Clinical trial NCT03342053
Conditions: Huntington's Disease
Sponsor: Hoffmann-La Roche
Start date: 2018-01-02; Completion date: 2019-10-08
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7234292 administered intrathecally to adult patients with Huntington's Disease.

Detailed description:

Arms: arm 1: RO7234292 is administered every 28 days intrathecally for 14 months. arm 2: RO7234292 is administered every 56 days intrathecally for 14 months following 2 monthly doses to serve as a loading dose.
Interventions: intervention 1: RO7234292 (RG6042)
Intervention descriptions: intervention 1: Intrathecal injection

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
An Open-Label Extension Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of RO7234292 (ISIS 
443139) in Huntington's Disease Patients Who Participated in Prior 
Investigational Studies of RO7234292 (ISIS 443139) 
NCT Number: 
NCT03342053   
Document Date: 
Protocol Amendment 4 (Version 5): 30-August-2018 
 
 
 


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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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.
PROTOCOL
TITLE:
AN OPEN-LABEL EXTENSION STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS 
OF RO7234292 (ISIS 443139) IN HUNTINGTON'S DISEASE PATIENTS 
WHO PARTICIPATED IN PRIOR INVESTIGATIONAL STUDIES OF 
RO7234292 (ISIS 443139)
PROTOCOL NUMBER:
BN40697 (ISIS 443139-CS2)
VERSION NUMBER:
Amendment 4 (Version 5)
EUDRACT NUMBER:
2017-002471-25
TEST PRODUCT:
RO7234292 (ISIS 443139 or RG6042)
MEDICAL MONITOR:
, M.D., M.Sc.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Original (Version 1):  19 June 2017
DATES AMENDED:
Amendment 1 (Version 2):  5 September 2017
Amendment 1 (Canada):  15 December 2017
Amendment 2 (Version 3):   30 January 2018
Amendment 2 (Canada):  31 January 2018
Amendment 3 (Version 4):  29 June 2018
Amendment 3 (Canada):  29 June 2018
Amendment 4 (Version 5):  See electronic date stamp below.
 
30-Aug-2018 06:27:53
Title
Approver's Name
Company Signatory
Date and Time (UTC)


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
2
Protocol Signature Page
Protocol Number:
BN40697 (ISIS 443139-CS2)
Protocol Title:
An Open-Label Extension Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of RO7234292 (ISIS 443139) 
in Huntington’s Disease Patients Who Participated in Prior 
Investigational Studies of RO7234292 (ISIS 443139)
Version:
Protocol Amendment 4 (Version 5)
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled 
“An Open-Label Extension Study to Evaluate the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of RO7234292 (ISIS 443139) in Huntington’s Disease Patients Who 
Participated in Prior Investigational Studies of RO7234292 (ISIS 443139),” and agree to conduct 
the Study as described herein.
I agree to comply with the International Council for Harmonisation Tripartite Guideline on Good 
Clinical Practice (E6).
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of F. Hoffmann-La Roche Ltd.
Investigator’s Signature
Investigator’s Name (please print)
Date (DD Month YYYY)


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
3
TABLE OF CONTENTS
Page
PROTOCOL AMENDMENT....................................................................................................................9
PROTOCOL SYNOPSIS.........................................................................................................................10
STUDY DESIGN AND TREATMENT SCHEMA................................................................................17
COHORT DOSING REGIMENS ...........................................................................................................18
STUDY GLOSSARY................................................................................................................................19
1.
OBJECTIVES..............................................................................................................................22
1.1
Primary Objectives ....................................................................................................................22
1.2
Secondary Objectives ................................................................................................................22
22
2.
BACKGROUND AND RATIONALE .......................................................................................22
2.1
Overview of Disease..................................................................................................................22
2.1.1
Epidemiology.............................................................................................................................22
2.1.2
Huntingtin Protein.....................................................................................................................23
2.1.3
Clinical Features and Diagnosis of HD .......................................................................................23
2.1.4
Treatments for HD.....................................................................................................................24
2.2
Therapeutic Rationale ...............................................................................................................25
2.3
RO7234292..............................................................................................................................26
2.3.1
Mechanism of Action.................................................................................................................26
26
27
2.3.4
Clinical Experience.....................................................................................................................27
2.4
Rationale for Study Design ........................................................................................................27
2.5
Risk Assessment ........................................................................................................................28
3.
EXPERIMENTAL PLAN...........................................................................................................29
3.1
Study Design..............................................................................................................................29
3.2
Number of Study Centers..........................................................................................................29
3.3
Number of Patients ...................................................................................................................29
3.4
Overall Study Duration and Follow-up......................................................................................29
3.4.1
Screening Period........................................................................................................................30
3.4.2
Treatment Period ......................................................................................................................30
3.4.3
Post-Treatment Period..............................................................................................................30
3.5
End-of-Study..............................................................................................................................30


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
4
4.
PATIENT ENROLLMENT........................................................................................................30
4.1
Screening...................................................................................................................................30
4.2
Randomization...........................................................................................................................31
4.3
Replacement of Patients ...........................................................................................................31
5.
PATIENT ELIGIBILITY ...........................................................................................................31
5.1
Inclusion Criteria........................................................................................................................31
5.2
Exclusion Criteria.......................................................................................................................33
6.
STUDY PROCEDURES .............................................................................................................33
6.1
Study Schedule ..........................................................................................................................33
6.1.1
Screening Period (Week -4 to Week -1)....................................................................................34
6.1.2
Treatment Period (Week 1 to Week 62) ...................................................................................34
6.1.3
Post-Treatment Period (Week 63 to Week 74) or Early Termination.......................................34
6.2
Study Assessments ....................................................................................................................35
6.2.1
Capacity to Consent...................................................................................................................35
6.2.2
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................................................35
6.2.3
Vital Signs Measurement...........................................................................................................35
6.2.3.1 Seated Blood Pressure Measurement.......................................................................................35
6.2.3.2 Standing Blood Pressure Measurement for Orthostatic Assessment.......................................36
6.2.4
Electrocardiogram.....................................................................................................................36
6.2.5
Physical Measurements (Height and Weight)...........................................................................36
6.2.6
Physical/Neurological Examination...........................................................................................36
6.2.7
Electrophysiological Assessments.............................................................................................36
6.2.8
Neuroimaging Assessments ......................................................................................................37
37
37
37
38
38
38
38
6.2.13 HD Cognitive Battery.................................................................................................................39
39
39
39
39
40


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
5
40
40
40
40
40
41
41
41
41
42
42
42
42
6.2.18 Collection of CSF........................................................................................................................42
6.2.19 Laboratory Assessments............................................................................................................42
6.2.19.1
Plasma and Serum Laboratory Assessments .......................................................................43
6.2.19.2
CSF Laboratory Assessments................................................................................................43
6.2.19.3
Urine Laboratory Assessments ............................................................................................43
6.2.20 Pregnancy Testing .....................................................................................................................43
6.3
Restriction on the Lifestyle of Patients .....................................................................................43
6.3.1
Contraception Requirements....................................................................................................43
6.3.2
Other Requirements..................................................................................................................45
7.
STUDY DRUG.............................................................................................................................45
7.1
Study Drug Description..............................................................................................................45
 
45
7.1.2
Roche Study Drug Provision after Change in Sponsor (Protocol 
BN40697, Amendment 4 and Subsequent Versions).................................................46
7.2
Packaging and Labeling .............................................................................................................46
7.2.1
Packaging and Labeling until Change in Sponsor (Original Protocol 
ISIS 443139-CS2 and Amendments 13) .......................................................................46
7.2.2
Packaging and Labeling after Change in Sponsor (Protocol BN40697, 
Amendment 4 and Subsequent Versions) ....................................................................47
7.3
Study Drug Accountability.........................................................................................................47
8.
TREATMENT OF PATIENTS ..................................................................................................47
8.1
Study Drug Administration........................................................................................................47


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
6
8.2
Other Protocol-Required Drugs.................................................................................................47
8.3
Other Protocol-Required Treatment Procedures......................................................................47
8.4
Treatment Precautions..............................................................................................................48
8.5
Safety Monitoring Rules............................................................................................................48
8.6
Stopping Rules...........................................................................................................................48
8.7
Adjustment of Dose and/or Treatment Schedule.....................................................................48
8.8
Discontinuation of Study Drug ..................................................................................................48
8.9
Withdrawal of Patients from the Study ....................................................................................49
8.10
Access to Treatment after Study Completion ....................................................................49
8.11
Concomitant Therapy and Procedures......................................................................................50
8.11.1 Concomitant Therapy................................................................................................................50
8.11.2 Concomitant Procedures...........................................................................................................52
8.12
Treatment Compliance..............................................................................................................52
9.
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING....................................52
9.1
Sponsor Review of Safety Information......................................................................................52
9.2
Regulatory Requirements..........................................................................................................52
9.3
Definitions .................................................................................................................................53
9.3.1
Adverse Event............................................................................................................................53
9.3.2
Adverse Reaction and Suspected Adverse Reaction.................................................................53
9.3.3
Serious Adverse Event (SAE)......................................................................................................53
9.4
Monitoring and Recording Adverse Events...............................................................................54
9.4.1
Serious Adverse Events .............................................................................................................54
9.4.2
Non-Serious Adverse Events .....................................................................................................54
9.4.3
Evaluation of Adverse Events (Serious and Non-Serious).........................................................54
9.4.3.1 Relationship to the Study Drug .................................................................................................55
9.4.3.2 Severity......................................................................................................................................55
9.4.3.3 Action Taken with Study Drug...................................................................................................55
9.4.3.4 Treatment Given for Adverse Event..........................................................................................56
9.4.3.5 Outcome of the Adverse Event .................................................................................................56
9.5
Procedures for Handling Special Situations ..............................................................................56
9.5.1
Abnormalities of Laboratory Tests............................................................................................56
9.5.2
Prescheduled or Elective Procedures or Routinely Scheduled Treatments..............................57
9.5.3
Dosing Errors .............................................................................................................................57
9.5.4
Contraception and Pregnancy...................................................................................................57
10.
STATISTICAL CONSIDERATIONS .......................................................................................58
10.1
Study Endpoints, Subsets, and Covariates ................................................................................58


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
7
10.1.1 Safety and Tolerability Endpoints..............................................................................................58
10.1.2 Pharmacokinetic Endpoints.......................................................................................................59
10.1.3 Pharmacodynamic and Clinical Endpoints ................................................................................59
10.2
Sample Size Considerations.......................................................................................................60
10.3
Populations................................................................................................................................60
10.4
Definition of Baseline ................................................................................................................60
10.5
Interim Analysis.........................................................................................................................61
10.6
Planned Methods of Analysis....................................................................................................61
10.6.1 Demographic and Baseline Characteristics...............................................................................61
10.6.2 Safety Analysis...........................................................................................................................61
10.6.3 Pharmacokinetic Analysis..........................................................................................................62
10.6.4 Pharmacodynamic and Clinical Analysis....................................................................................62
11.
INVESTIGATOR’S REGULATORY OBLIGATIONS..........................................................62
11.1
Informed Consent......................................................................................................................62
11.2
Ethical Conduct of the Study.....................................................................................................63
11.3
Independent Ethics Committee/Institutional Review Board ....................................................63
11.4
Patient Confidentiality...............................................................................................................64
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..............................................................64
12.1
Protocol Amendments...............................................................................................................64
12.2
Study Termination.....................................................................................................................64
12.3
Study Documentation and Storage ...........................................................................................65
12.4
Study Monitoring.......................................................................................................................65
12.5
Language ...................................................................................................................................66
12.6
Compensation for Injury............................................................................................................66
13.
REFERENCES.............................................................................................................................67
14.
APPENDICES..............................................................................................................................72
Appendix A
Schedule of Procedures..............................................................................................73
Appendix B List of Laboratory Analytes..................................................................................................79
Appendix C PK Sampling Schedule .........................................................................................................82
Appendix D
Grading Scale for Adverse Events Relating to Laboratory Abnormalities..................84
LIST OF TABLES
Page
45
                
46


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
8
LIST OF FIGURES
Page
26


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
9
PROTOCOL AMENDMENT
Protocol Number:
BN40697 (ISIS 443139-CS2)
Protocol Title:
An Open-Label Extension Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
RO7234292 (ISIS 443139) in Huntington’s Disease Patients Who 
Participated in Prior Investigational Studies of RO7234292 (ISIS 
443139)
Amendment Number:
Amendment 4 (Version 5)
Protocol BN40697 (previously referred to as ISIS 443139-CS2) has been amended to change the 
Sponsor and include a new study drug manufacturer, to make a provision for access to 
treatment following completion of the study, and to collect or generate a Huntington's disease 
identification number (HDID) number for participating patients.  Changes to the protocol, along 
with a rationale for each change, are summarized below:

F. Hoffmann-La Roche Ltd has taken over the future development of study drug RO7234292 
(previously ISIS 443139) from Ionis Pharmaceuticals, Inc.  As a consequence, the study drug 
name has changed from ISIS 443139 to RO7234292, and the study drug will be 
manufactured and packaged by F. Hoffmann-La Roche Ltd (Sections 7.1 and 7.2 and 
throughout the protocol).  With the change in Sponsor, a new Medical Monitor will be 
assigned. 

