controls and prodromal individuals 
(e.g., for CSF mHTT [Southwell et al. 2015; Wild et al. 2015]) as well as longitudinal
differences on other outcomes (e.g., for NfL, brain atrophy, and clinical endpoints
[Byrne et al. 2017]). The population also represents the stage of manifest HD that might 
be more plausibly reversed or slowed in response to a therapeutic intervention versus 
more advanced patients with more neurodegeneration present at baseline who 
experience less longitudinal decline in clinical parameters such as the TFC score
(Penney et al. 1990).  Since this population overlaps with the population targeted for the 
upcoming clinical efficacy studies of the RO7234292 development program, the natural 
history study will provide useful comparative data.

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3.3.2
Rationale for Clinical Assessments
3.3.2.1
Patient-Reported, Clinician-Reported, Observer-Reported, and 
Performance Outcome Questionnaires
Individuals with HD exhibit a triad of motor, cognitive, and behavioral/psychiatric 
symptoms that contribute to clinical progression and/or morbidity and quality of life.
A recent survey of patients and caregivers/companions reported executive 
function/cognitive decline, chorea movement/balance, and depression/apathy as the 
most impactful symptoms (Simpson et al. 2016).
A comprehensive battery of patient-, clinician-, observer-reported, and performance 
outcome assessments (PRO, ClinRO, ObsRO, and PerfO, respectively) will be used to 
document changes over time. The proposed endpoint strategy captures measures 
known to be sensitive to clinical progression from a clinician and patient perspective, as 
well as assessments solicited by companion/caregiver report.  
The Unified Huntington's Disease Rating Scale (UHDRS) is a collection of assessments 
commonly used to assess disease status (including symptoms and their impact) and 
progression in patients with HD (Huntington Study Group 1996).  The individual scales of 
the UHDRS include the TFC score; the highly correlated Independence and Functional 
Assessment Scales; the TMS; SDMT; SWR; verbal fluency test; and a behavioral 
assessment.  The cUHDRS is a composite of weighted subcomponents of the UHDRS,
which also covers multiple domains (motor, cognitive, and functional) and possesses 
greater sensitivity to detect longitudinal change compared to the UHDRS or its individual 
subtests (Schobel et al. 2017). 
Apathy, depression, anxiety, and irritability are core behavioral symptoms associated 
with HD (Simpson et al. 2016). The Apathy Evaluation Scale (AES) is a widely used and 
valid measure of apathy. To assess change in other behavioral symptoms, a newly 
developed scale, the Symptoms of Major Depressive Disorder Scale (SMDDS), will be 
used to capture depressive symptoms as well as irritability and anxiety. This scale was 
selected for its excellent coverage of these core symptoms.
To complement the PerfO measures of cognition (SDMT and SWR), the Quality of Life in 
Neurological Disorders (Neuro-Qol) Cognition Function Short Form assesses
self-reported issues with cognition, such as slow thinking or difficulty learning new tasks.
Speech difficulty is a common issue (with both cognitive and motor deficits impacting 
ability) and will be measured by a novel single-item measure, the Huntington’s 
DiseaseSpeaking Difficulty Item (HD-SDI).
The clinician will complete a Clinical Global Impression of Severity (CGI-S) at baseline 
and a Clinical Global Impression of Change (CGI-C), and the patient will complete the 
Patient Global Impression of Severity (PGI-S) and the Patient Global Impression of 
Change (PGI-C).

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Concepts such as health-related quality of life (HRQoL), health state utilities, and 
societal impacts (e.g., work productivity) are of particular interest to European Health 
Technology Assessment agencies. The WHO Disability Assessment Schedule 2.0 
(WHODAS 2.0) and the EuroQol 5-Dimension, 5-Level (EQ-5D-5L) Questionnaire will 
assess HRQoL and health state utilities, respectively. The Work Productivity and 
Activity Impairment (WPAI) Scale will capture changes in employment status, including a 
reduction of work hours or loss of productivity. 
Further details on these assessments are included in Section 4.5.10.
3.3.2.2
Roche Huntington's Disease Mobile App
The Roche HD mobile app collects sensor data from smartphones and wrist-worn 
wearables.  Smartphones and wrist-worn wearables have high-quality sensors that 
enable remote, non-invasive, frequent, and precise measurement of motor and 
non-motor symptoms.  Such technology has been used previously in Parkinson disease 
(Maetzler et al. 2013; Arora et al. 2015; Ossig et al. 2016) and HD
(Andrzejewski et al. 2016; Dinesh et al. 2016).
Several cognitive and motor measures sensitive to symptom progression in early HD 
(Tabrizi et al. 2012) lend themselves to sensor-based measurement.  Fine motor 
impairments can be measured using touch sensors (e.g., circle tracing [Say et al. 2011] 
and speeded tapping [Tabrizi et al. 2012]).  Gait and balance have previously been
successfully captured using wearable sensors (Dalton et al. 2013; 
Andrzejewski et al. 2016; Dinesh et al. 2016), as has choreatic movement in HD patients 
(Reilmann et al. 2011; Kegelmeyer et al. 2017).
Patients will be asked to complete daily "active" tests and then carry the devices with 
them as they go about their daily routines (i.e., "passive monitoring").  The collected 
sensor data will be correlated with traditional clinical assessments as mentioned above
and will be used to track the longitudinal trajectory of motor, cognitive, behavioral, and 
functional parameters.  
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 MRI 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 will facilitate understanding of HD pathophysiology 
and progression.

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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
and neuronal degeneration or inflammation in blood will facilitate understanding of HD 
pathophysiology and progression.
3.3.3.3
Genetic Testing to Determine CAG Repeat Length
HD is 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. Above 
35 CAG repeats, the age of HD onset is inversely correlated with the length of the 
expansion (Duyao et al. 1993). CAG repeat length will be determined by direct DNA 
testing.  
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
previously described to explore, for example, their influence on progression rates.
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 pathophysiological mechanisms of neurologic and 
neuropsychiatric disease. Several MRI techniques have shown sensitivity to detect 
abnormal structure and function within brains of individuals suffering from HD. 
Structural Magnetic Resonance Imaging
Numerous structural MRI studies have demonstrated wide-spread brain atrophy,
including neocortex, striatum, white matter, and cerebellum 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, the whole brain, caudate, and 
ventricular volumes can predict and track progressive clinical decline in patients with HD 
and also associate with molecular markers of neurodegeneration, such as NfL
(Tabrizi et al. 2012). 
Diffusion Magnetic Resonance Imaging
Widespread changes of basal gangliacortical structural connectivity have also been 
observed in patients with early manifest HD (Novak et al. 2015), including associations 
between striatum-sensorimotor cortex connections and UHDRS motor scale

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(Bohanna et al. 2011), suggesting that the clinical phenotype in manifest HD may be a 
result of altered structural connectivity.
Resting-State Functional Magnetic Resonance Imaging
Resting-state functional MRI studies have generated solid 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.
Structural MRI will be used to assess brain volume, diffusion MRI will be used to 
examine structural brain connectivity, and resting-state functional MRI will be employed 
to identify functional connectivity. All of the measures will be assessed at the 
whole-brain and regional levels. The acquisition parameters of each sequence, 
structure, and length of each MRI session and image processing algorithms will be 
outlined in a separate MRI manual.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The study will enroll up to approximately 100 patients with early manifest Stage I or II HD.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Capacity to consent to participate in the study as assessed using the Evaluation to 
Sign Consent tool and investigator judgment

Age 25 to 65 years, inclusive, at the time of signing Informed Consent Form

Early manifest, Stage I or Stage II HD (defined as TFC of 713, inclusive)

Genetically confirmed disease (CAG repeat length 36 in huntingtin gene by direct 
DNA testing)

Body mass index 18 and 32 kg/m2; total body weight 50 kg  

Ability to undergo and tolerate MRI scans (e.g., no claustrophobia, no metal 
implants including MRI-incompatible intrauterine devices or metal dental braces, 
chorea of a severity that precludes MRI scans, or any condition that renders testing 
intolerable for the patient)

Ability to tolerate blood draws and lumbar puncture

Ability and willingness to comply with all aspects of the protocol, including 
completion of interviews and questionnaires and carrying/wearing of a digital 
monitoring device

Stable medical, psychiatric, and neurological status for at least 12 weeks prior to 
screening and at the time of enrollment  

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Patients may be managed according to clinical judgment during study 
observational period.