The protocol has been updated to make a provision for post-trial access to treatment 
through an open-label extension study (Study BN40955) (Section 8.10).  

In addition, a provision has been made for the collection of patients' HDID numbers to 
enable data between this study and other studies and registries to be linked (Sections 6.3.2
and 11.4).

Protocol version numbering has been changed throughout to align with the Sponsor's 
numbering convention.
Revisions from a previous country-specific amendment (Amendment 3, Canada) have been 
incorporated into Amendment 4 (Version 5) as outlined below:

Additional clarity has been added around the platelet exclusion criteria, so patients are not 
unnecessarily excluded (Section 5.2).
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.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
10
PROTOCOL SYNOPSIS
Protocol Title
An Open-Label Extension Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of RO7234292 (ISIS 443139) in 
Huntington’s Disease Patients Who Participated in Prior Investigational 
Studies of RO7234292 (ISIS 443139)
Study Phase
2
Indication
Huntington’s disease
Primary Objective
To evaluate the safety and tolerability of monthly and bimonthly (every other 
month) intrathecal (IT) bolus administrations of RO7234292 to patients with 
Huntington’s disease (HD).
Secondary Objectives
To characterize the cerebrospinal fluid (CSF) pharmacokinetics of monthly 
and bimonthly IT doses of RO7234292.
To explore effects of monthly and bimonthly IT doses of RO7234292 on key 
pharmacodynamic biomarkers and clinical endpoints relevant to HD, 
including:

Mutant Htt protein level in CSF

Structural MRI (ventricular, caudate and whole brain volumes)

Quantitative electroencephalography

Assessments of physical functioning, activities of daily living, gait, 
mobility and cognitive functioning
Study Design
This is an open-label extension (OLE) of Study ISIS 443139-CS1.  
Study ISIS 443139-CS1 was a multiple-ascending dose (MAD) study in 
46 patients with early manifest HD aged 25-65 years, inclusive.  In the MAD 
study, patients received 4 doses of ISIS 443139 or placebo.  Eligibility for 
Study BN40697 (ISIS 443139-CS2) is based on completion of the 4-dose 
Treatment Period of the prior MAD study and absence of deterioration in 
health or intervening activities that would introduce risk to the patient 
sufficient to preclude participation in the OLE.
This is a multi-center study with study duration of up to 18 calendar months.  
Two (2) dosing regimens will be tested – monthly and bimonthly.  
Randomization between regimens (1:1) will be stratified by Study Center.

“Monthly” regimen:  administrations of RO7234292 every 28 days for 
62 weeks (2-dose Loading Period followed by 14-dose Maintenance 
Period)

“Bimonthly” regimen:  2 administrations of RO7234292 separated by 
28 days (2-dose Loading Period) followed by administrations every 
56 days for 56 weeks (7-dose Maintenance Period)


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
11
PROTOCOL SYNOPSIS Continued
Study Design Continued
The RO7234292 doses used in these regimens will not exceed 120 mg/dose, 
the highest dose evaluated in the prior MAD study.
A final visit will be held approximately 14 weeks after the last dose.  
The extent of screening procedures required for this study varies depending 
on the amount of time that has elapsed between participation in the MAD 
study and the start of the OLE (see Appendix A, Schedule of Procedures).
Number of Subjects
Up to 46 (patients who previously participated in ISIS 443139-CS1)
Study Population
Inclusion Criteria
Signed Written Informed Consent
1.
Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all 
study requirements
2.
Must be capable of giving informed consent (in the opinion of the 
Investigator)
Target Population
3.
Must have completed the Treatment Period of Study ISIS 443139-CS1
4.
Able and willing to meet all study requirements in the opinion of the 
Investigator, including:
a.
Adequately supportive psychosocial circumstances 
b.
Have a trial partner who is reliable, competent and at least 
18 years of age, is willing to accompany the patient to select trial 
visits and to be available to the Study Center by phone if needed, 
and who (in the opinion of the Investigator) is and will remain 
sufficiently knowledgeable of patient’s ongoing condition to 
respond to Study Center inquiries about the patient, such as 
providing information related to HDWF and PBA-s
c.
Able to undergo MRI scans and able to tolerate them (e.g., no 
metal implants including MRI incompatible IUDs, chorea of a 
severity that precludes MRI scans or any condition that renders 
testing intolerable for the patient)
d.
Able to tolerate blood draws and lumbar puncture (LP)
e.
Stable medical, psychiatric and neurological status for at least 
12 weeks prior to Screening visit


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
12
PROTOCOL SYNOPSIS Continued
Study Population Continued
Reproductive Status
5.
Females must be non-pregnant, non-lactating and either
a.
surgically sterile (e.g., bilateral tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy);
b.
post-menopausal (defined as 12 months of spontaneous 
amenorrhea without an alternative medical cause and FSH levels 
in the postmenopausal range for the laboratory involved);
c.
abstinent* or,
d.
if engaged in sexual relations of child-bearing potential, agree to 
use highly effective contraception (refer to Section 6.3.1) from the 
time of signing the informed consent form until at least 5 months 
after the last dose of RO7234292
If not surgically sterile, must have a negative HCG pregnancy test at 
Screening visit and prior to each dose administration
Males must be surgically sterile, abstinent* or, if engaged in sexual 
relations with a female of child-bearing potential, must agree to use an 
acceptable contraceptive method (refer to Section 6.3.1) from the time 
of signing the informed consent form until at least 5 months after the 
last dose of RO7234292
*
Abstinence is only acceptable as true abstinence, i.e., when this is in 
line with the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a trial and withdrawal are not 
acceptable methods of contraception
Exclusion Criteria
Prohibited and Restricted Medications and Procedures
1.
Treatment with an investigational drug (other than ISIS 443139 in 
Study ISIS 443139-CS1), biological agent, or device within 1 month of 
Screening, or 5 half-lives of investigational agent, whichever is longer.  
Concurrent or planned concurrent participation in any clinical study 
(including observational and non-interventional studies) without 
approval of the Sponsor Medical Monitor
2.
Antiplatelet or anticoagulant therapy within the 14 days prior to first 
lumbar puncture in the study or anticipated use during the study, 
including but not limited to aspirin (unless ≤81 mg/day), clopidogrel, 
dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
3.
Prior treatment with an antisense oligonucleotide including siRNA 
(other than ISIS 443139 in Study ISIS 443139-CS1)
4.
Presence of an implanted shunt for the drainage of CSF or an 
implanted CNS catheter


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
13
PROTOCOL SYNOPSIS Continued
Study Population Continued
Medical History and Concurrent Disease
5.
Clinically-relevant hematological, hepatic, cardiac or renal disease or 
event.  Clinically-significant abnormal hepatic, renal or hematology lab 
tests at Screening must be discussed with the Sponsor Medical 
Monitor
6.
Malignancy within 5 years of Screening, except for basal or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix that has 
been successfully treated
7.
Any condition that significantly increases risk of meningitis unless 
patient is receiving appropriate prophylactic treatment
8.
History of bleeding diathesis or coagulopathy, platelet count < LLN 
unless stable and assessed by the Investigator and Sponsor Medical 
Monitor to be not clinically significant
9.
Have any other condition which, in the opinion of the Investigator or 
Sponsor, would make the patient unsuitable for inclusion or could interfere 
with the patient participating in or completing the study
Treatment Groups
Patients will receive RO7234292 as part of the Monthly Cohort or the 
Bimonthly Cohort.

Monthly Cohort:  administrations of RO7234292 every 28 days for 
62 weeks (2-dose Loading Period followed by 14-dose Maintenance 
Period)

Bimonthly Cohort:  2 administrations of RO7234292 separated by 
28 days (2-dose Loading Period) followed by administrations every 
56 days for 56 weeks (7-dose Maintenance Period)
Study Drug Dosage and 
Administration
The RO7234292 doses used in this study will not exceed 120 mg/dose, the 
highest dose evaluated in the prior MAD study (ISIS 443139-CS1).
Each dose of RO7234292 will be administered as a single IT bolus injection.  
Administration will be via lumbar puncture using a needle inserted into the 
L3/L4 space, although placement at a different level (either in the space 
above or the space below) is allowed if patient anatomy or clinical judgment 
dictates.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
14
PROTOCOL SYNOPSIS Continued
Rationale for Dose and Schedule 
Selection
RO7234292 dose levels will be selected based on safety, pharmacokinetic 
and pharmacodynamic data generated in the prior MAD study 
(Study ISIS 443139-CS1), with interpretation of the pharmacological 
relevance of the doses aided by comparison to expected effects based on 
preclinical pharmacokinetic/pharmacodynamic modeling.
 
 
 
 
 
 
 
 
Two (2) dosing regimens will be tested: the monthly regimen and the 
bimonthly regimen, defined above.  Monthly dosing is expected to achieve 
steady state RO7234292 in the brain cortex tissue by Study Day 92 (i.e., after 
4 doses).  Bimonthly dosing (after 2 monthly doses to serve as a load) will be 
investigated to determine if sufficient pharmacological effect can be achieved 
with a less-frequent dosing regimen.
Adjustment of Dose and/or 
Treatment Schedule
Dose regimen adjustments are not planned.  Any observation in a patient that 
causes the Investigator to propose a change in dose level or frequency must 
be discussed with the Sponsor Medical Monitor.
Study Visit Schedule and 
Procedures
After informed consent is obtained, patients will undergo necessary screening 
procedures within a 4-week period.  Patients who meet the eligibility criteria 
will visit the Study Center on Study Day -1 to undergo baseline clinical, blood, 
and electrophysiological evaluations.  On Study Day 1, patients will be 
admitted to the Study Center, undergo pre-dose evaluations and receive an 
IT bolus injection of RO7234292.  Following this IT injection, patients will be 
kept at the Study Center for at least 24 hours and carefully monitored for any 
adverse clinical symptoms or signs.  Assessments during the admission 
period include neurological examination, vital signs, ECGs, blood sampling, 
urine collection and clinical laboratory analyses.  At subsequent dosing visits, 
patients will be monitored for at least 5 hours post-dosing prior to discharge 
from the Study Center.  
RO7234292 administration will take place every 28 days during the Loading 
Period and then either every 28 days or every 56 days during the 
Maintenance Period, according to patient randomization.  
The Study Center will monitor the patient’s condition via telephone between 
clinic study visits.  During the Post-Treatment Period, patients will visit the 
Study Center once (on Study Day 519) for in-clinic assessments.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
15
PROTOCOL SYNOPSIS Continued
Study Visit Schedule and 
Procedures Continued
CSF samples will be taken at the Screening visit, pre-dose on each injection 
day and at the Post-Treatment visit.  These samples will be utilized for 
evaluation of pharmacokinetics, Htt protein and other biomarker and 
laboratory analyses.
If a patient terminates early from the Loading or Maintenance Period, he/she 
will be encouraged to return for the Post-Treatment Period visit (Day 519) 
approximately 14 weeks after last administration of RO7234292.
Safety and Tolerability 
Evaluations
Safety and tolerability evaluations include:

Columbia - Suicide Severity Rating Scale (C-SSRS)

Physical examination and standard neurological assessment (including 
fundi)

Pregnancy testing

Vital signs (HR, BP, orthostatic changes, weight)

ECG

AEs and concomitant medications

CSF safety labs (cell counts, protein, glucose)

Plasma laboratory tests (clinical chemistry, hematology)

Urinalysis

Neuroimaging assessments (safety sequences) 
The safety and tolerability of RO7234292 will be assessed by determining the 
incidence, severity and dose-relationships of AEs, ECG changes and 
changes in laboratory parameters by dose.  
Pharmacokinetic Evaluations
CSF 
 samples will be used for evaluation of pharmacokinetic 
parameters.  
Concentration of RO7234292 in CSF will be summarized using descriptive 
statistics and the RO7234292 half-life in CSF will be calculated, if possible.  
 