Signed study companion consent for participation, if a study companion is available
A study companion should be reliable, competent, and at least 18 years of age; 
willing to accompany the patient to clinic visits and to be available to the study 
site by telephone if needed; and (in the opinion of the investigator) a person 
who is and will remain sufficiently knowledgeable of the patient's ongoing 
condition to respond to study site enquiries about the patient.  The study 
companion will complete study companion assessments and will provide 
demographic and social status data (e.g., relationship to patient and 
employment status).

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use acceptable contraceptive methods during the 
observational 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).
The following are acceptable contraceptive methods:  bilateral tubal ligation; 
male sterilization; hormonal contraceptives; hormone-releasing intrauterine 
devices; copper intrauterine devices; male or female condom with or without 
spermicide; and cap, diaphragm, or sponge with spermicide.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the observational 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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Any condition, including severe chorea, that would prevent either writing or 
performing pen-and-paper or smartphone-based tasks

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 active suicidal ideation is demonstrated by the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  If suicidal ideation is generally 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 

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on participation should be made carefully and in consultation with appropriately 
qualified mental health professional per judgment of the investigator.

Current active psychosis, confusional state, or violent behavior

Any serious medical condition or clinically significant laboratory, vital sign, or 
electrocardiogram abnormalities at screening that, in the investigator's judgement, 
precludes the patient's safe participation in and completion of the study

Pregnant or breastfeeding, or intending to become pregnant during the study 

Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg)
at screening

Known HIV infection

Current or previous use of an antisense oligonucleotide (including small interfering 
RNA)

Current use of antipsychotics prescribed for psychosis, cholinesterase inhibitors, 
memantine, amantadine, or riluzole including use within 12 weeks of enrollment
Use of antipsychotics for motor symptoms and/or tetrabenazine or 
deutetrabenazine is not permitted unless on stable dose for at least 12 weeks
prior to screening.

Treatment with an investigational drug within 30 days prior to screening or 
5 half-lives of the investigational drug, 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 81mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban, 
and apixaban

History of bleeding diathesis or coagulopathy; platelet count lower limit of normal
unless stable and assessed by the investigator and Sponsor Medical Monitor to be 
not clinically significant

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

History of gene therapy or cell transplantation or any other experimental brain 
surgery

Concurrent or planned concurrent participation in any clinical study without approval 
of the Medical Monitor

Presence of implanted shunt for the drainage of CSF or an implanted CNS catheter

Preexisting structural brain lesion (e.g., tumor, arterio-venous malformation) as 
assessed by MRI scan

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4.2
METHOD AND STRATEGY OF ENROLLMENT
Enrollment in the study will be competitive, and an interactive voice or web-based 
response system (IxRS) system will be used to manage enrollment of patients across 
different sites.
A patient will be enrolled after written informed consent has been obtained, all screening 
assessments have been completed, and the investigator has verified that the patient is 
eligible per criteria in Sections 4.1.1 and 4.1.2. Further, for a patient to be enrolled in 
this study, the patient must match a participant from the ongoing OLE study
(Clinicaltrials.gov Identifier NCT03342053, BN40697). The matching criteria are defined 
as follows: 

Disease stage (Stage I or II) 

Sex

Age (5 years)

CAG repeats (2)
Of note, due to the characteristics of the baseline multiple-ascending dose (MAD)
sample (i.e., all participants had Stage I HD, TFC 1113), it is anticipated that only a 
small proportion of patients from the MAD study (Clinicaltrials.gov Identifier 
NCT02519036, ISIS 433139-CS1) who enroll in the MAD OLE study (Clinicaltrials.gov 
Identifier NCT03342053, BN40697) will have progressed to Stage II HD (defined as 
TFC 710).  Accordingly, the majority of participants in this study are anticipated to have
Stage I HD, TFC 1113. 
The matching algorithm will be implemented through an IxRS system, allowing only the 
enrollment of "matched" patients and constantly updating the list of OLE study 
(BN40697) participants still remaining to be matched. Further details on the matching 
procedure (e.g., what to do if a patient matches multiple OLE participants) will be 
provided in a separate IxRS document. To facilitate enrolment, CAG matching is based 
on local CAG results. The study analysis will utilize the centrally assessed CAG result.
The Sponsor will attempt to find matches for at least 40 OLE study (BN40697) 
participants and will thereafter find a second match based on the aforementioned criteria.
However, if this proves more difficult than predicted and extends timelines beyond what 
is acceptable, the Sponsor may change the enrollment strategy (i.e., amending the IxRS 
specification as needed) and could eventually continue recruiting patients in Stages I 
and II of manifest HD without all or some of the matching constraints. This decision will 
be communicated to the study investigators in a timely manner.  
4.3
ACCESS TO TREATMENT AFTER STUDY COMPLETION
After completing this study, the patient will be eligible to enroll in an OLE study (Study 
BN40955, ClinicalTrials.gov Identifier NCT03842969) with active RO7234292 
compound for a period of approximately 15 months (may be adjusted based on 

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emerging data), provided the data from the ongoing RO7234292 program support 
continued development, the patient meets the inclusion and exclusion criteria for the 
OLE, and subject to approval by the relevant competent authorities and Institutional 
Review Boards/Ethics Committees (IRBs/ECs). 
Following the OLE, the Sponsor will offer continued access to Roche Investigational 
Medicinal Product (IMP) (RO7234292) free of charge to eligible patients in accordance 
with the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
as outlined below.
A patient will be eligible to receive Roche IMP (RO7234292) after completing the study if 
all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them
A patient will not be eligible to receive Roche IMP (RO7234292) after completing the 
study if any of the following conditions are met:

The Roche IMP is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for HD

The Sponsor has reasonable safety concerns regarding the IMP as treatment for 
HD

Provision of the Roche IMP is not permitted under the laws and regulations of the 
patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient from the screening visit 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).

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4.4.1
Permitted Therapy 
Throughout the study, investigators or treating physicians may prescribe concomitant 
medications or treatment deemed necessary to provide adequate supportive care or for 
treatment of adverse events. 
In general, investigators should manage a patient's care with supportive therapies as 
clinically indicated, per local standard practice.  
4.4.2
Prohibited Therapy
Patients are prohibited from receiving other experimental agents during the study.  This 
includes marketed agents at experimental doses that are being tested for the treatment 
of HD.  The following agents are also specifically prohibited:

Antiplatelet or anticoagulant therapy, including, but not limited to, aspirin 
(unless 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban,
and apixaban

Sedation for any procedures in the study
Depending on institutional guidelines, local anesthesia may be used for the 
lumbar puncture procedure.  

Anti-anxiety medication for imaging-related anxiety during the screening scan
Anti-anxiety medication is strongly discouraged during scheduled scans at
postbaseline clinic visits.  If anti-anxiety medication is used for a postbaseline 
scan, the scan must be performed at the end of the assessment day or 
preferably on a different day, to avoid impacting other assessments.
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All mandatory activities must be performed and documented for each patient.  
4.5.1
Capacity to Consent
Patients' capacity to consent to participate in the study will be assessed using the 
Evaluation to Sign Consent tool (DeRenzo et al. 1998).  This is a brief, five-item 
questionnaire utilized by study site personnel during a targeted interview with the patient.  
Patient responses to the questionnaire will not be collected by the Sponsor and are 
intended only to guide study site personnel in their evaluation of each potential patient’s 
capacity to consent.
4.5.2
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 enrolled patients/study companions and for patients/study 
companions who are not subsequently enrolled will be maintained at the study site.