 
  Concentration of RO7234292 in urine 
following first dose will be summarized.
Pharmacodynamic and Clinical 
Evaluations
Pharmacodynamic and clinical evaluations include:

Mutant Htt protein level in CSF and other plausible fluid biomarkers of 
Huntington’s disease progression

Structural MRI (ventricular, caudate and whole brain volumes),
 
 

Quantitative electroencephalography

Assessments of physical functioning, activities of daily living, gait, 
mobility, cognitive functioning and neuropsychiatric condition


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
16
PROTOCOL SYNOPSIS Continued
Pharmacodynamic and Clinical 
Evaluations Continued
 
 
 
Evaluations will include comparisons between Monthly and Bimonthly 
Cohorts, where appropriate, and correlations between pharmacokinetic and 
pharmacodynamic parameters.
Statistical Considerations
The sample size is dictated by the number of patients enrolled in the prior 
MAD study (Study ISIS 443139-CS1).  Based on experience with generation 
2 ASOs administered by IT injection, this number of patients (N ≈46) is 
expected to be sufficient to ensure that the safety, tolerability, 
pharmacokinetics and pharmacodynamics are adequately assessed.
Sponsor
F. Hoffmann-La Roche Ltd




BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
18
COHORT DOSING REGIMENS


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
19
STUDY GLOSSARY
Abbreviation
Definition
2ʹ-MOE
2ʹ-O-(2-methoxyethyl)
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AP
Anterior-posterior
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase (SGOT)
βhCG
Beta-subunit of human chorionic gonadotropin (pregnancy test)
Bimonthly
Every other month
BP
Blood pressure
BUN
Blood urea nitrogen
cl
clinic
CRF
Case report form
CSF
Cerebrospinal fluid
C-SSRS
Columbia suicide severity rating scale
CTCAE
Common Terminology Criteria for Adverse Events 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EEG
Electroencephalogram
FSE
Fast spin echo
GCP
Good Clinical Practice
HD
Huntington’s disease
HDID
Huntington's disease identification number
HDWF
Huntington’s disease work function
Htt
Huntingtin / Htt protein
HR
Heart rate
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
20
IL-1β
Interleukin-1 beta
IMP
investigational medicinal product
INR
International normalized ratio
IRB
Institutional Review Board
IT
Intrathecal(ly)
MAD
Multiple-ascending dose
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
NCS
Not clinically-significant
OLE
Open-label extension
on Study
The patient is ‘on Study’ from signing of the informed consent until his/her last 
study visit
OTS
One touch stockings
pH
Measure of the acidity or basicity of a solution
ph
phone
PK
Pharmacokinetic(s)
PBA-s
Problems behavior assessment for Huntington’s disease – short form
PT
Prothrombin time
qEEG
Quantitative EEG
RO7234292
Antisense inhibitor of HTT, previously known as ISIS 443139
RNase H1
Ribonuclease H1 (a non-specific endonuclease and catalyzes the cleavage of 
RNA via a hydrolytic mechanism)
SAE
Serious adverse event
siRNA
Small interfering ribonucleic acid


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
21
SAP
Statistical Analysis Plan
Study Day 1
Defined as the first day Study Drug is administered to the patient
Study Drug
RO7234292 (previously known as ISIS 443139)
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
TFC
Total functional capacity
TMS
Total motor scale
TSE
Turbo spin echo
UHDRS
Unified Huntington’s disease rating scale
WBC
White blood cell


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
22
1.
OBJECTIVES
1.1
Primary Objectives
To evaluate the safety and tolerability of monthly and bimonthly (every other month) 
intrathecal (IT) bolus administrations of RO7234292 to patients with Huntington’s disease 
(HD).
1.2
Secondary Objectives
To characterize the cerebrospinal fluid (CSF) pharmacokinetics of monthly and bimonthly IT
doses of RO7234292.
To explore effects of monthly and bimonthly IT doses of RO7234292 on key pharmacodynamic 
biomarkers and clinical endpoints relevant to HD, including:

Mutant huntingtin protein (mutant Htt) level in CSF

Structural MRI (ventricular, caudate and whole brain volumes)

Quantitative electroencephalography

Assessments of physical functioning, activities of daily living, gait, balance, mobility, and 
cognitive functioning
 
 
2.
BACKGROUND AND RATIONALE
2.1
Overview of Disease
2.1.1
Epidemiology
Huntington’s disease is an autosomal dominant neurodegenerative disease.  The prevalence is
approximately 5.7 per 100,000 in Europe and North America (Pringsheim et al. 2012), with the 
early onset/juvenile (Westphal variant or akinetic-rigid HD) form occurring in approximately 16% 
of all cases (Shoulson and Young 2011).  Huntington’s disease 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 (Htt).  Above 35 CAG repeats, the age of HD
onset is inversely correlated with the length of the expansion (Duyao et al. 1993).  Variable 
age-dependent penetrance occurs between 36 and 39 CAG repeats, and full penetrance occurs 
at 40 or more repeats (Langbehn et al. 2004).


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
23
2.1.2
Huntingtin Protein
While the exact function of Htt protein has been elusive, studies suggest that it has an essential 
role in the earliest stages of embryogenesis (Duyao et al. 1995; Nasir et al. 1995; 
Zeitlin et al. 1995; White et al. 1997; Ismailoglu et al. 2014).  Many pathogenic mechanisms have 
been hypothesized for the apparent toxic gain-of-function of this polyglutamine-expanded 
protein, including abnormalities in cellular proteostasis, altered gene transcription, 
mitochondrial dysfunction and oxidative stress, excitotoxicity, synaptic and neuronal failure, 
deficient axonal transport, spread of mutant Htt protein from cell-to-cell in a prion-like fashion 
and loss of trophic support (for reviews see Kuermmerle et al. 1999; Moumné et al. 2013; Ross 
et al. 2014).  Mutant HTT messenger ribonucleic acid (mRNA) transcripts have also been shown 
to contribute to neuronal toxicity (Bañez-Coronel et al. 2012).
2.1.3
Clinical Features and Diagnosis of HD
Huntington’s disease classically manifests with a triad of signs and symptoms, including motor, 
cognitive and behavioral features (Huntington 1872; Folstein 1989).  Motor and cognitive 
symptoms, including chorea, dystonia, bradykinesia, rigidity and executive function deficits, 
usually progress over time (Huntington Study Group 1996; Hogarth et al. 2005; Paulsen et al. 
2013; Papoutsi et al. 2014).  Behavioral features, including emotional disorders and personality 
changes, are not universal and do not usually progress steadily over time (Ross et al. 2014).
Although genetic testing can be used to identify individuals who will develop the disease, the 
actual diagnosis of HD occurs when an expert clinician judges that the motor abnormalities
observed are ≥99% likely due to HD or when the patient exhibits “the unequivocal presence of
an otherwise unexplained extrapyramidal movement disorder” (Huntington Study Group 1996; 
Hogarth et al. 2005).  Motor onset is one of the more robust and consistently-agreed disease 
features among the considerable diagnostic heterogeneity of the disease.  However, 
phenoconversion cannot be interpreted as a simple dichotomy between sick and unwell, as 
disease onset is really a process that occurs gradually over years or even decades.  
Neurodegeneration is evident in functional brain imaging studies in patients long before 
diagnosis, suggesting that the brain undergoes functional reorganization in response to 
neurodegeneration to preserve motor and cognitive performance (Papoutsi et al. 2014).
Individuals with HD can be categorized as having either premanifest disease (prior to motor 
symptom onset) or manifest disease (diagnosed based on motor symptom onset).  The 
premanifest disease period can be subdivided into presymptomatic and prodromal periods.  
During the presymptomatic period, typically spanning 10-15 years prior to disease onset, 
individuals are not clinically distinguishable from controls (i.e., individuals without the HD gene 
mutation).  During the prodromal period, subtle motor changes and variable cognitive and 
behavioral changes appear but are not sufficient to make the diagnosis of HD.
Manifest disease, the period of disease beginning at HD diagnosis, typically lasts for 10-20 years
and is characterized by motor and cognitive changes that progress inexorably over the course of 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
24
the illness until death.  The manifest disease period can be subdivided into 5 stages based on 
evolving changes in motor symptoms and functional capacity (Ross et al. 2014).  Stage 1 
represents the highest level of capacity and is characterized by mild or no incapacity in terms of 
independence in daily activities, managing personal finances and ability to maintain 
employment; Stage 5 represents severe disability and dependence on full-time care 
(Shoulson and Fahn 1979).  The 5 stages also correlate with score on the Unified Huntington’s 
Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) Scale, with Stage 1 corresponding 
to TFC scores of 11-13, Stage 2 to scores of 7-10, Stage 3 to scores of 3-6, Stage 4 to scores of 1-
2 and Stage 5 to a score of 0 (Shoulson et al. 1989).  Early stage HD (Stage 1 and 2) is generally 
characterized by involuntary movements of the face, fingers, feet or thorax with progressive 
emotional, psychiatric and cognitive disturbances (Folstein 1989).  Early neuropsychiatric 
symptoms include anxiety, apathy, disinhibited behavior, anhedonia, obsessive behaviors and 
irritability (Craufurd et al. 2001).  The most frequent psychiatric symptom is depression, and HD 
patients are at an increased risk for suicidal ideation (Craufurd et al. 2001).  Patients may 
experience weight loss, alterations in sexual behavior and disturbances in the wake-sleep cycle 
(Petersen et al. 2005).  Less commonly, delusions and hallucinations emerge (Paulsen et al. 
2001).  As the disease progresses, cognitive impairments are marked by a decline in executive 
functioning affecting judgment, insight and the ability to organize, eventually impairing all 
aspects of cognition (Walker 2007; Roos 2010; Sturrock and Leavitt 2010).  Motor disturbances 
in later stages of the disease include chorea, speech and swallowing difficulties, rigidity, 
bradykinesia and akinesia (Roos 2010).  Oral motor dysfunction eventually leads to incoherence 
of speech and inability to eat (Sturrock and Leavitt 2010).  Over time, relentless cognitive and 
physical deterioration forces patients to become dependent on full-time care.  Pneumonia, 
followed by suicide, is the most common cause of death (Roos 2010).
2.1.4
Treatments for HD
Treatments for HD are limited.  There are no therapies that can delay the onset of the disease or 
slow its progression, so current treatments aim to reduce the burden of symptoms, maximize 
function and benefit the patient’s quality of life (Nance et al. 2011).
Symptomatic treatment options are tailored to the individual patient’s symptoms and stage of 
disease progression, however patients with HD are highly vulnerable to side effects, particularly 
cognitive side effects, of medications.
Tetrabenazine (e.g., Xenazine®, Tetmodis®) and deutetrabenazine (AustedoTM), vesicular 
monoamine transporter 2 inhibitors, are the only drugs currently approved for HD, with labels 
specific for the treatment of chorea associated with Huntington’s disease.  Tetrabenazine is 
approved in the United States, New Zealand, Australia, Canada, Israel and some European 
countries.  Deutetrabenazine is approved in the United States.  These drugs have been linked to 
many significant adverse events (AEs), including Parkinsonism, akathisia, sedation, depression 
and suicidal thoughts (Xenazine label 2011; Austedo label 2017).  They are contraindicated in 
patients who are actively suicidal and in patients with untreated or inadequately treated 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
25
depression, a population that includes approximately > 40% of HD patients (Chen et al. 2012).  
Additionally, they may prolong the corrected QT interval, and caution is advised when used in 
combination with other drugs or medical conditions that potentially prolong the QTc.
Other medications are utilized in HD to address particular symptoms, such as antidepressants 
(for depression, agitation, irritability), anticonvulsants (for irritability, impulsive behavior), 
anxiolytics (for anxiety), cognitive enhancing agents (for cognitive disturbances) and 
neuroleptics (for chorea) (Paulson and Albin 2011).  To date, no treatment has been shown to 
delay the onset of HD or to slow its progression.
2.2
Therapeutic Rationale
There are currently no treatments that cure or modify HD progression.  Neuropathological 
abnormalities in HD appear to be the consequence of a toxic gain-of-function of the mutant 
huntingtin protein (mutant Htt) (Wexler et al. 1987; Walker 2007; Moumné et al. 2013).  A
therapy that reduces synthesis of the toxic mutant protein would directly target the primary 
disease mechanism.  Because the genetic origin of HD is localized to just 1 gene, inhibiting HTT
expression is a promising therapeutic option (Stanek et al. 2013).
RO7234292 is being developed to reduce the synthesis of Htt protein by targeting HTT mRNA 
and directing its catalytic degradation through the action of ribonuclease H1 (RNase H1), an 
endogenous enzyme present in most mammalian cells (Crooke and Bennett 1996;
Cerritelli and Crouch 2009), including cells of interest in the CNS (e.g., neurons and glia).  
Reduction of mutant HTT gene mRNA, which limits translation of the mutant huntingtin protein,
could potentially inhibit all downstream toxic effects and generate sustained reversal in HD
symptoms.
Pharmacology data support selective targeting of HTT mRNA transcripts as a potentially safe and 
effective mechanism for the treatment of HD.  Using ASOs targeting human HTT mRNA in 
rodents and non-human primates, significant reduction of mutant HTT mRNA transcripts, 
wild-type HTT mRNA transcripts and mutant Htt protein has been achieved throughout most 
brain regions (Kordasiewicz et al. 2012).  Furthermore, transient delivery of these ASOs in
transgenic mouse models of HD delayed disease progression and mediated a sustained reversal 
of disease phenotype that persisted longer than HTT mRNA knockdown (Kordasiewiecz et al. 
2012; Stanek et al. 2013).  Detailed descriptions of these studies are available in the 
Investigator’s Brochure.
The known potential risks associated with RO7234292 are elaborated on in the Guidance to 
Investigator section of the Investigator’s Brochure.  Additional study associated risks related to 
the lumbar puncture (LP) procedure are also described in the Guidance to Investigator section of 
the Investigator’s Brochure.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
26
2.3
RO7234292
2.3.1
Mechanism of Action
RO7234292 is a second-generation antisense oligonucleotide drug targeted to the huntingtin
gene (HTT).  It is complementary to a nucleotide sequence in the HTT mRNA transcript and binds 
to the mRNA by Watson and Crick base pairing.  The hybridization (binding) of RO7234292 to 
the cognate mRNA results in the RNase H1-mediated degradation of the HTT mRNA, thus 
preventing production of the Htt protein.  Both wild-type and mutant HTT mRNA are targeted by 
RO7234292.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
27
 
 
 
 
 
 
 
 
 
 
 
 
2.3.4
Clinical Experience
A first-in-human, Phase 1 clinical study of RO7234292 is complete.  In this study, the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple ascending doses of 
RO7234292 administered IT to patients with early manifest HD were assessed in a double-blind 
placebo-controlled manner.  Based on data review by the Sponsor and the study’s Data Safety 
Monitoring Board, available safety, PK and exploratory PD findings support initiation of
Study BN40697, an open-label extension study for patients who participated in 
Study ISIS 443139-CS1.
2.4
Rationale for Study Design
The proposed study will test the safety, tolerability, PK and PD of multiple doses of RO7234292
administered as IT injections.  Two (2) dose regimens will be evaluated.  The dose utilized will 
not exceed the highest dose level found to be well-tolerated in the prior first-in-human study.  
The length of the Maintenance Period (56 weeks) was selected to provide sufficient duration for 
meaningful evaluation of imaging and clinical measures relevant to HD.
ISIS 443139 dose levels evaluated in the prior study, Study ISIS 443139-CS1, were 10, 30, 60, 90 
and 120 mg/dose.  These doses were selected based on preclinical toxicology and 
pharmacokinetic observations from monkey studies utilizing repeat dosing (for 13 weeks) IT 
administration and consideration of the target tissue concentration anticipated for drug 
pharmacology.  
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
28
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The dose interval for the loading period (i.e., administration every 28 days) was selected based 
on the nonclinical pharmacokinetic and pharmacodynamic (HTT mRNA reduction) data required 
to achieve RO7234292 brain cortex tissue levels that are predicted to be at steady state by 
Day 92 and to achieve reduction in HTT mRNA levels.  Monthly dosing is expected to be safe and 
well-tolerated by patients, and continued monthly dosing is predicted to produce prolonged 
suppression of HTT mRNA and Htt protein.  Bimonthly dosing (after 2 monthly doses to serve as 
a load) will be investigated to determine if sufficient pharmacological effect can be achieved 
with a less-frequent dosing regimen.
Additional details on dose scaling and expected CSF and tissue concentrations are summarized 
in the Investigator’s Brochure.
2.5
Risk Assessment
The known potential risks to study participants associated with IT administration of 
RO7234292 are elaborated on in the Guidance to Investigator section of the Investigator’s 
Brochure.  
In brief, there are no apparently deleterious effects associated with reduction of HTT mRNA in 
normal adult mice or adult non-human primate (McBride et al. 2008; Boudreau et al. 2009; 
Drouet et al. 2009; McBride et al. 2011; Kordasiewicz et al. 2012).  No abnormal behavioral 
deficits appear to result from heterozygous HTT inactivation by translocation in man, i.e., a 50% 
reduction in expression of the normal gene product (Ambrose et al. 1994); and silencing of both 
mutant HTT and wild-type HTT appears to dramatically improve HD-related behavioral 
abnormalities in HD mice models (Kordasiewicz et al. 2012).  


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
29
Intrathecal administration of RO7234292 requires lumbar puncture (LP), which is associated 
with known risk for post-LP injection syndrome (e.g., headaches, nausea, vomiting, nerve 
irritation pain).  Headache is the most common symptom, affecting up to 5-30% of participants.  
Headache usually resolves spontaneously within a few days, but in a minority of patients the 
headache can persist for weeks if untreated (Vandam and Dripps 1956; Costigan and Sprigge 
1996; Turnbull and Shepherd 2003).  The very rare risk for events of infection (e.g., meningitis) 
and hemorrhage (e.g., spinal hematoma) following LP are mitigated by protocol 
inclusion/exclusion criteria and study procedures.
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with RO7234292 are justified by the anticipated 
benefits that may be afforded to patients with HD.
3.
EXPERIMENTAL PLAN
3.1
Study Design
This study is an OLE for patients who participated in Study ISIS 443139-CS1.  Study ISIS 443139-
CS1 was a multiple-ascending dose (MAD) study in 46 patients with early manifest HD aged 25-
65 years, inclusive.  In the MAD study, patients received 4 doses of ISIS 443139 or placebo.  
Eligibility for Study BN40697 is based on completion of the 4-dose Treatment Period of the 
prior MAD study and absence of deterioration in health or intervening activities that would 
introduce risk to the patient sufficient to preclude participation in the OLE.
The study consists of 2 cohorts: a “Monthly Cohort” and a “Bimonthly Cohort”.  Both cohorts 
receive 2 doses of RO7234292 during the Loading Period, with doses 28 days apart.  In the 
Maintenance Period, the Monthly Cohort continues to receive doses at 28-day intervals (14 
doses over 56 weeks) and the Bimonthly Cohort receives doses at 56-day intervals (7 doses over 
56 weeks).  Patients will be randomized (1:1) to either the Monthly Cohort of the Bimonthly 
Cohort, with randomization stratified by Study Center.  The cohorts will be enrolled 
concurrently.
3.2
Number of Study Centers
This study will be conducted at multiple centers worldwide.
3.3
Number of Patients
Up to 46 patients are planned to be enrolled in this study.
3.4
Overall Study Duration and Follow-up
The overall study duration will be approximately 18 calendar months.  The study will consist of a 
2-4-week Screening Period, a 6-week Loading Period, a 56-week Maintenance Period and a 12-
week Post-Treatment Period (for patients who will not enter the OLE Study BN40955).  
Please refer to the Schedule of Procedures in Appendix A.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
30
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study 
Medical Monitor in consultation with the Investigator.
3.4.1
Screening Period
Patient eligibility for the study will be determined within 4 weeks prior to patient entry into the 
Treatment Period.
3.4.2
Treatment Period
Eligible patients will report to the Study Center for administration of RO7234292 and for 
additional, non-dosing visits as described in the Schedule of Procedures in Appendix A.  The 
Treatment Period consists of a 6-week Loading Period, in which all patients receive 2 doses of 
RO7234292 at 28-day intervals, and a 56-week Maintenance Period, in which the Monthly 
Cohort receives doses at 28-day intervals (14 doses over 56 weeks) and the Bimonthly Cohort 
receives doses at 56-day intervals (7 doses over 56 weeks).
3.4.3
Post-Treatment Period
After completing study treatment in Study BN40697, the patient will be eligible to 
enroll in another OLE study (BN40955) with active RO7234292 compound, provided 
the data from the ongoing RO7234292 program support continued development, the 
patient meets the inclusion and exclusion criteria for the OLE, and the OLE meets 
approval by the relevant competent authorities, IRBs, and ECs. 
Patients who will not enter the OLE study will return to the Study Center for one follow-up 
visit 14 weeks after the last dose of RO7234292.  The final study visit will be 
Study Day 428/Week 62 for patients who enter OLE Study BN40955 and Study Day
519/Week 74 for those patients who do not.
3.5
End-of-Study
The End-of-Study is defined as last patient, last study visit.
4.
PATIENT ENROLLMENT
4.1
Screening
Before patients may be enrolled into the Study, the Sponsor or designee requires a copy of the 
Study Center’s written Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
approval of the protocol, informed consent form, and all other patient information and/or 
recruitment material.
Patients must sign the consent form before any screening tests or assessments are performed.  
At the time of consent, the patient will be considered enrolled into the study and will be 
assigned a unique screening number before any study procedures, including screening 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
31
procedures, are performed.  Patients will also be assigned a unique patient identification 
number.  This number will be used to identify the patient throughout the trial and must be used 
on all study documentation related to that patient.  Each patient will be assigned to the same 
screening and patient identification numbers as in the prior MAD study (Study ISIS 443139-CS1).  
The screening number and patient identification number must remain constant throughout the 
entire study.  Screening numbers and patient identification numbers, once assigned, will not be 
re-used.
4.2
Randomization
A patient will be randomized after all Screening assessments have been completed and after the 
Investigator has verified that the patient is eligible per criteria in Sections 5.1 and 5.2.  No 
patient may begin treatment prior to randomization and assignment of a unique patient
identification number.
Eligible patients will be randomized centrally by an automated system to receive RO7234292
as part of the Monthly Cohort or the Bimonthly Cohort.  Randomization between regimens (1:1)
will be stratified by Study Center.
The Sponsor or designee will prepare the randomization list.
4.3
Replacement of Patients
Patients who withdraw from the study will not be replaced.
5.
PATIENT ELIGIBILITY
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time point specified in the individual eligibility criterion listed.
5.1
Inclusion Criteria
Signed Written Informed Consent
1.
Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements
2.
Must be capable of giving informed consent (in the opinion of the Investigator)
Target Population
3.
Must have completed the Treatment Period of Study ISIS 443139-CS1
4.
Able and willing to meet all study requirements in the opinion of the Investigator, 
including:
a.
Adequately supportive psychosocial circumstances 
b.
Have a trial partner who is reliable, competent and at least 18 years of age, is willing 
to accompany the patient to select trial visits and to be available to the Study Center 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
32
by phone if needed, and who (in the opinion of the Investigator) is and will remain 
sufficiently knowledgeable of patient’s ongoing condition to respond to Study 
Center inquiries about the patient, such as providing information related to HDWF 
and PBA-s.
c.
Able to undergo MRI scans and able to tolerate them (e.g., no metal implants 
including MRI incompatible IUDs, chorea of a severity that precludes MRI scans or 
any condition that renders testing intolerable for the patient)
d.
Able to tolerate blood draws and lumbar puncture (LP)
e.
Stable medical, psychiatric and neurological status for at least 12 weeks prior to 
Screening visit
Reproductive Status
5.
Females must be non-pregnant, non-lactating and either
a.
surgically sterile (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy);
b.
post-menopausal (defined as 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved);
c.
abstinent* or,
d.
if engaged in sexual relations of child-bearing potential, agree to use highly effective 
contraception (refer to Section 6.3.1) from the time of signing the informed consent 
form until at least 5 months after the last dose of RO7234292
If not surgically sterile, must have a negative HCG pregnancy test at Screening visit and 
prior to each dose administration
Males must be surgically sterile, abstinent* or, if engaged in sexual relations with a 
female of child-bearing potential, must agree to use an acceptable contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent form until 
at least 5 months after the last dose of RO7234292
* Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
33
5.2
Exclusion Criteria
Prohibited and Restricted Medications and Procedures
1.
Treatment with an investigational drug (other than ISIS 443139 in Study 
ISIS-443139-CS1), biological agent, or device within 1 month of Screening, or 5 half-lives 
of investigational agent, whichever is longer.  Concurrent or planned concurrent 
participation in any clinical study (including observational and non-interventional 
studies) without approval of the Sponsor Medical Monitor
2.
Antiplatelet or anticoagulant therapy within the 14 days prior to first lumbar puncture in 
the study or anticipated use during the study, including but not limited to aspirin (unless 
≤81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
3.
Prior treatment with an antisense oligonucleotide including small interfering ribonucleic 
acid (siRNA) (other than ISIS 443139 in Study ISIS 443139-CS1)
4.
Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
Medical History and Concurrent Disease
5.
Clinically-relevant hematological, hepatic, cardiac or renal disease or event.  
Clinically-significant abnormal hepatic, renal or hematology lab tests at Screening must 
be discussed with the Sponsor Medical Monitor
6.
Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix that has been successfully treated 
7.
Any condition that significantly increases risk of meningitis unless patient is receiving 
appropriate prophylactic treatment
8.
History of bleeding diathesis or coagulopathy, platelet count < LLN unless stable and 
assessed by the Investigator and Sponsor Medical Monitor to be not clinically 
significant
9.
Have any other condition which, in the opinion of the Investigator or Sponsor, would 
make the patient unsuitable for inclusion or could interfere with the patient 
participating in or completing the study
6.
STUDY PROCEDURES
6.1
Study Schedule
All required study procedures are outlined in Appendices A, B and C.  Additional patient visits 
may be scheduled if required for further evaluation of an abnormal laboratory value or a 
reported AE.
All reasonable attempts should be made to ensure compliance with the visit schedule and visit 
windows as outlined in Appendix A.  However, in the event that a visit does not occur or is 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
34
delayed, all subsequent visits should be calculated based on the time elapsed since Study Day 1 
rather than from the date of the previous visit.
6.1.1
Screening Period (Week -4 to Week -1)
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures.  During the Screening Period, 
inclusion/exclusion criteria will be evaluated to determine patient eligibility for the study.  A 
single CSF sample will be collected during the Screening Period.  At least 2 weeks must elapse 
between the screening CSF collection and Study Day 1.  Abnormal laboratory screening results 
may be retested for review by the Study Medical Monitor for eligibility purposes.
6.1.2
Treatment Period (Week 1 to Week 62)
During the Loading Period, RO7234292 will be administered 2 times, with doses separated by 
28 days.  During the Maintenance Period, RO7234292 will be administered either every 28 
days (Monthly Cohort) or every 56 days (Bimonthly Cohort) according to regimen assignment at 
randomization.
Eligible patients will report to the Study Center on Study Day -1 (the day prior to first 
RO7234292 administration) for baseline assessments.  Assessments should be completed at 
approximately the same time of day from visit to visit.  At the completion of assessments on 
Study Day -1, patients will be discharged unless the Investigator feels it is in the patient’s best 
interest for him/her to remain in the Study Center overnight.  Patients will return to the Study 
Center on Study Day 1 to undergo CSF sampling and RO7234292 administration via lumbar 
puncture, followed by overnight observation in the Study Center, safety assessments on Study 
Day 2 and then discharge.  On Study Day 3, the Study Center will conduct a brief visit with the 
patients by phone to capture any AEs or changes in concomitant medication usage.  (See 
Appendices A and C.)  On Study Day 8, the patients will return to the Study Center for additional 
assessments.
Subsequent RO7234292 administrations will be conducted in a similar manner, with pre-dose 
assessments conducted either the day before or the day of RO7234292 administration,
in-clinic observation of at least 5 hours after RO7234292 administration (longer or overnight if 
necessary for safety reasons) and in-clinic assessments or phone assessments on the days 
following RO7234292 administration.
All patients, regardless of cohort assignment, will appear at the Study Center at least every 
4 weeks throughout the Treatment Period for routine monitoring.
6.1.3
Post-Treatment Period (Week 63 to Week 74) or Early Termination
After completion of the Treatment Period, patients who do not enter the OLE Study 
BN40955 will enter the 12-week Post-Treatment Period.  This period consists of 1 Study Center 
visits during Week 74, as outlined in the Schedule of Procedures in Appendix A.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
35
Patients who terminate early from the study for a reason other than withdrawal of consent
should be encouraged to attend the final study visit (Study Day 519).  This visit should be 
conducted approximately 14 weeks after last administration of RO7234292.  (Also see 
Appendices A and C and Study Design and Treatment Schema.)
6.2
Study Assessments
All efforts should be made to adhere to a consistent order of assessments throughout the study.  
Patients should be permitted rest periods as needed to minimize testing fatigue.
6.2.1
Capacity to Consent
Patients’ capacity to consent to participation in the study will be assessed using the Evaluation 
to Sign Consent tool (DeRenzo et al. 1998).  This is a brief, 5-item questionnaire utilized by Study 
Center personnel during a targeted interview with the patient.  The patient responses to the 
questionnaire will not be collected by the Sponsor and are intended only to guide Study Center 
personnel in their evaluation of each potential patient’s capacity to consent.
6.2.2
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a structured tool to assess suicidal ideation and behavior.  Four (4) 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 (C-CASA) and meets the criteria 
listed in the recent FDA draft guidance for assessment of suicidality in clinical trials
(FDA Sept 2010).  The C-SSRS will be used to assess eligibility for the study and to monitor the 
patients throughout the study.
In any event of suspected active suicidal intent or significant suicidal behavior or clinical finding 
suggesting that the patient is dangerous to himself or herself, the patient should be referred for 
immediate psychiatric evaluation.
6.2.3
Vital Signs Measurement
Vital signs are to be measured at visits indicated in Appendix A.  Refer to the manufacturer’s 
manual for proper operation, calibration, care and handling of the monitor.  Select an 
appropriately sized BP cuff.
For each vital sign measurement, record the patient’s position and the arm used for the 
measurement.
6.2.3.1
Seated Blood Pressure Measurement
Situate the patient in a quiet environment with feet flat on the floor, back against the chair and 
arm resting on a table or other support so that the midpoint of the cuff is at the level of the 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
36
heart.  The patient must rest for at least 10 minutes in the seated position prior to measuring 
blood pressure (BP).
6.2.3.2
Standing Blood Pressure Measurement for Orthostatic Assessment
To assess for the presence of orthostatic hypotension, additional BP and pulse rate will be 
assessed at selected study visits (see Appendix A) or as needed at the discretion of the 
Investigator.  After measurement of seated BP, the patient will change to a standing position.  
After 2 minutes of standing, BP and pulse rate will be measured 3 times, with each test 
separated by at least 1 minute from the prior test.  If the diastolic BP readings from the 3 tests 
are not all within 5 mm Hg, 2 additional standing BP readings must be obtained (total of 5 BP 
readings), with each test separated by at least 1 minute from the prior test.
6.2.4
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be recorded at selected study visits (see 
Appendix A).  The ECG will be performed in triplicate at the Screening visit only.  A central ECG
service will be utilized for reading all ECGs.  Refer to the ECG Manual for proper operation, care 
and handling of the machine.
6.2.5
Physical Measurements (Height and Weight)
For measurements of body weight, the same weighing scales should be used to weigh a given 
patient throughout the study.  Scales should be calibrated and reliable; scales should be zeroed 
just prior to each patient’s weigh-in session.  A patient should void just prior to being weighed.  
Weight should be recorded before a patient’s meal (if applicable) and at approximately the 
same time of day at each visit.  Patients should be minimally clothed (i.e., no shoes or heavy 
over-garments).
6.2.6
Physical/Neurological Examination
Neurological examinations include assessment of mental status, level of consciousness, sensory 
function, motor function, cranial nerve function and reflexes.  Neurological examinations will be 
performed at the times/dates according to the schedule as shown in Appendix A (Schedule of 
Procedures).
6.2.7
Electrophysiological Assessments
Quantitative EEGs (qEEGs) will be performed to characterize cortical activity during the resting 
brain state, including quantification by standard measures such as alpha and delta power and 
the anterior-posterior (AP) gradient of relative alpha power.  Huntington’s disease patients have 
been shown to differ from healthy controls in these parameters, and relative alpha AP gradient 
loss is associated with lower total functional capacity and greater cognitive dysfunction 
(Hunter et al. 2010).  QEEGs will be performed according to the schedule as shown in 
Appendix A (Schedule of Procedures).