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All screening evaluations must be completed and reviewed to confirm that patients meet 
eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
A maximum of one re-screening will be allowed within 8 weeks of the initial screening 
failure for patients who fail the initial screening (e.g., as a consequence of abnormal 
laboratory values or general medical status not meeting inclusion or exclusion criteria).  
If re-screening is required, central CAG repeat length testing from the initial screening 
does not need to be repeated, and the screening MRI and viral serology from the initial 
screening may be acceptable as part of the re-screening assessments if performed within 
12 weeks of the baseline visit. Participants are not required to re-sign the consent form 
if they are re-screened.
4.5.3
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse, will be recorded at baseline.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient from screening to 
the study completion/discontinuation visit will be recorded.  At the time of each follow-up 
physical examination, an interval medical history should be obtained and any changes in 
medications, smoking, use of alcohol or drugs of abuse, any major procedures or 
hospitalizations, and any physician visits for HD or general medical care should be 
recorded.
Demographic data will include age, sex, and self-reported race/ethnicity and education 
level based upon International Standard Classification of Education scale. Demographic 
data and social status data (e.g., relationship to patient and employment status) will also 
be collected for the study companion.
A unique HD identification number (HDID) will be collected from patients who already 
have an HDID.  For patients without an HDID who are willing to be assigned one, the 
number will be created via a web portal (see Section 8.4).
4.5.4
Physical/Neurological Examinations
A complete physical examination will be performed at screening, baseline, Months 3, 9, 
15, and as clinically indicated.  The examination should include an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  
Neurological examination includes assessment of mental status, level of consciousness, 
sensory function, motor function, cranial nerve function, and reflexes. Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 

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Conditions eCRF.  Changes from baseline abnormalities should be recorded in patient 
notes.  New or worsened clinically significant abnormalities associated with a study 
procedure should be recorded as adverse events on the Adverse Event eCRF.
4.5.5 
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position after resting for 
approximately 5 minutes, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.
4.5.6 
Collection of Cerebrospinal Fluid (Lumbar Puncture Procedure) 
Patients will have CSF collected at baseline and at Months 3, 9, and 15. Prior to 
performing each scheduled lumbar puncture, local laboratory analysis of coagulation 
factors (INR and/or PT, aPTT) and platelets must be conducted and results reviewed. 
Collection for these local labs may occur at any time in the 72 hours prior to the lumbar 
puncture. The lumbar puncture should be performed at approximately the same time at 
each visit (ideally in the morning between 08:00 and 12:00 hours) to minimize potential 
diurnal variation of CSF parameters. CSF fluid (20 mL) is to be collected for analyses 
using a standard lumbar puncture collection kit. If there are difficulties in collecting
20 mL of CSF fluid, a minimum of 15 mL should be collected. A 24G Whitacre 
(atraumatic) needle should be used.  Depending on institutional guidelines, local 
anesthesia may be used for the procedure. Sedation is not allowed. Spinal ultrasound 
may be used for the lumbar puncture procedure if deemed necessary, but is not required. 
Ultrasound guidance may be used if attempts at lumbar puncture without imaging are 
unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate
use of ultrasound with each lumbar puncture. Fluoroscopy guidance can also be used, if local 
institutional guidelines dictate and if locally required approvals of the technique are ob-
tained, but it is not required.  Where fluoroscopy is used, patients should also be in-
formed and consent obtained.
If there is the occurrence of a failed CSF collection procedure due to inadequate 
establishment of access to the IT space, a second attempt may occur up to 14 days after 
the original attempt.  For this additional visit, local laboratory analysis of coagulation 
factors (INR and/or PT, aPTT) and platelets must be conducted and the results 
reviewed, within 72 hours prior to performing the LP.  In addition, neurological 
examination, vital signs and a review of AEs and concomitant medication should occur 
as part of the safety and tolerability evaluations on the day of LP.

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4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory
or to a central laboratory for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit and platelet count
are required; differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells) as per local practice

Serum chemistry panel:  sodium, potassium, chloride, bicarbonate, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, 
ALP, ALT, AST, uric acid, GGT, CPK, as per local standard practice

Coagulation:  INR and/or PT, aPTT

Thyroid panel: thyroid-stimulating hormone

Viral serology:  HBsAg, HCV antibody

Pregnancy test
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.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)
as per local standard practice and microscopic examination (sediment, RBCs, 
WBCs, casts, crystals, epithelial cells, bacteria) as per local standard practice, if 
indicated. Microscopic examination is only required in case of an abnormal dipstick 
result (for example, blood in urine or high protein value).

CSF: RBC count, WBC count, glucose, and protein
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Whole blood sample for determination of CAG repeat length in huntingtin gene (HTT) 
by direct DNA testing, for patient eligibility into the study

Whole 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, and inflammation
Samples may also be used to support the development of additional biomarker 
assays to detect huntingtin protein or other proteins related to HD 
pathophysiology.

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, and inflammation

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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exception:

Blood samples for clinical genotyping, CSF, and plasma samples collected for 
biomarker research will be destroyed no later than 10 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.
4.5.8 
Neuroimaging Assessments
The MRI should be performed using a 3-Tesla (3T) magnet.  If a 3T magnet is not 
available in reasonable proximity to the study site, in exceptional circumstance, with prior 
agreement from the Medical Monitor, a 1.5T magnet may be used. The acquisition 
parameters of each sequence, structure, and length of each MRI session, as well as 
image processing algorithms, will be outlined in a separate MRI manual. MRI scans will 
be managed by a central laboratory to monitor and ensure the integrity and quality of the 
acquired data.  Local neuroradiologists will assess MRI-related study eligibility criteria at 
screening and for safety monitoring.  For MRI scans at Months 3, 9, and 15, the MRI 
should be scheduled to occur before the lumbar puncture. It can be scheduled in the
days prior to the lumbar puncture (provided it occurs within the visit window), or it can be 
scheduled to occur on the same day as the lumbar puncture (provided it is prior to the 
lumbar puncture). If re-scanning at a post-screening visit is necessary due to a non-usable origi-
nal scan, the re-scanning should be conducted more than 3 days after the lumbar puncture and 
within one week of the original scan, if at all possible.  If the rescan falls outside of the study 
visit window, this should be reported as a minor deviation.

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4.5.9
Electrocardiograms
A single ECG recording will be obtained at screening. 
The ECG recordings must be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  Lead placement should be as consistent as possible.  ECG recording 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 30 minutes after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.
The investigator must review, sign, and date all ECG tracings.  Paper copies of ECG 
tracings will be kept as part of the patient's permanent study file at the site.  
4.5.10
Patient-Reported, Clinician-Reported, Observer-Reported, and 
Performance Outcomes
PRO, ClinRO, ObsRO, and PerfO data will be collected in clinic to document the change 
from baseline over time. Additionally PRO, ObsRO and PerfO data will be collected 
remotely.  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, 
questionnaires will be self-administered or administered by a trained rater
(as appropriate). In-clinic data should be collected prior to the performance of the 
lumbar puncture procedure.
Patients, clinicians, and study companions (if participating) will use an electronic device 
to capture outcome data during clinic visits and scoring of ClinRO and PerfO measures 
will be supervised during acquisition and entry into a tablet to ensure instructions are 
given and appropriately followed.  Paper must not be used to capture clinical outcome 
data unless it is for performance outcome measures (e.g., SWR, SDMT, and MoCA). 
Performance measure outcomes must be completed in ink and not pencil.
Study companions will use an electronic device to capture data remotely. Patients will 
use a smartphone or wrist-worn wearable to capture outcome data (see Section 4.5.11).  
The electronic device and/or instructions for completing the questionnaires electronically 
will be provided by site staff.  Electronic device data will be transmitted to a centralized 
database maintained by the electronic device vendor.  The data will be available for 
access by appropriate study personnel.  See Appendix 2 and Appendix 3 for a summary 
of timing and duration of each PRO, ClinRO, ObsRO, and PerfO assessment.
Appendix 4 shows the order and approximate timing of assessments at each clinic visit. 