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
37
6.2.8
Neuroimaging Assessments
Neuroimaging assessments will be conducted using a 3T MRI scanner, and scans must be 
reviewed locally by a trained radiologist.
A 3D T1-weighted structural MR scan will be used to quantitate whole brain, caudate and 
intraventricular volumes.  In addition, the following scans will be performed:  T2 flair, T2 star 
and T2 Fast Spin Echo (FSE)/Turbo Spin Echo (TSE).
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
38
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
39
6.2.13
HD Cognitive Battery
The HD Cognitive Battery was developed as a means of measuring cognitive dysfunction in late 
premanifest and early manifest HD patients (Stout et al. 2014).  The 6 tests that comprise the 
battery were selected based on test sensitivity, practice effects, reliability, domain coverage, 
feasibility for use in clinical trials and tolerability.  A composite cognitive score can be calculated 
by the average z-score of the 6 individual tests.  
.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
40
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
41
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
42
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
6.2.18
Collection of CSF
Patients will have CSF collected at the Screening Visit, prior to administration of each dose of 
RO7234292 and at the Post-Treatment Visit.  At each collection, 20 mL of CSF fluid is to be
collected for analyses.  If there are difficulties in collecting 20 mL of CSF fluid, a minimum of 15 
mL should be collected.  A 24G atraumatic needle (Whitacre or other if approved by Sponsor 
prior to use) will be used.  Depending on institutional guidelines, local anesthesia may be used 
for the procedure.  Sedation may not be used.  Spinal ultrasound may be used for the LP 
procedure, if deemed necessary, but is not required.
6.2.19
Laboratory Assessments
Samples for assessment of laboratory analytes will be collected throughout the study.  A list of 
these analytes is contained in Appendix B.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
43
6.2.19.1
Plasma and Serum Laboratory Assessments
Routine chemistry and hematology panels will be conducted as indicated in the Schedule of 
Assessments (Appendix A).  
 
immunogenicity (anti-RO7234292 antibody assessment) will be conducted using samples 
collected as described in Appendices A and C.
 
For each scheduled lumbar puncture, local laboratory analysis of coagulation factors 
(prothrombin time [PT], International normalized ratio [INR] and activated partial 
thromboplastin time [aPTT]) and platelets must be conducted and results reviewed prior to 
performing the lumbar puncture.  Collection for these local labs may occur at any time in the 
72 hours prior to the lumbar puncture.
6.2.19.2
CSF Laboratory Assessments
CSF will be used for standard laboratory measurement of cells, glucose, protein and for
RO7234292 pharmacokinetic analyses.  CSF will also be used for evaluation of CSF biomarkers, 
shown in Appendix B.
Any CSF remaining after performing the planned analyses will be stored for investigation of 
possible biomarkers of HD; the pharmacodynamic effects of RO7234292; for profiling of drug 
binding proteins, bioanalytical method validation purposes, stability assessments, metabolite 
assessments, immunogenicity assessments (including assay development and validation 
purposes) or to assess other actions of RO7234292 with CSF constituents.
6.2.19.3
Urine Laboratory Assessments
Urine will be collected for routine testing and for RO7234292 concentration analysis and 
pharmacokinetic analyses.
6.2.20
Pregnancy Testing
Pregnancy tests will be conducted in all female patients who are not surgically sterile, as shown
in the Schedule of Assessments (Appendix A).
6.3
Restriction on the Lifestyle of Patients
6.3.1
Contraception Requirements
All male patients and women patients of childbearing potential must refrain from sperm/egg 
donation and practice effective contraception from the time of signing the informed consent 
form until at least 5 months after the last dose of RO7234292.
Male patients must also encourage their female partner to use effective contraception from the 
time of signing the informed consent through the end of the study.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
44
For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche and does not meet 1 of the following conditions:

Postmenopausal:  12 months of spontaneous amenorrhea without an alternative 
medical cause and FSH levels in the postmenopausal range for the laboratory involved

6 weeks after surgical bilateral tubal occlusion, hysterectomy, bilateral salpingectomy or 
bilateral oophorectomy with or without hysterectomy

Post hysterectomy
For the purposes of the study, effective contraception is defined as follows:
For male patients:

Effective male contraception includes a vasectomy with negative semen analysis at 
follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository

Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the RO7234292
For female patients:

Surgical sterilization (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) or using 2 methods from signing ICF until at 
least 5 months after the last dose of RO7234292.  The 2 methods should include at 
least 1, highly-effective barrier method (e.g., intrauterine device or any of the following 
in combination with spermicidal foam/gel/film/cream/suppository:  male condom*, 
female condom*, diaphragm, sponge, cervical cap) and at least 1 other method (e.g., 
oral, injected or implanted hormonal methods).
For female partners of male patients:

Using any of the following acceptable methods of contraception:  surgical sterilization 
(e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy); oral, injected or implanted hormonal contraception; intrauterine 
contraception/device; or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository
*Note: A female condom and a male condom should not be used together as friction between 
the 2 can result in either or both products failing.






BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
47
7.2.2
Packaging and Labeling after Change in Sponsor (Protocol BN40697, 
Amendment 4 and Subsequent Versions)
RO7234292 will be provided by Roche to investigational centers on a regular basis.  
Packaging of investigational products will be overseen by the Roche Global Clinical 
Trial Supplies department.  The supply will be packed bearing labels in accordance with 
Roche standards and local regulations.
Upon arrival of investigational products at the site, site personnel should check them 
for damage and verify proper identity, quantity, integrity of seals, and temperature 
conditions.  Site personnel should report any deviations or product complaints to the 
monitor upon discovery.
7.3
Study Drug Accountability
The study staff is required to document the receipt, dispensing, and return/destruction of 
RO7234292 provided by the Sponsor according to Sponsor instruction and in accordance with 
institutional policy.
8.
TREATMENT OF PATIENTS
8.1
Study Drug Administration
RO7234292 dosing will occur at the Study Center.  On administration days, each patient will 
undergo an LP procedure for collection of CSF (see Section 6.2.18) followed by a single IT bolus 
(1-3 minute) LP injection of RO7234292.  A 24G atraumatic needle (Whitacre or other if 
approved by Sponsor prior to use) will be used, oriented with the opening rostral (toward the 
patient’s head).  The target site for needle insertion is the L3/L4 space but may be 1 segment 
above or 1-2 segments below this level, if needed.  Depending on institutional guidelines, local 
anesthesia may be used for the LP procedure.  Sedation may not be used.  Spinal ultrasound 
may be used for the LP procedure, if deemed necessary, but is not required.
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for dose preparation and administration, including volume of administration.  These 
instructions must be followed for each dose administration.
8.2
Other Protocol-Required Drugs
There are no other protocol required drugs.  Depending on institutional guidelines, local 
anesthesia may be used for the LP procedure, following institutional procedures.  Sedation may 
not be used.
8.3
Other Protocol-Required Treatment Procedures
There are no other protocol required treatment procedures.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
48
8.4
Treatment Precautions
Patients will be discouraged from resting supine after the lumbar puncture procedure and will 
be encouraged to mobilize immediately.
Throughout the study, patients will be monitored for post-LP headache and for any signs or 
symptoms of infection.  The Study Manual will provide guidance for site personnel on 
differentiating between and managing treatment of pressure headaches and 
encephalitic/meningitic headaches.
Epinephrine for subcutaneous injection, diphenhydramine for intravenous injection and any 
other medications and resuscitation equipment for the emergency management of anaphylactic 
reactions must be close to the location where the injection is being performed.
8.5
Safety Monitoring Rules
Please refer to the Guidance to Investigator section of the Investigator Brochure.
8.6
Stopping Rules
Please refer to Section 8.8 and the current RO7234292 Investigator's Brochure.  The 
Investigator should discuss significant concerns relating to individual patients with the 
Sponsor Medical Monitor to ensure that it is appropriate for the patient to continue in the 
study.
8.7
Adjustment of Dose and/or Treatment Schedule
For a given patient, no adjustment of dose is planned.  If a situation prevents the dosing 
procedure (i.e., lumbar puncture) from being performed safely but discontinuation of
RO7234292 is not warranted, an adjustment in the dose schedule may be permitted at the 
discretion of the Investigator, in consultation with the Sponsor Medical Monitor.  Examples of 
situations where the dosing schedule may be altered include the following:

If a clinically significant abnormality is observed in the laboratory tests conducted prior 
to lumbar puncture (protocol Section 6.2.19.1) that increases lumbar puncture-related 
risk to the patient, further lumbar punctures must be delayed to allow for investigation 
into the finding.  Prior to resuming treatment, the Investigator and Medical Monitor 
must agree to resume dosing.

If patient is experiencing a concurrent illness that increases lumbar puncture-related risk 
to the patient, such as a skin infection near the area for injection, further lumbar 
punctures must be delayed until Investigator and Medical Monitor agree to resume 
dosing.
8.8
Discontinuation of Study Drug
A patient must permanently discontinue study treatment for any of the following:


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
49

The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4

The patient withdraws consent

The patient experiences an AE that necessitates permanent discontinuation of 
RO7234292
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation.
Patients who terminate early from the study during the Treatment Period (for reason other than 
withdrawal of consent) should be encouraged to complete the Study Day 519/Study Week 74 
visit.  This visit should be conducted approximately 14 weeks after last administration of 
RO7234292.  (Also see Appendices A and C and Study Design and Treatment Schema.)
8.9
Withdrawal of Patients from the Study
Patients must be withdrawn from the study for any of the following:

Withdrawal of consent

The patient is unwilling or unable to comply with the protocol
Other reasons for withdrawal of patients from the study might include:

At the discretion of the Investigator for medical reasons

At the discretion of the Investigator or Sponsor for noncompliance

Significant protocol deviation

Administrative decision by the Investigator or Sponsor
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must 
be recorded in the eCRF.
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.
For patients withdrawn from the study during the Treatment Period for reasons other than 
withdrawal of consent, every effort should be made to encourage the patient to participate in 
the Week 74 visit as an Early Termination Visit.  This visit should be conducted approximately 
14 weeks after last administration of RO7234292.  
8.10
Access to Treatment after Study Completion
The Sponsor will offer continued access to Roche investigational medicinal product 
(IMP) (RO7234292) free of charge to eligible patients in accordance with the Roche 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
50
Global Policy on Continued Access to Investigational Medicinal Product, as outlined 
below.
A patient will be eligible to receive Roche IMP (RO7234292) after completing 
Study BN40697 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 
Study BN40697 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.pd
f
Patients may be eligible to receive Roche IMP (RO7234292) as part of an extension 
study, as described in Section 3.4.3.
8.11
Concomitant Therapy and Procedures
The use of concomitant therapies or procedures defined below must be recorded on the 
patient’s eCRF.  AEs related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF.
8.11.1
Concomitant Therapy
A concomitant therapy is any non-protocol specified drug or substance (including 
over-the-counter medications, herbal medications and vitamin supplements) administered 
between date of first dose of RO7234292 and end of study.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
51
Patients should consult with the Site Investigator or qualified designee prior to initiating any 
new medication, including non-prescription compounds or any other non-drug therapy.
Allowed Concomitant Therapy
Throughout the study, Site Investigators or designated licensed physicians involved in the study 
may prescribe concomitant medications or treatments deemed necessary for AEs or to provide 
adequate supportive care.
In addition, the following therapies are permitted:

Contraceptive agents, as described in Section 6.3.1

Supplements (e.g., coenzyme Q10, vitamins, creatine) if at a stable dose for at least
6 weeks prior to Screening and dosage is not anticipated to change during the study

Antipsychotics (only if prescribed for motor symptoms or as a mood stabilizer) and/or 
tetrabenazine/deutetrabenazine if at a stable dose for at least 12 weeks prior to 
Screening and the dose is not anticipated to change during the study

Antidepressant or benzodiazepine if at a stable dose for at least 12 weeks prior to 
Screening and with a dose regimen that is not anticipated to change during the study

Aspirin at doses ≤81 mg/day

Depending on institutional guidelines, local anesthesia may be used for the lumbar 
puncture procedure.  Sedation may not be used.

Anti-anxiety medication use for imaging-related anxiety is prohibited during the 
Screening Period and strongly discouraged during scheduled scans in the Post-
Treatment Period.  If anti-anxiety medication is used for a Post-Treatment scan, the scan 
must be performed at the end of the assessment day or, preferably on a different day, 
so as not to impact other assessments.
Disallowed Concomitant Therapy
Study 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 specifically prohibited:

Antipsychotics unless prescribed for motor symptoms or mood stabilization (not 
psychosis) and at a stable dose for at least 12 weeks prior to Screening and the dose is 
not anticipated to change during the study

Cholinesterase inhibitors

Memantine

Amantadine


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
52

Tetrabenazine or deutetrabenazine unless at a stable dose for at least 12 weeks prior to 
Screening and the dose is not anticipated to change during the study

Riluzole

Supplements (e.g., coenzyme Q10, vitamins, creatine) unless at a stable dose for at least 
6 weeks prior to Screening and the dose is not anticipated to change during the study

Antidepressant or benzodiazepine use unless stable dose for at least 12 weeks prior to 
Screening and with a dose regimen that is not anticipated to change during the study

Antiplatelet or anticoagulant therapy including but not limited to aspirin (unless 
≤81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban

Sedation is not permitted for any procedures in the study
8.11.2
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between
date of first dose of RO7234292 and End-of-Study.
8.12
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded in the CRF by Study Center
staff.
9.
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING
9.1
Sponsor Review of Safety Information
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the Safety Management Plan throughout the conduct of the clinical trial.
9.2
Regulatory Requirements
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of serious adverse events (SAEs) including suspected unexpected serious adverse 
reactions (SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A and 
ICH E6.  Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines.
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) will be notified of any 
SAE according to applicable regulations.  
The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that the RO7234292 caused the AE and, therefore, meets the definition 
of a SUSAR.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
53
9.3
Definitions
9.3.1
Adverse Event
An adverse event is any unfavorable and unintended sign (including a clinically-significant
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product.
9.3.2
Adverse Reaction and Suspected Adverse Reaction
An adverse reaction is any AE caused by the Study Drug.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction.
9.3.3
Serious Adverse Event (SAE)
A serious adverse event is any AE that in the view of either the Investigator or Sponsor, meets 
any of the following criteria:

Results in death

Is life threatening: that is, poses an immediate risk of death at the time of the event
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an admission of greater than 24 hours to a medical facility 
and does not always qualify as an AE

Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

Results in a congenital anomaly or birth defect in the offspring of the patient (whether 
the patient is male or female)

Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent 1 of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
54
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse
9.4
Monitoring and Recording Adverse Events
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of 
the Study (i.e., before informed consent) should be recorded as Medical History and not 
recorded as AEs unless the pre-existing condition worsened.  The Investigator should always 
group signs and symptoms into a single term that constitutes a single unifying diagnosis if 
possible.
9.4.1
Serious Adverse Events
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the informed consent form and stop at the end of the patient’s
follow-up period which is defined as Study Day 519 or the time of enrollment in OLE Study 
BN40955.  When the Investigator is reporting by telephone, it is important to speak to 
someone in person versus leaving a message.  An Initial Serious Adverse Event Form should be 
completed and a copy should be faxed to the Sponsor or designee.  The fax number for 
reporting SAEs can be found in the Study Reference Manual.
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event Forms as soon as additional information becomes available.  All SAEs will be followed until 
resolution.  SAEs that remain ongoing past the patient’s last protocol-specified follow-up visit 
will be evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the 
patient’s condition is unlikely to resolve, the Investigator and Sponsor will determine the 
follow-up requirement.
9.4.2
Non-Serious Adverse Events
The recording of non-serious AEs will begin after the patient signs the informed consent form 
and will stop at the end of the patient’s follow-up period, which is defined as Study Day 519 or 
the time of enrollment in OLE Study BN40955.  The Investigator will monitor each patient
closely and record all observed or volunteered AEs on the Adverse Event Case Report Form.
9.4.3
Evaluation of Adverse Events (Serious and Non-Serious)
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form:


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
55
9.4.3.1
Relationship to the Study Drug
The event’s relationship to the RO7234292 is characterized by 1 of the following:

Related:  There is clear evidence that the event is related to the use of Study Drug, e.g.,
confirmation by positive re-challenge test

Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and RO7234292 administration

Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to RO7234292 administration and/or exposure suggests that a causal 
relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped 
together with Not Related)

Not Related:  The event can be readily explained by the patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and Study Drug
9.4.3.2
Severity
For laboratory AEs, the severity should be indicated according to Appendix D, which is based on 
the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
guidelines, Version 4.03.
For AEs not listed in Appendix D, the event’s severity is characterized by 1 of the following:

Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual 
daily activities

Moderate:  The event causes the patient more discomfort and interrupts the patient ’s 
usual daily activities

Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities
9.4.3.3
Action Taken with Study Drug
Action taken with RO7234292 due to the event is characterized by 1 of the following:

None:  No changes were made to RO7234292 administration and dose

Permanently Discontinued:  RO7234292 was discontinued and not restarted

Temporarily Interrupted, Restarted – Same Dose:  Dosing was temporarily interrupted
or delayed due to the AE and restarted at the same dose


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
56
9.4.3.4
Treatment Given for Adverse Event
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form.  Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate.
9.4.3.5
Outcome of the Adverse Event
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following:

AE Persists:  Patient terminates from the trial and the AE continues

Recovered:  Patient recovered completely from the AE

Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE)

Change in Severity (if applicable):  AE severity changed
If the event is an SAE, then the event’s outcome is characterized by 1 of the following:

Ongoing:  SAE continuing

Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF (the 
SAE resolution date should be entered as the date of onset of that AE)

Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date)

Fatal:  Patient died (the date of death should be entered as the SAE resolution date)
9.5
Procedures for Handling Special Situations
9.5.1
Abnormalities of Laboratory Tests
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to 
thrombocytopenia, tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  
Whenever possible, the underlying diagnosis should be listed in preference to abnormal 
laboratory values as AEs.  Clinically-significant abnormalities will be monitored by the 
Investigator until the parameter returns to its baseline value or until agreement is reached 
between the Investigator and Sponsor Medical Monitor.  Laboratory abnormalities deemed not 
clinically-significant (NCS) by the Investigator should not be reported as AEs.  Similarly, 
laboratory abnormalities reported as AEs by the Investigator should not be deemed NCS on the 
laboratory sheet.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
57
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents.
9.5.2
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the patient’s
consent to participate in the Study

The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the Investigator between the patient’s consent to participate in the Study and the 
timing of the procedure or treatment

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission
9.5.3
Dosing Errors
RO7234292 dosing errors should be documented as Protocol Deviations.  A brief description 
should be provided in the deviation, including whether the patient was symptomatic (list 
symptoms) or asymptomatic, and the event accidental or intentional.
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of RO7234292 that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented as an AE and be reported per Section 9.4.
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours.
9.5.4
Contraception and Pregnancy
Patients must continue to use appropriate contraception with their partners, or refrain from 
sexual activity, as described in Section 6.3.1.
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or 
believes that he has made someone pregnant during the Study, then the Study Center staff must 
be informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported on Follow-up Pregnancy Forms and 
reported within 24 hours.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
58
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.
Female patients:  If a suspected pregnancy occurs while on the Study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with RO7234292.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures 
do not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion).  If the pregnancy results in the birth of a child, the Study Center and 
Sponsor may require access to the mother and infant’s medical records for an additional 8 
weeks after birth.
Male patients:  The progress of the pregnancy of a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, additional follow-up information may 
be requested for the mother and infant.  Follow-up will be performed to the extent permitted 
by the applicable regulations and privacy considerations.
10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints, Subsets, and Covariates
There is no single primary endpoint for this study.  Important endpoints that will be evaluated 
are identified in the following sections.
10.1.1
Safety and Tolerability Endpoints