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4.5.10.1
Total Functional Capacity Scale 
The TFC represents the investigator's assessment of the patient's capacity to perform a 
range of activities of basic daily living, including working, chores, managing finances, 
eating, dressing, and bathing.  The 5-item assessment is based on a brief interview with 
the patient and the study companion (if available).  The TFC score ranges from 0 to 13, 
with a higher score representing better functioning.  The TFC takes approximately 
10 minutes to administer and will be completed at clinic visits.
4.5.10.2
Total Motor Scale
The TMS score is the sum of the individual motor ratings obtained from administration of 
the 31-item motor assessment portion of the UHDRS by the investigator.  The score 
ranges from 0 to 124, with a higher score representing more severe impairment. The 
TMS takes approximately 15 minutes to administer and will be completed at clinic visits.
4.5.10.3
Symbol Digit Modalities Test
The SDMT is used to assess attention, visuoperceptual processing, working memory, 
and psychomotor speed.  It has been shown to have strong reliability and validity 
(Smith 1982).  The patient pairs abstract symbols with specific numbers according to a 
translation key.  The test measures the number of items correctly paired (maximum 
of 110 correct pairs) in 90 seconds.  The SDMT will be administered at clinic visits and 
can be completed in under 5 minutes.  It will also be administered remotely on the 
Roche HD mobile app (via electronic SDMT) and at clinic visits after clinical 
assessments are complete.
4.5.10.4
Stroop Word Reading Test 
The SWR Test is a measure of processing and psychomotor speed.  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.  The SWR will be administered at clinic visits 
and an electronic adaptation will be administered remotely on the Roche HD mobile app 
and at clinic visits after clinical assessments are complete.
4.5.10.5
Independence Scale
A patient's IS score is a measure of disease progression in functional disability. The IS 
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 patients is fed by tube and requires total bed care.
4.5.10.6
Clinical Global ImpressionSeverity and Clinical Global 
ImpressionChange
The CGI-S is a single-item measure of current global severity and is completed by the 
clinician at clinic visits.  Several variations exist, with minor adaptations made to ensure 

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the scale is specific to the study/disease area of interest.  The CGI-S is assessed using 
an 11-point numeric rating scale (NRS), where higher scores indicate greater severity.  
The CGI-S can be completed in approximately 3 minutes.
The CGI-C is a single-item measure of change in global status (from baseline) and is 
completed by the clinician at postbaseline visits.  As with the CGI-S, several variations 
exist.  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 3 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 wellbeing.
4.5.10.7
Patient Global ImpressionSeverity and Patient Global 
ImpressionChange
The PGI-S is a single-item measure of current global severity and is completed by the 
patient at clinic visits.  Several variations exist, with minor adaptations made to ensure 
the scale is specific to the study/disease area of interest.  The PGI-S is assessed using 
an 11-point NRS, where higher scores indicate greater severity.  
The PGI-C is a single-item measure of change in global status (from baseline) and is 
completed by the patient at postbaseline visits.  As with the PGI-S, several variations 
exist.  The PGI-C has seven response options:  "very much worse," "much worse," 
"minimally worse," "no change," "minimally improved," "much improved," and "very much 
improved." To assess the relevance of this change, a follow-up question with 
dichotomous response options (“yes” or “no”) asks if the change has had a meaningful 
impact on the patient's wellbeing.
4.5.10.8
Montreal Cognitive Assessment
The Montreal Cognitive Assessment is an 11-item clinician-reported assessment that is 
used to detect cognitive impairment.  It contains a series of basic assessments, including 
attention and visuospatial tasks.  The total score ranges from 030, where lower scores 
indicate greater impairment.  It will be used in this study to characterize patients at 
screening and takes approximately 10 minutes to administer.
4.5.10.9
WHO Disability Assessment Schedule 2.0
The WHODAS 2.0 (12-item version) assesses disability and aspects of HRQoL.  It is 
intended for use in any disease population, and it is linked to the concepts in the 
International Classification of Functioning, Disability, and Health.  The 12-item version 
contains 15 items, 12 of which produce a total score, with 3 additional questions 
administered to assess overall difficulty and activity impairment.  All items are scored on 
a 04 Likert-type scale.  The total raw score is converted onto a 0100 point scale, 
where higher scores indicate greater difficulty. The WHODAS 2.0 will be completed by 
both the patient and study companion (if available, about the patient) at baseline and 
postbaseline clinic visits on an electronic device.  In addition, it will be completed 

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monthly by the patient remotely on the Roche HD mobile app and by the study 
companion remotely on an electronic device. The WHODAS 2.0 will take approximately 
10 minutes to complete.
4.5.10.10
Work Productivity and Activity Impairment
The WPAI contains 6 items assessing the impact of disease on employment status 
(yes/no), hours missed due to disease, hours missed due to other reasons, hours 
worked, and impact on productivity and on daily activities (both using an 11-point NRS, 
where higher scores indicate greater impact). The WPAI takes approximately 5 minutes 
to complete. The WPAI will be completed by the patient and study companion
(if available, about the patient and him/herself). It will be completed monthly by the 
patient remotely on the Roche HD mobile app and by the study companion remotely on 
an electronic device.
4.5.10.11
Apathy Evaluation Scale
The AES is an 18-item assessment of apathy, including overt behavior, cognitive 
aspects of motivation, and emotional responsivity. Each item is scored on a 4-point 
Likert scale, from 1 ("Not at all") to 4 ("A lot"). A total score is created by summing the
18 items (scores range from 18 to 72; 3 items are reverse scored), with higher scores 
indicating greater apathy. The AES takes approximately 10 minutes to complete and will 
be completed by the patient and study companion (if available) at clinic visits.
4.5.10.12
Neuro-Qol Cognition Function Short Form, Version 2
The Neuro-Qol Cognition Function Short Form contains 8 items (including "trouble 
concentrating" and difficulty "learning new tasks or instructions"), each assessed using a 
5-point Likert scale, where lower scores indicate greater difficulty (4 items) or greater 
frequency (4 items). The raw sum score is converted to a T-score distribution 
(mean50, SD10). The Neuro-Qol Cognition Function Short Form takes 
approximately 5 minutes to complete and will be completed by the patient at clinic visits.
4.5.10.13
Huntington's DiseaseSpeaking Difficulty Item
The HD-SDI is a single question assessing difficulty speaking over the past 7 days.  It is 
assessed using a 5-point Likert scale, where higher scores indicate a greater frequency 
of difficulty. The HD-SDI can be completed in less than 1 minute and will be completed 
by the patient weekly remotely on the Roche HD mobile app.
4.5.10.14
Symptoms of Major Depressive Disorder Scale 
The SMDDS is a newly developed, valid, and reliable self-report assessment of 
depression (McCarrier et al. 2016). It contains 16 items, measuring concepts such as 
sadness, irritability, worry, and sleep disturbance. Each item is assessed on a 5-point 
Likert scale, from "Not at all" to "Extremely" (9 items) and from "Never" to "Always"
(7 items). Item scores from 15 of the items (the least severe of the two eating items is 
dropped) are summed to create a 060 score, where higher scores indicate more severe 