Columbia - Suicide Severity Rating Scale (C-SSRS)

Physical examination and standard neurological assessment (including fundi)

Pregnancy testing

Vital signs (heart rate [HR], BP, orthostatic changes, weight)

ECG

AEs and concomitant medications

CSF safety labs (cell counts, protein, glucose)

Plasma laboratory tests (clinical chemistry, hematology)

Urinalysis

Safety neuroimaging assessments


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
59
10.1.2
Pharmacokinetic Endpoints
 
  CSF elimination half-life and trough drug levels will be assessed, 
where appropriate.  Urinary excretion parameters such as amount of drug excreted and renal 
clearance will be determined, as appropriate. 
10.1.3
Pharmacodynamic and Clinical Endpoints

Biochemical
o
CSF levels of mutant Htt, 
 
 
 

Neuroimaging volumes, including but not limited to:
o
Structural MRI

Caudate volume

Whole brain volume

Ventricular volume

Electrophysiological
o
qEEG

Clinical
o
Cognitive and motor tests:

HD Cognitive Battery


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
60
10.2
Sample Size Considerations
The sample size is dictated by the number of patients enrolled in the prior MAD study 
(Study ISIS 443139-CS1).  Based on experience with generation 2 ASOs administered by IT
injection, this number of patients (N ≈46) is expected to be sufficient to ensure that the safety, 
tolerability, pharmacokinetics and pharmacodynamics are adequately assessed.
10.3
Populations
Safety Population:  All patients who are randomized and receive at least 1 dose of RO7234292.
Per Protocol Population: All patients who are randomized and receive all protocol-specified 
doses of RO7234292.
PK Population:  All patients who are randomized to RO7234292 and receive at least 1 dose of 
RO7234292 and have sufficient sampling to permit pharmacokinetic evaluation.
10.4
Definition of Baseline
For vital signs (BP, HR, respiration rate and temperature), baseline will be defined as the average 
of the values collected prior to first dose (Screening, Study Day -1 and Study Day 1).  For CSF 
laboratory tests, baseline will be defined as the average of the values collected prior to first 
dose (Screening and Study Day 1).  For all other measures and parameters, baseline will be 
defined as the last non-missing measure prior to the first dose.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
61
10.5
Interim Analysis
The Sponsor may choose to conduct one or more interim analyses including safety, PK, PD 
biomarkers and clinical endpoints as relevant. Details of each interim analysis will be described 
in a dedicated SAP, which will be finalized before the conduct of the interim analysis.
10.6
Planned Methods of Analysis
All CRF data, lab data transfers, and any outcomes derived from the data will be provided in the 
patient data listings.  Patient data listings will be presented for all patients enrolled into the
study.  Descriptive summary statistics including n, mean, median, standard deviation, standard 
error, interquartile range (25th percentile, 75th percentile), and range (minimum, maximum) for 
continuous variables, and counts and percentages for categorical variables will be used to 
summarize most data.  Where appropriate, comparisons between regimens may be conducted 
and p-values may be reported.  Statistical tests will be conducted using 2-sided tests with 5% 
Type I error rate unless otherwise stated in the Statistical Analysis Plan (SAP).
10.6.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized using descriptive statistics by 
regimen.  Patient disposition will be summarized by regimen.  All patients enrolled will be 
included in a summary of patient disposition.
10.6.2
Safety Analysis
The safety analysis will be conducted on the Safety Population.
Treatment duration and amount of RO7234292 received will be summarized by regimen.
All treatment-emergent adverse events (TEAEs) and SAEs will be summarized for each regimen 
and for all patients using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system by system organ class, preferred term, relationship to Study Drug, and severity.
Narratives of “on-study” deaths, serious and significant AEs, including early withdrawals due to 
AEs, will be provided.
Laboratory tests to ensure patient safety including chemistry panel, hematology panel, CSF 
safety labs (cell counts, protein, glucose) and urinalysis, will be summarized by study visit for 
each regimen.  These safety variables will also be presented as change and percent change from 
baseline over time, as appropriate.
Vital sign and ECG measures will be tabulated by regimen.  In addition, the number of patients 
who experience abnormalities in clinical laboratory evaluations will be summarized by regimen.
Columbia – Suicide Severity Rating Scale will be summarized by study visit for each regimen.  
Physical examination, standard neurological assessment (including fundi), and clinical and 
neuroimaging results will be summarized, if appropriate, and listed.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
62
10.6.3
Pharmacokinetic Analysis
The pharmacokinetic analysis will be conducted on the PK Population.
The CSF concentrations will be summarized using descriptive statistics and the RO7234292
half-life in CSF will be calculated, if possible.
 
 
 
 
 
 
 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the 
PK scientist.  Additional details regarding the PK analysis will be described in the SAP.
10.6.4
Pharmacodynamic and Clinical Analysis
The analyses of pharmacodynamic and clinical endpoints will be conducted on the Per Protocol 
and Safety Populations.
These evaluations will be summarized using descriptive statistics by study visit and regimen.  
Change and percent change from baseline over time will be summarized as appropriate.  
Comparison between regimens may be performed.  
Additional analyses to investigate the relationship between the disease burden score (i.e.,
calculated from patients’ age and CAG repeat length, CAGn, using the formula: (CAGn - 35.5) x
age) and these endpoints may be performed as where deemed appropriate.
Details will be described in the SAP.
11.
INVESTIGATOR’S REGULATORY OBLIGATIONS
11.1
Informed Consent
Huntington’s disease is known to cause behavioral changes, and patients who wish to 
participate in this study may have disturbances in judgment and decision-making (Walker 2007).  
During the consent process, the Investigator must carefully evaluate the patient’s capacity to 
consent.  To facilitate this evaluation, the Evaluation to Sign Consent questionnaire will be 
administered (DeRenzo et al. 1998).  In cases where the Investigator is uncertain as to whether 
the patient possesses capacity to consent, the patient should be referred to an independent 
expert for further assessment of capacity.  A prospective patient’s consent will be sought only if 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
63
he or she demonstrates during the consent process an adequate level of understanding of the 
study, its requirements and its risks.
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor or designee.
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or RO7234292 is administered.  The patient must be given sufficient time 
to consider whether to participate in the study.  Consent for genetic testing within the study will 
be obtained separately from consent for participation in the other aspects of the study.
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
patient.
11.2
Ethical Conduct of the Study
The Guidelines of the World Medical Association Declaration of Helsinki dated October 2002 the 
applicable regulations and guidelines of current Good Clinical Practice (GCP) as well as the 
demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed.
11.3
Independent Ethics Committee/Institutional Review Board
A copy of the protocol, proposed informed consent/assent forms, other written patient
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent form 
must be received by the Sponsor or designee before recruitment of patients into the Study and 
shipment of Study Drug.  A copy of the written approval of any other items/materials that must 
be approved by the Study Center or IEC/IRB must also be received by the Sponsor or designee 
before recruitment of patients into the Study and shipment of Study Drug.  The Investigator’s 
Brochure must be submitted to the IEC/IRB for acknowledgement.
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IEC/IRB of deviations from the protocol in accordance with ICH
GCP Section 4.5.2.  The Investigator should also notify the IEC/IRB of SAEs occurring at the Study 
Center and other AE reports received from the Sponsor or designee, in accordance with local 
procedures.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
64
The Investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout 
the duration of the Study.  Copies of the Investigator’s reports, all IEC/IRB submissions and the 
IEC/IRB continuance of approval must be sent to the Sponsor or designee.
11.4
Patient Confidentiality
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms (CRFs) or other documents submitted to the Sponsor or designee, patients should be 
identified by initials, if permitted by local law, and a patient identification number only.  
Documents that are not for submission to the Sponsor or designee (e.g., signed informed 
consent forms) should be kept in strict confidence by the Investigator.
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data 
and used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  Linking 
of data will be facilitated by the HDID number (see Section 6.3.2).
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
12.1
Protocol Amendments
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and 
amendments to the informed consent document.  The regulatory authority and IEC/IRB must be 
informed of all amendments and give approval for any amendments likely to affect the safety of 
the patients or the conduct of the trial.  The Investigator must send a copy of the approval letter 
from the IEC/IRB to the Sponsor or designee.
12.2
Study Termination
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves 
the right to terminate their participation in the study, according to the terms of the site 
contract.  The Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s 
completion or early termination and send a copy of the notification to the Sponsor or designee.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
65
12.3
Study Documentation and Storage
An electronic case report form (eCRF) utilizing an Electronic Data Capture application will be 
used for this study.
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form.
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, eCRFs
may not be used as source documents.
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  Elements should include:

Patient files containing completed CRFs, informed consents, and supporting copies of 
source documentation

Study files containing the protocol with all amendments, Investigator’s Brochure, copies 
of pre-study documentation and all correspondence to and from the IEC/IRB and the 
Sponsor or designee

If drug supplies are maintained at the Study Center, proof of receipt, Study Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug
product reconciliation, and all drug-related correspondence
In addition, all original source documents supporting entries in the CRFs must be maintained 
and be readily available.
No study document should be destroyed without prior written agreement between the Sponsor 
or designee and the Investigator.  Should the Investigator wish to assign the study records to 
another party or move them to another location, he/she must notify the Sponsor or designee.
12.4
Study Monitoring
The Sponsor representative and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., CRFs and other pertinent data) provided that 
patient confidentiality is respected.
The Sponsor monitor or designee is responsible for inspecting the CRFs at regular intervals 
throughout the Study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
66
The monitor should have access to patient medical records and other study-related records 
needed to verify the entries on the CRFs.
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits, including delays in completing CRFs, are resolved.
In accordance with ICH GCP and the Sponsor’s audit plans, this Study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or designees).  
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and 
review of study-related records will occur to evaluate the trial conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements.
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor or designee.  During this review, patient data will be 
checked for consistency, omissions, and any apparent discrepancies.  In addition, the data will 
be reviewed for adherence to the protocol and GCP.  To resolve any questions arising from the 
clinical data management review process, data queries and/or Study Center notifications will be 
sent to the Study Center for completion and return to Sponsor or designee.
The Principal Investigator will sign and date the indicated places on the CRF.  These signatures 
will indicate that the Principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content.
12.5
Language
Case report forms must be completed in English.  Generic names for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade
name in English.
All written information and other material to be used by patients and investigative staff must 
use vocabulary and language that are clearly understood.
12.6
Compensation for Injury
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
67
13.
REFERENCES
 
Ambrose CM, Duyao MP, Barnes G, et al. Evidence against simple inactivation due to an expanded CAG 
repeat.  Somat Cell Molec Genet 1994; 20: 27-38.
 
 
Austedo (deutetrabenazine) [package insert]. North Wales, PA: Teva; 2017.
Bañez-Coronel M, Porta S, Kagerbauer B, et al. A pathogenic mechanism in Huntington’s disease involves 
small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 2012; 8(2): e1002481.
 
  
Boudreau RL, McBride JL, Martins I, et al. Nonallele-specific silencing of mutant and wild-type huntingtin 
demonstrates therapeutic efficacy in Huntington's disease mice. Mol Ther 2009 Jun; 17(6): 1053-1063.
Brossman B, Williams JK, Downing N, et al. Development of the Huntington disease work function scale. J 
Occup Environ Med 2012; 54(10): 1300-1308.
 
Cerritelli SM and Crouch RJ. Ribonuclease H: the enzymes in eukaryotes. FEBS J 2009; 276: 1494-1505.
Chen JJ, Ondo WG, Khashayar D, Swope DM. Tetrabenazine for the treatment of hyperkinetic movement 
disorders: a review of the literature. Clin Therapeutics 2012; 34: 1487-1504.
Costigan SN and Sprigge JS. Dural puncture: the patients’ perspective. A patient survey of cases at a DGH 
maternity unity 1983-1993. Acta Anaesthesiol Scand 1996 Jul; 40 (6): 710-714.
Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington’s disease. Neuropsychiatry 
Neuropsychol Behav Neurol 2001; 14(4): 219-226.
Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol 
Toxicol 1996; 36: 107-129.
 
DeRenzo EG, Conley RR, Love R. Assessment of capacity to give consent to research participation: state-of-
the-art and beyond. J Health Care Law Policy 1998; 1(1): 66-87.
 
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
68
Drouet V, Perrin V, Hassig R, et al. Sustained effects of nonallele-specific huntingtin silencing. Ann Neurol 
2009 Mar; 65(3): 276-285.
Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat instability and age of onset in Huntington’s 
disease. Nat Gen 1993; 4: 387-392.
Duyao MP, Auerbach AB, Ryan A, et al. Inactivation of the mouse Huntington’s disease gene homolog 
Hdh. Science 1995; 269: 407-410.
FDA: DRAFT Guidance for Industry Suicidality: Prospective Assessment of Occurrence in Clinical Trials, 
September 2010.
Folstein SE. The psychopathology of Huntington’s disease. J Nerv Ment Dis 1989; 177: 645.
 