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depressive symptomatology. The SMDDS takes approximately 10 minutes to complete
and will be completed by the patient at clinic visits.
4.5.10.15
EuroQol 5-Dimension, 5-Level Questionnaire
The EQ-5D-5L is a validated self-report health status questionnaire used to calculate a 
health status utility score for use in health economic analyses (EuroQol Group 1990; 
Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There are two components to 
the EQ-5D-5L:  a 5-item health state profile that assesses mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, as well as a visual analogue scale 
(VAS) that measures health state.  Published weighting systems allow for creation of a 
single composite score of the patient's health status (Index score) from the 5-item scores 
(i.e., does not include the VAS).  The EQ-5D-5L takes approximately 5 minutes to 
complete.  The Index score will be used in this study for informing pharmacoeconomic 
evaluations.  The VAS score will be used to assess HRQoL.  The EQ-5D-5L will be 
completed both by the patient (about him/herself) and by the study companion
(if available, about him/herself) at baseline and postbaseline clinic visits on an electronic 
device.  In addition, it will be completed weekly by the patient remotely on the Roche HD 
mobile app and weekly by the study companion remotely on an electronic device.
4.5.10.16
Columbia-Suicide Severity Rating Scale
The C-SSRS is a structured tool to assess suicidal ideation and behavior and should be 
performed by a study qualified physician.  Four constructs are measured:  severity of 
ideation, intensity of ideation, behavior, and lethality of actual suicide attempts.  Binary 
(yes/no) data are collected for 10 categories, and composite endpoints based on the 
categories are followed over time to monitor patient safety (Posner et al. 2011).  It maps 
to the Columbia-Classification Algorithm for Suicide Assessment and meets the criteria 
listed in the U.S. Food and Drug Administration (FDA) draft guidance for assessment of 
suicidality in clinical trials (FDA 2012).  The C-SSRS will be used to assess eligibility for 
the study (full version at screening, requiring approximately 20 minutes to administer)
and to monitor the patients from baseline throughout the study at clinic visits (follow-up 
version, requiring approximately 5 minutes to administer, assuming absence of suicidal 
ideation and no change in clinical status from previous administration).
The patient should be referred for immediate psychiatric evaluation in any event of 
suspected active suicidal intent, significant suicidal behavior, or clinical finding 
suggesting that the patient is dangerous to himself or herself.
4.5.11
Roche HD Mobile App (Smartphone and Wrist-Worn Wearable)
Each patient will receive a preconfigured smartphone and wrist-worn wearable with 
installed software for the Roche HD Mobile App assessments.  Patients will use the 
devices and software to continuously assess motor and non-motor symptoms, as well as 
activities associated with routine daily living. Additional details are available in the 
"Roche HD Mobile App (Smartphone) Manual."

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4.5.11.1
Roche HD Mobile App Remote Monitoring
Patients will be provided devices and trained on their use during screening.  During the 
study, patients will be instructed to conduct an "active test" every day at approximately 
the same time (ideally in the morning, after breakfast).  The active test consists of a 
short, preconfigured schedule of tasks that assess motor symptoms (upper and lower 
body movements, upper limb dexterity, voice) and non-motor symptoms (processing 
speed/voice).  For "passive monitoring," patients will be instructed to carry the 
smartphone and wear the wrist-worn wearable throughout the day as they go about their 
daily routine. 
Device sensor data will be recorded continuously, throughout the active tests and 
passive monitoring.  Sound will only be recorded during selected active test tasks.  Data 
are encrypted and uploaded to secure servers when the smartphone is connected 
to WiFi.
Patients will be asked to charge the devices overnight.  If patients have a WiFi network 
at home, they will be encouraged to connect their smartphone to enable data transfer.  If 
no WiFi network is available, the sensor data will be transferred during site visits or after 
the devices have been returned.
4.5.11.2
Roche HD Mobile App In-Clinic Assessments
Patients will be instructed to bring the smartphone and wearable to every clinic visit to 
check adherence and technical status of the devices.  At clinic visits, patients will be 
asked to conduct the "active test" tasks under the supervision of trained site staff. 
The smartphone and wearable must be returned to the clinic in cases where the patient 
does not meet eligibility criteria, at the end of the study, and upon early termination.  
At the end of the study or at the time when the patient has completed the study, patients 
will be asked to complete a pen-and-paper satisfaction survey about their experience
using the smartphone and wrist-worn wearable during the study.
4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens 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.
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with adverse events or disease progression

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
To increase knowledge and understanding of disease biology

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR 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 4.5.12) will not be applicable at that site.
4.5.12.3
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 target or diseases:

Leftover CSF and plasma biomarker samples, and any derivatives thereof 
(e.g., proteins, peptides)

Blood (for RBR DNA and RBR RNA) and serum samples collected at baseline and 
at 15-month visits 
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), next-generation sequencing, or other genomic analysis methods.  
Genomics is increasingly informing researcher's 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.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
4.5.12.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.

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Patient medical information associated with RBR specimens 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 specimens, 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 specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
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 specimens.  
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 
specimens and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  However, if RBR specimens 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 
specimens, the investigator must inform the Medical Monitor in writing of the patient's 
wishes through use of the appropriate RBR Subject Withdrawal Form and, if the trial is 
ongoing, must enter the date of withdrawal on the RBR Research Sample Withdrawal of 
Informed Consent eCRF.  The patient will be provided with instructions on how to 
withdraw consent after the trial is closed.  A patient's withdrawal from Study BN40422

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does not, by itself, constitute withdrawal of specimens from the RBR.  Likewise, a 
patient's withdrawal from the RBR does not constitute withdrawal from Study BN40422.
4.5.12.7
Monitoring and Oversight
RBR specimens 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 specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
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

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study may be replaced, particularly if 
withdrawal is early-on (e.g., within first 6 months).
4.6.2
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:

Patient enrollment is unsatisfactory

Program termination
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.3
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

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
Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice or any other pertinent local law or guideline

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
After informed consent has been obtained and after the initiation of study procedures, 
both adverse events and serious adverse events related to a study procedure will be 
reported until the last clinic visit. 
5.2
SAFETY PARAMETERS
Since no study medication will be given to the patients, safety assessments will consist 
of monitoring and recording adverse events, including serious adverse events related to 
study procedures.
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.
In the case of this non-drug study, any untoward medical occurrence in a clinical 
investigation subject that is related to a protocol-mandated intervention is considered an 
adverse event (e.g., invasive procedures such as lumbar punctures).
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 5.3.5.8)

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)

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)

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The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria (see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions)
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
In the case of this non-drug study, this section is not applicable.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that adverse events related to a 
protocol-mandated intervention (see Section 5.2.1 for definition) are recorded on the 
Adverse Event eCRF and reported to the Sponsor in accordance with instructions 
provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality to study procedure (see Section 5.3.4).
In the case of this non-drug study, investigators and patients are reminded to report any 
adverse reactions (for which they suspect a causal role of a medicinal product 
[e.g., concomitant medication]) that come to their attention, either to the marketing 
authorization holder of the suspected medicinal product or to the concerned competent 
authorities, via the national spontaneous reporting system.
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events related to a protocol-mandated 
intervention at each patient contact. All adverse events related to a protocol-mandated 
intervention, 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 until the 
patient’s last visit or withdrawal.
After informed consent has been obtained, serious adverse events caused by a protocol-
mandated intervention (e.g., invasive procedures such as lumbar punctures) should be 
reported (see Sections 5.45.6 for instructions for reporting serious adverse events) until 
the patient's last visit or withdrawal.

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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
Table 1 provides guidance for assessing adverse event severity.
Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. 
Refer to definition of a serious adverse event (see 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 a study procedure, indicating "yes" or "no" 
accordingly. The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study procedure

Known association of the event with the procedure 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procedure-related factors that are known to be associated with the 
occurrence of the event
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events related to a protocol-mandated intervention 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.

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5.3.5.1
Diagnosis versus Signs and Symptoms
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
related to a protocol-mandated intervention based on signs and symptoms should be 
nullified and replaced by one adverse event related to a protocol-mandated intervention
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events Occurring Secondary to Other Events
In general, adverse events occurring secondary to other events related to a 
protocol-mandated intervention (e.g., cascade events or clinical sequelae) should be 
identified by their primary cause, with the exception of severe or serious secondary 
events. However, medically significant adverse events occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events related to a protocol-mandated intervention should be recorded 
separately on the Adverse Event eCRF if it is unclear as to whether the events are 
associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event related to a protocol-mandated intervention 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 of 
the event should be recorded, and the severity should be updated to reflect the most 
extreme severity any time the event worsens. If the event becomes serious, the 
Adverse Event eCRF should be updated to reflect this.
A recurrent adverse event related to a protocol-mandated intervention is one that 
resolves between patient evaluation timepoints and subsequently recurs. Each 

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recurrence of an adverse event should be recorded separately on the Adverse Event 
eCRF.
5.3.5.4
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

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 related to a protocol-mandated intervention.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.3.5.5
Abnormal Liver Function Tests
In the case of this non-drug study, this section is not applicable.
5.3.5.6
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see
Section 5.3.1), regardless of relationship to study procedure, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
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").
5.3.5.7
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.

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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").
5.3.5.8
Hospitalization or Prolonged Hospitalization 
Any adverse event related to a protocol-mandated intervention 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
5.3.6
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived from PRO or ObsRO data by the Sponsor, and 
safety analyses will not be performed using PRO or ObsRO data.  Sites are not 
expected to review the PRO or ObsRO data for adverse events.

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

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5.4.2
Reporting Requirements for Serious Adverse Events
After informed consent has been obtained, serious adverse events (see Section 5.2.2) 
caused by a protocol-mandated intervention should be reported until the patient's last 
visit or withdrawal. 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.  
5.4.3
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. The investigator should then 
withdraw the patient from the study in the case of pregnancy. 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 counsel the patient and make referral to 
appropriate medical professional. 
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event related to a protocol-mandated 
intervention 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-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. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.

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5.5.2
Sponsor Follow-Up
For serious adverse events related to a protocol-mandated intervention and pregnancies, 
the Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring 
visit to obtain additional case details and outcome information (e.g., from hospital 
discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as
Section 5.3.1) if the event is believed to be related to a protocol-mandated intervention.  
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 related to a 
protocol-mandated intervention against cumulative procedure experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable health authorities based on applicable legislation.
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 CONSIDERATION AND ANALYSIS PLAN
This is a non-interventional study and is exploratory in nature. As such, there is no 
predefined hypothesis testing, and all analyses will be regarded as exploratory. 
Where applicable, parameter estimates will be reported together with 90% CI. 
P-values may still be reported.
Basic assumptions of the proposed analyses will be checked, and data transformation 
(e.g., logarithm transformation) or other analyses could be carried out, if appropriate.
The fact that patients in this study are matched to the OLE study (Clinicaltrials.gov 
Identifier NCT03342053) may offer the future opportunity to compare the current 
observational study against the OLE study.  Details of this analysis are not in the scope 
of this protocol and may be described in a separate document not related to 
Study BN40422.

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6.1
DETERMINATION OF SAMPLE SIZE
In this study, up to approximately 100 patients are expected to be enrolled across 
approximately 20 sites.  This number is driven by the objective of having a 2:1 match, 
based on baseline characteristics, to patients from the OLE study.
6.2
ANALYSIS POPULATION 
All patients who fulfill the entry criteria at screening and have been enrolled in the study 
will be included in the analysis.
6.3
PRIMARY ANALYSES 
The primary objective of this study is to investigate whether baseline CSF mHTT is a 
predictor of the change from baseline to 15 months for the following variables:

Clinical endpoints (cUHDRS, TFC, TMS, SDMT, SWR, and IS) 

CSF and blood biomarkers

Brain imaging (MRI)
Initially, a linear model will be used to evaluate the association between each response 
variable (e.g., change from baseline to 15 months in cUHDRS) and baseline CSF mHTT 
without adjustment for any baseline characteristics. 
The same model will then be considered again, adjusting for baseline level of the 
response variable (e.g., baseline cUHDRS), baseline CSF mHTT levels, CAG, and 
baseline CAP (the latter defined as the product of age at baseline by [CAG33.66]
(Zhang et al. 2011). A sensitivity analysis to evaluate the impact of additional baseline 
characteristics (e.g., gender, education level) may be performed.  
Other approaches may be used in the case of severe multicollinearity, which would 
result in model instability.
6.4
SECONDARY ANALYSES
The secondary objective for this study is to investigate the within-patient change from 
baseline in CSF mHTT levels and the association between changes from baseline in 
CSF mHTT levels at 3, 9, and 15 months and changes in clinical measures (cUHDRS, 
TFC, TMS, SDMT, SWR, and IS), biomarkers of neuronal injury, and brain atrophy 
endpoints.
Initially, a linear model will be used to evaluate the association between each response 
variable (e.g., change from baseline to 15 months in CSF NfL levels) and the change in 
CSF mHTT level, without adjustment for any baseline characteristics. A similar model 
will then be considered, adjusting for baseline level of the response variable, CAG, and
baseline CAP.  A sensitivity analysis to evaluate the impact of additional baseline 
characteristics (e.g., baseline mHTT, gender, education level) may be performed.

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6.5
SAFETY ANALYSES
The safety analysis population will consist of all patients who underwent study-specific 
procedures. Given the non-drug nature of this study, limited safety analyses will be 
reported.
The number of unique patients who experience and report an adverse event, each 
adverse event, and the number of adverse events themselves will be tabulated by 
MedDRA System Organ Class and Preferred Term.  Adverse events will also be 
summarized by severity (see Section 5.3.3). 
Laboratory absolute values at screening will be listed and summarized descriptively.  
Values outside the normal range will be listed and summarized.
6.6
EXPLORATORY ANALYSES
The association between standard clinical endpoints and Roche HD mobile app versions
(e.g., SWR and eSWR, SDMT, and eSDMT) will be evaluated.
Finally, longitudinal changes over time will be described, adjusted on baseline 
characteristics, for most variables. Signal-to-noise ratio, defined as the change in the 
endpoint divided by the corresponding variability, will be derived where applicable.
Additional exploratory analyses may be performed as appropriate. Data from this study 
may be combined with data from other studies to inform disease and causal models.
6.7
INTERIM ANALYSES
The Sponsor may choose to conduct one or more interim analyses. The decision to 
conduct such an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor’s study master file prior to the conduct of the interim 
analysis.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Data entered manually will be collected via EDC through use of 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data, electronic data 
from clinic visits (see Section 7.3), and electronic data obtained from the Roche HD 
mobile app (see Section 7.4) will be sent directly to the Sponsor, using the Sponsor's 
standard procedures to handle and process the electronic transfer of these data.

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

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No patient identifiable information is stored on the devices.  For selected "Active Test” 
tasks, touch and sound is also recorded.  Video is not recorded.
HD Mobile App data are encrypted and uploaded to secure servers whenever the 
smartphone is connected to WiFi.  All HD Mobile App data will be managed by the 
Sponsor who will monitor and ensure the integrity and quality of the acquired data.  This 
includes, but is not limited, to the analysis of sensor data together with protocol-specified
assessments and activities associated with routine daily living.
7.5
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.  
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.7.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.6
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.

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7.7
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study, including eCRFs, 
electronic PRO, ClinRO, ObsRO (if applicable), and PerfO data, Informed Consent 
Forms, and laboratory test results, 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.
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 (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
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, Mobile Nursing Informed Consent Form, 
or Study Companion ICF, 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 IRB/EC submission.  The final IRB/ECapproved Consent 
Forms must be provided to the Sponsor for health authority submission purposes 
according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.

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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.  If a study 
companion is available, the study companion must also sign and date a consent form 
prior to participation in the study.  The case history or clinical records for each patient 
shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).

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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4 
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed
to third parties only as permitted by the Informed Consent Form (or separate
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker and Roche HD 
Mobile App 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 Roche policy on 
study data publication (see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or shared with re-
searchers, government agencies, companies, or other groups that are not participating in this 
study.  These data may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization of products 
to treat and diagnose disease.  Linking of data will be facilitated by the HDID number (see Section  
4.5.3).  The HDID is not specific to Study BN40422 but is a unique coded identifier for 
persons participating in studies in HD.  This HDID will stay the same for a person 
throughout all trials.  The use of the unique identifier will assure that people are only en-
rolled once in large observational studies like Enroll-HD, REGISTRY, COHORT, 
PREDICT, and TRACK-HD and will also allow approved comparison and combination 
of data between studies.  The HDID is a 9 digit number created by a secure one-way al-
gorithm, based on unchanging information (date of birth, birth name, place
of birth and mother’s maiden name).  The identifying data are used for the split second

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needed by the algorithm needed to generate the HDID and are never stored 
electronically on the web portal or in the study database.  For patients without a 
preexisting HDID number in the source notes, the investigator should store the 
original data and the newly generated HDID in the patient’s source documents and in 
the investigator file.  The HDID can be generated within the web portals of the 
observational studies or in the specially defined portal for the HDID generation at:
https://hdid.enroll-hd.org.  In addition, redacted clinical study reports and other 
summary reports will be provided upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.

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9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
and contract research organization will provide clinical operations management, and the 
Sponsor will provide data management and medical monitoring.
Approximately 20 sites globally will participate to enroll up to approximately 100 patients.  
Additional countries and sites may be added or substituted if underperforming.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, neuroimaging, electrophysiological assessment, and 
biomarker analyses), as specified in Section 4.5.  Accredited local laboratories will be 
used for routine monitoring; local laboratory ranges will be collected.
9.5
PUBLICATION 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, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the physician 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 physician.
In accordance with standard editorial and ethical practice, Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating physician 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 the Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the physician and the 
appropriate Sponsor’s personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.

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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
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Zhang Y, Long JD, Mills JA, et al Indexing disease progression at study entry with 
individuals at-risk for Huntington disease. Am J Med Genet B Neuropsychiatr 
Genet 2011;156:75163.

F. Hoffmann-La Roche Ltd
68/ Protocol BN40422, Version 3
Appendix 1 Schedule of Activities
Study Day
Screening 
Period
Observational Period
Follow-Up
(or Early 
Termination) a
Days 29 
to 2
Day 1 to 1 
(Baseline)
Day 85
(Month 3)
Day 169
(Month 6)
Day 253
(Month 9)
Day 337
(Month 12)
Day 421
(Month 15)
Visit Window (days)
7
10
7
10
7
Type of visit
CL
CL
CL
PH
CL
PH
CL
CL or PH
Capacity to consent assessment 
and informed consent b
x
Demographic data
x
Medical history and baseline 
conditions
x
x
Vital signs c
x
x
x
x
x
Height d
x
Weight e
x
x
x
x
x
Physical examination f
x
x
x
x
x
Neurological examination g
x
x
x
x
x
CAG repeat length h
x
Chemistry, hematology, urinalysis i
x
x
x
x
x
Viral serology j
x
Pregnancy test k
x
x
x
x
Coagulation l
x
x
x
x
x
Thyroid panel
x
ECG (12-lead)
x

Appendix 1 Schedule of Activities (cont.)
F. Hoffmann-La Roche Ltd
69/Protocol BN40422, Version 3
Study Day
Screening 
Period
Observational Period
Follow-Up
(or Early 
Termination) a
Days 29 
to 2
Day 1 to 1 
(Baseline)
Day 85
(Month 3)
Day 169
(Month 6)
Day 253
(Month 9)
Day 337
(Month 12)
Day 421
(Month 15)
Visit Window (days)
7
10
7
10
7
Type of visit
CL
CL
CL
PH
CL
PH
CL
CL or PH
Lumbar puncture and CSF sample m
x
x
x
x
MRI n
x
x
x
x
ClinROs, ObsROs, PerfOs, and 
PROs conducted in clinic o
x
x
x
x
x
C-SSRS p
x
x
x
x
x
Roche HD mobile app equipment 
training
x
Roche HD mobile app in-clinic 
assessment q
x
x
x
x
x
Roche HD mobile app remote data 
collection q
Continuous remote data collection
Whole blood sample for clinical 
genotyping
x
Plasma samples for biomarkers
x
x
x
x
RBR DNA (optional) r
x
RBR RNA (optional) r
x
x
RBR serum (optional) r
x
x
Change in medical information 
since last visit s
x
x
x
x
x

Appendix 1 Schedule of Activities (cont.)
F. Hoffmann-La Roche Ltd
70/Protocol BN40422, Version 3
Study Day
Screening 
Period
Observational Period
Follow-Up
(or Early 
Termination) a
Days 29 
to 2
Day 1 to 1 
(Baseline)
Day 85
(Month 3)
Day 169
(Month 6)
Day 253
(Month 9)
Day 337
(Month 12)
Day 421
(Month 15)
Visit Window (days)
7
10
7
10
7
Type of visit
CL
CL
CL
PH
CL
PH
CL
CL or PH
Adverse events t
x
x
x
x
x
x
x
x
Concomitant medications u
x
x
x
x
x
x
x
x
CLclinic; ClinROs clinician-reported outcomes; CSFcerebrospinal fluid; C-SSRSColumbia-Suicide Severity Rating Scale; eCRF electronic 
Case Report Form; HBsAg hepatitis B surface antigen; HCVhepatitis C virus; HDHuntington disease; MRImagnetic resonance imaging; 
ObsROs observer-reported outcomes; PerfOs performance outcomes; PHphone; PROs patient-reported outcomes; RBRResearch 
Biosample Repository.
a Post-observational follow-up visit will take place 2 weeks after end of observational period and will occur via clinic visit or by telephone call.  
Early termination visit should occur via clinic visit where possible.
b Capacity to consent assessment (patient only) and informed consent (for both the patient and study companion [if available]).must be 
documented before any study-specific screening procedure is performed and may be obtained more than 28 days before baseline visit. A 
maximum of one re-screening will be allowed within 8 weeks of the initial screening failure for patients who fail the initial screening (e.g., as 
a consequence of abnormal laboratory values or general medical status not meeting inclusion or exclusion criteria).  If re screening is required, 
central CAG repeat length testing from the initial screening does not need to be repeated, and the screening MRI and viral serology from the 
initial screening may be acceptable as part of the re screening assessments if performed within 12 weeks of the baseline visit.
c Includes measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position after 
resting for approximately 5 minutes, and temperature.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. 
d Height in meters.
e Weight in kilograms.
f Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  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 associated with a study procedure should be recorded as adverse events on the Adverse Event eCFR.

Appendix 1 Schedule of Activities (cont.)
F. Hoffmann-La Roche Ltd
71/Protocol BN40422, Version 3
g Neurological examination includes assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function 
and reflexes.  Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  New or worsened 
clinically significant abnormalities associated with a study procedure should be recorded as adverse events on the Adverse Event eCRF.
h At screening, a mandatory whole blood sample will be obtained for DNA extraction for analysis of CAG repeat length.
i
Screening laboratory assessments include hematology (WBC count, RBC count, hemoglobin, hematocrit, platelet count, all required; differential 
count including neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells as per local practice); serum chemistry (sodium, 
potassium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, uric acid, GGT, CPK, as per local standard practice); and urinalysis (dipstick including pH, specific gravity, glucose, protein, ketones, 
blood and microscopic examination, including sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria, as per local standard practice). 
Microscopic examination is only required in case of an abnormal dipstick result (for example, blood in urine or high protein value).
j
Viral serology: HBsAg and HCV antibody.
k 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.
l
Coagulation:  INR and/or PT, aPTT.
m Patients will have CSF collected at baseline and at Months 3, 9, and 15 for the assessment of RBC count, WBC count, glucose, and protein.  
Prior to performing each scheduled lumbar puncture, local laboratory analysis of coagulation factors (INR and/or PT, aPTT) and platelets must 
be conducted and results reviewed.  Collection for these local labs may occur at any time in the 72 hours prior to the lumbar puncture.  The 
lumbar puncture should be performed at approximately the same time at each visit (ideally in the morning between 08:00 and 12:00 hours) to 
minimize potential diurnal variation of CSF parameters.  CSF fluid (20 mL) is to be collected for analyses using a standard lumbar puncture 
collection kit.  If there are difficulties in collecting 20 mL of CSF fluid, a minimum of 15 mL should be collected.  A 24G Whitacre (atraumatic) 
needle should be used.  Depending on institutional guidelines, local anesthesia may be used for the procedure.  Sedation is not allowed.  Spinal 
ultrasound may be used for the lumbar puncture procedure if deemed necessary, but is not required. Ultrasound guidance may be used if 
attempts at lumbar puncture without imaging are unsuccessful, if it is local practice to use ultrasound, or if institutional guidelines dictate use of 
ultrasound with each lumbar puncture. In the case of a failed CSF collection procedure due to inadequate establishment of access to the IT 
space, a second attempt may occur up to 14 days after the originally attempt.  For this additional visit, local laboratory analysis of 
coagulation factors (INR and/or PT, aPTT) and platelets must be conducted and the results reviewed, within 72 hours prior to performing the 
LP.  In addition, neurological examination, vital signs and a review of AEs and concomitant medication should occur as part of the safety and 
tolerability evaluations on the day of LP.

Appendix 1 Schedule of Activities (cont.)
F. Hoffmann-La Roche Ltd
72/Protocol BN40422, Version 3
n For MRI scans at Months 3, 9, and 15, the MRI should be scheduled to occur before the lumbar puncture. It can be scheduled in the days prior 
to the lumbar puncture (provided it occurs within the visit window), or it can be scheduled to occur on the same day as the lumbar puncture 
(provided it is prior to the lumbar puncture). If re-scanning at a post-screening visit is necessary due to a non-usable original scan, the 
re-scanning should be conducted more than 3 days after the lumbar puncture and within one week of the original scan, if at all possible. If the 
rescan falls outside of the study visit window, this should be reported as a minor deviation.
o Questionnaires will be self-administered or administered by trained rater (as appropriate) at screening and at each clinic visit prior to the lumbar 
puncture.  See Appendix 2 and Appendix 3 for details. 
p The C-SSRS must be administered on scheduled timepoints and may be performed at other timepoints per investigator's discretion.
q The Roche HD mobile app includes a short, preconfigured schedule of daily tasks (“active test”) that assess motor symptoms (upper and lower 
body movements, upper limb dexterity, voice) and non-motor symptoms (processing speed/voice). In addition, passive monitoring data is 
collected. During the in-clinic assessment, the entire suite of active tests should be performed. 
r
Not applicable for a site that has not been granted approval for RBR sampling.  Performed only for patients who have provided written informed 
consent to participate at participating sites.
s At the time of each follow-up physical examination, 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.
t
After informed consent has been obtained, adverse events caused by a protocol-mandated intervention should be reported until the patient's last 
visit or withdrawal.  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 protocol-related procedures until a final outcome can be reported.
u Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient during the study (from screening to the study completion/discontinuation visit).

F. Hoffmann-La Roche Ltd
73/ Protocol BN40422, Version 3
Appendix 2 Clinician-Reported Outcomes
Assessment
Name
Items
Concepts
Approx. Duration
Timing
CGI-C
Clinical Global 
ImpressionChange
1
Overall change 
in patient status
3 min
Postbaseline clinic visits
CGI-S
Clinical Global 
ImpressionSeverity
1
Overall severity 
of patient status
3 min
Baseline and postbaseline clinic 
visits
C-SSRS
Columbia-Suicide 
Severity Scale
5
Suicidal ideation 
and behavior
20 min full version; 
5 min follow-up
version
Full version at screening in clinic;
follow-up version at baseline and all 
postbaseline clinic visits 
TFC
Total Functional 
Capacity Scale
5
Overall function
10 min
All clinic visits
TMS
Total Motor Score
31
Motor function
15 min
All clinic visits
IS
Independence Scale
1
Functional 
disability
3 min
All clinic visits

F. Hoffmann-La Roche Ltd
74/ Protocol BN40422, Version 3
Appendix 3 Patient-Reported, Observer-Reported, and Performance Outcomes
and Roche HD Mobile Application
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO,
PerfO, Behavior
Timing
AES
Apathy Evaluation Scale
18
Apathy
10
PROObsRO
Baseline and postbaseline 
clinic visits
Roche HD 
mobile app 
Roche HD mobile app with 
daily Active Test and 
Passive Monitoring
NA
Tasks (“active test”) that 
assess motor symptoms 
(upper and lower body 
movements, upper limb 
dexterity, voice) and 
non-motor symptoms 
(processing speed/voice); 
continuous passive monitoring
47
Sensor data, 
PRO, PerfO
Dailyat clinic visits on 
Roche HD mobile app
EQ-5D-5L
EuroQol 5-Dimension, 
5-Level Questionnaire
6
Health utilities
5
PROObsRO
Baseline and postbaseline 
clinic visits and
weekly on Roche HD 
mobile app and electronic 
device
HD-SDI
Huntington's 
DiseaseSpeaking Difficulty 
Item 
1
Speech
1
PRO
Weekly on Roche HD 
mobile app
MoCA
Montreal Cognitive 
Assessment
11
Overall cognitive status
10
PerfO
Screening
Neuro-Qol 
Cog Func
Neuro-Qol Cognitive 
Function Short Form
8
Cognition
5
PRO
Baseline and postbaseline 
clinic visits

F. Hoffmann-La Roche Ltd
75/Protocol BN40422, Version 3
Appendix 3 Patient-Reported, Observer-Reported, and Performance Outcomes
and Roche HD Mobile Application (cont.)
Assessment
Name
Items
Concepts
Approx.
Duration
(min)
PRO, ObsRO, 
PerfO, Behavior
Timing
PGI-C
Patient Global 
ImpressionChange
1
Overall change in patient 
status
3
PRO
Postbaseline clinic visits
PGI-S
Patient Global 
ImpressionSeverity
1
Overall severity of patient 
status
3
PRO
Baseline and postbaseline 
clinic visits
SDMT/
eSDMT
Symbol Digit Modalities 
Test
Max 
no. in 
90 sec
Cognitive
5
PerfO
All clinic visits
(SDMT/eSDMT); weekly on
Roche HD mobile app
(eSDMT)
SMDDS
Symptoms of Major 
Depressive Disorder Scale
16
Depression, anxiety, irritability, 
sleep
10
PRO
Baseline and postbaseline 
clinic visits
SWR/eSWR
Stroop Word Reading Test
Max 
no. in 
45 sec
Cognitive
5
PerfO
All clinic visits
(SWR/eSWR); weekly on
Roche HD mobile app
(eSWR)
WHODAS
2.0
WHO Disability 
Assessment Schedule 2.0
(12-item scale)
15
Broad coverage
10
PROObsRO
Baseline and postbaseline 
clinic visits and
monthly on Roche HD 
mobile app and electronic 
device
WPAI
Work Productivity and 
Activity Impairment
6
Work productivity
5
PROObsRO
Monthly on Roche HD 
mobile app and electronic 
device
ADLactivities of daily living; minminute; ObsROobserver-reported outcome; PRO patient-reported outcome; PerfOperformance outcome.

F. Hoffmann-La Roche Ltd
76/ Protocol BN40422, Version 3
Appendix 4 Order and Approximate Timing 
of Assessments at Clinic Visits
Block
Assessments
Total Duration 
(minutes)
Site Staff 
Responsible
1
Total Functional Capacity Scale1
~4560
1: Qualified 
study 
physician
2: Qualified 
study 
personnel
Independence Scale1
Total Motor Score1
Symbol Digit Modalities Test2
Stroop Word Reading Test2
Montreal Cognitive Assessment (screening only) 2
Columbia-Suicide Severity Rating Scale1
Clinical Global ImpressionSeverity1
Clinical Global ImpressionChange (postbaseline 
visits only)1
Break
20
2
Apathy Evaluation Scale
~30
Qualified 
study 
personnel
Neuro-Qol Cognition Function Short Form
WHO Disability Assessment Schedule 2.0
EuroQol 5-Dimension, 5-Level Questionnaire 
Break
10
3
Symptoms of Major Depressive Disorder Scale
~15
Qualified 
study 
personnel
Patient Global ImpressionSeverity
Patient Global ImpressionChange
(postbaseline visits only)
Break
10
4
Roche HD mobile application
~20
Qualified 
study 
personnel
Note:  Not all assessments will be completed at all visits.  Consult Appendix 3 for 
timing.