 
Hinton-Bayre AD, Geffen GM, Geffen LB, et al. Concussion in contact sports: reliable change indices of 
impairment and recovery. Clin Exp Neuropsychol 1999; 21: 70-86.
Hogarth P, Kayson E, Kieburtz K, et al. Interrater agreement in the assessment of motor manifestations of 
Huntington’s disease. Mov Disord 2005; 20: 293-297.
Hunter A, Bordelon Y, Cook I, Leuchter A. QEEG measures in Huntington’s disease: a pilot study. PLoS Curr 
2010 Oct 25; 2: RRN1192.
Huntington G. On chorea. Med Surg Reporter 1872; 26: 320-321.
Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov 
Disord 1996; 11: 136-142.
 
Ismailoglu I, Chen Q, Popowski M, et al. Huntingtin protein is essential for mitochondrial metabolism, 
bioenergetics and structure in murin embryonic stem cells. Dev Biol 2014; 391: 230-240.
Johnson SA, Stout JC, Solomon AC, et al; and Predict-HD Investigators of the Huntington Study Group. 
Beyond disgust: impaired recognition of negative emotions prior to diagnosis in Huntington’s disease. 
Brain 2007; 130: 732-744.
 
 
Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease 
by transient repression of huntingtin synthesis. Neuron 2012; 74: 1031-1044.
Kuermmerle S, Gutekunst CA, Klein AM, et al. Huntingtin aggregates may not predict neuronal death in 
Huntington’s disease. Ann Neurol 1999; 46: 842-843.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
69
Langbehn DR, Brinkman RR, Falush D, et al; and International Huntington’s Disease Collaborative Group. A 
new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG 
length. Clin Gen 2004; 65(4): 267-277.
 
McBride JL, Boudreau RL, Harper SQ, et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the 
brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci USA 2008 Apr 15; 105(15): 
5868-5873.
McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the 
rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther 2011; 19: 2152-2162.
 
 
Moumné L, Betuing S, Caboche J. Multiple aspects of gene dysregulation in Huntington's disease. Front 
Neurol 2013; 4: 127.
Nance M, Paulsen JS, Rosenblatt A, Wheelock V. A physician’s guide to the management of Huntington’s 
disease, 3rd Ed, Huntington’s Disease Society of America 2011.
Nasir J, Floresco SB, O'Kusky JR, et al. Targeted disruption of the Huntington’s disease gene results in 
embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995; 81(5): 811-
823.
 
 
Papoutsi M, Labuschagne I, Tabrizi SJ, Stout JC. The cognitive burden in Huntington's disease: pathology, 
phenotype, and mechanisms of compensation. Mov Disord 2014; 29(5): 673-683.
Paulsen J, Ready R, Hamilton J, et al. Neuropsychiatric aspects of Huntington’s disease. J Neurol
Neurosugery and Psychiatry 2001; 97: 310-314.
Paulsen JS, Smith MM, Long JD; and PREDICT HD Investigators and Coordinators of the Huntington Study 
Group. Cognitive decline in prodromal Huntington disease; implications for clinical trials. J Neurol 
Neurosurg Psychiatry 2013; 84: 1233-1239.
Paulson HL and Albin RL. Huntington’s Disease. Clinical features and routes to therapy. In: Lo DC, Hughes
RE, Eds. Neurobiology of Huntington’s disease: Applications to drug discovery. Boca Raton, FL. CRC Press 
2011: Chapter 1.
Petersen A, Gil J, Maat-Shieman ML, et al. Orexin loss in Huntington’s disease. Hum Mol Genet 2005;
14(1): 39-47.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
70
Posner K, Brown GK, Stanley B, et al. The Columbia-suicide severity rating scales: initial validity and 
internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 
2011; 168: 1266-1277.
Pringsheim T, Wiltshire K, Day L, et al. The incidence and prevalence of Huntington’s disease: a systematic 
review and meta-analysis. Mov Disord 2012; 27(9): 1083-1091.
 
 
 
Roos R. Huntington’s disease: A clinical review. Orphanet J Rare Dis 2010; 5: 40.
Ross CA, Aylward EH, Wild EJ, et al. Huntington disease: natural history, biomarkers and prospects for 
therapeutics. Nat Rev Neurol 2014; 10(4): 204-216.
 
Shoulson I and Fahn S. Huntington disease: clinical care and evaluation. Neurol 1979; 29: 1-3.
Shoulson I, Kurlan R, Rubin AJ, et al. Assessment of functional capacity in neurodegenerative movement 
disorders: Huntington’s disease as a prototype. In Munsat TL, Ed, Quantification of Neurological Deficit. 
Boston. Butterworth 1989: Chapter 20.
Shoulson I and Young AB. Milestones in Huntington disease. Mov Disord 2011; 26: 1127-1133.
Smith A. Symbol digit modalities test: Manual. 1982; Los-Angeles: Western Psychological Services.
Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of transcriptional 
dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington’s disease. J 
Huntington’s Disease 2013; 217-228.
Stout JC, Queller S, Baker KN, et al; and HD-CAB Investigators. HD-CAB: A cognitive assessment battery for 
clinical trials in Huntington’s disease. Mov Disord 2014; 29: 1281-1288.
Sturrock A and Leavitt B. The clinical and genetic features of Huntington’s disease. J Geriatric Psychiatry 
Neurol 2010; 23: 243-259.
 
Turnbull DK and Shepherd DB. Post-dural puncture headache: pathogenesis, prevention and treatment. Br 
J Anaesth 2003 Nov; 91(5): 718-729.
Vandam LD and Dripps RD. Long-term follow-up of patients who received 10,098 spinal anesthetics; 
syndrome of decreased intracranial pressure (headache and ocular and auditory difficulties). J Am Med 
Assoc 1956 Jun 16; 161(7): 586-591.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
71
 
Walker FO. Huntington's disease. Lancet 2007; 369 (9557): 218-228.
Wexler NS, Young AB, Tanzi RE, et al. Homozygote for huntinton’s disease. Nat 1987; 326: 194-197.
White JK, Auerbach W, Duyao MP, et al. Huntingtin is required for neurogenesis and is not impaired by 
the Huntington's disease CAG expansion. Nat Genet 1997; 17(4): 404-410.
Xenazine (tetrabenazine) [package insert]. Deerfield, IL: Lundbeck; 2011.
Zeitlin S, Liu JP, Chapman DL, et al. Increased apoptosis and early embryonic lethality in mice nullizygous 
for the Huntington's disease gene homologue. Nat Genet 1995; 11(2): 155-163.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
72
14.
APPENDICES


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
73
Appendix A
Schedule of Procedures


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
74
Appendix A
Schedule of Procedures
Study Period
Screen
Treatment Period
(62 weeks)
Post-
Treatment 
Period**
(12 weeks)
Loading Period
(6 weeks)
Maintenance Period1
(56 weeks)
Study Week
-4 to -1
1
2
5
6
7-62
74/ET
Study Day
-29 to -2
-1
1
2
3
8
28
29
30
36
57, 85, … 
421
58, 86, … 
422
64, 92, … 
428
519
Visit Window (days)*
-
*
0
*
*
±2
*
±5
*
±2
±5
*
±2
±21
Visit Type (cl = clinic, ph = phone)
cl
cl
cl
cl
ph
cl
cl
cl
ph
ph
cl
ph
ph
cl
Overnight Stay
X
Capacity to Consent Assessment and Informed 
Consent
X
Inclusion/Exclusion
X
Medical History
X
Vital Signs (BP, HR, RR, T)
X2
X
Xa
X
X
X
Xa
Xa
X
Orthostasis 
X2
Xb
X
Physical and Neurological Exam3
X2
X
Xa
Xc
X
X
Xa
Xa
X
Height
X
Body Weight
X2
X
X
X
X
C-SSRS4
X
X
Xb
X
X
X
Xb
Xb
X
Pregnancy Test5
X2
X
X
Xb
X
FSH
X5
Chemistry, Hematology, Urinalysis
X6
X
X
Xb
X
24-hour urine collection7
X
Serum Biomarker Sample
X6
X
X
Xb
X
PT, INR, aPTT
X6
X
X
Xb
X
Archived Serum Sample8
X6
X
X
Xb
X


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
75
Appendix A
Schedule of Procedures Continued
Study Period
Screen
Treatment Period
(62 weeks)
Post-
Treatment 
Period**
(12 weeks)
Loading Period
(6 weeks)
Maintenance Period1
(56 weeks)
Study Week
-4 to -1
1
2
5
6
7-62
74/ET
Study Day
-29 to -2
-1
1
2
3
8
28
29
30
36
57, 85, … 
421
58, 86, … 
422
64, 92, … 
428
519
Visit Window (days)*
-
*
0
*
*
±2
*
±5
*
±2
±5
*
±2
±21
Visit Type (cl = clinic, ph = phone)
cl
cl
cl
cl
ph
cl
cl
cl
ph
ph
cl
ph
ph
cl
Local PT, INR, aPTT, Platelets9
X
X
Xb
Xb, 10
X
Thyroid Panel
X
X
X b
X
Plasma Sampling for Immunogenicity Testing
Xb
Xb
Xb
X
CSF Sample for PK/Safety/Biomarkers/Archive
X11
Xb
Xb
Xb, 10
X
ECG (12-lead; in Triplicate at Screening Visit 
Only)
X6
X
X
Xb, 14
X
qEEG
X13
Xb, 14
X
Structural MRI
X13
Xb, 14
X15
T2 flair, T2 star, T2 FSE/TSE MRI
X13
Xb, 14
X15
RO7234292 Administration
X
X
X10
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
76
Appendix A
Schedule of Procedures Continued
Note:  If not specifically labeled, “X” means anytime; ET = early termination
*
All visits windows are calculated relative Study Day 1, i.e., the date of first dose administration in this 
protocol.  Visits with an asterisk (*) do not have a visit window and must be conducted on the exact day 
shown relative to the corresponding dosing day.
** 
Only patients who do not enter the open-label extension study (Study BN40955) will attend the 
Post-Treatment/End-of-Study visit.
1
Patients are randomized to the Monthly Cohort or the Bimonthly Cohort.  Patients in the Monthly Cohort 
receive RO7234292 every 28 days during the Maintenance Period (14 doses in the Maintenance 
Period).  Patients in the Bimonthly Cohort receive RO7234292 every 56 days during the Maintenance 
Period (7 doses in the Maintenance Period).  Study visits are shown below.
Monthly Cohort Study Visits during the Maintenance Period:
Study 
Weeks
Study Visit Day
(Clinic Visit)
RO7234292
Dosing Visit?
Day After 
Dosing Visit
(Phone Visit)
Seven Days After 
Dosing Visit
(Phone Visit)
9/10
57
Y
58
64
13/14
85
Y
86
92
17/18
113
Y
114
120
21/22
141
Y
142
148
25/26
169
Y
170
176
29/30
197
Y
198
204
33/34
225
Y
226
232
37/38
253
Y
254
260
41/42
281
Y
282
288
45/46
309
Y
310
316
49/50
337
Y
338
344
53/54
365
Y
366
372
57/58
393
Y
394
400
61/62
421
Y
422
428




BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
78
8
Stored at -80 °C for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of 
cytokine and/or chemokine levels, measurement of additional markers of kidney function, measurement 
of antibodies) in this or subsequent clinical studies of RO7234292.
9
Local laboratory analysis of PT, INR, aPTT and platelets must be conducted and results reviewed prior 
to performing the lumbar puncture.  Sample collection may occur at any time within 72 hours prior to the 
planned lumbar puncture.
10
Only at dosing visits.  (See tables in Footnote 1.)
11
Screening CSF sample collected at least 2 weeks prior to Study Day 1.  Screening sample is for 
Safety/Biomarkers/Archive only.
 
 
 
 
 
 
 
13
If the Screening visit is conducted within 3 months of the patient’s last visit in Study ISIS 443139-CS1 
and this assessment was performed at that visit, this assessment does not need to be performed 
separately for Study BN40697 (i.e., the result from the patient’s last visit in Study ISIS 443139-CS1 may 
serve as the Screening result for Study BN40697).
14
This assessment is conducted on Study Days 85, 253 and 421 only.  If necessary for ease of logistics, 
the assessment may be performed on a different calendar day than the dose administration (must be 
prior to the dose administration and within the required visit window).  
15
If imaging is conducted after CSF collection, at least 1 day must elapse between the LP and the 
imaging session to avoid LP-related artifacts on the images.
 
 
  
 
 
 
  
Time (in reference to time of RO7234292 administration):
a
Pre-dose; also 3 and 5 hours after administration of RO7234292 (3- and 5-hour assessments are only
performed if RO7234292 has been administered)
b
Pre-dose at dosing visits (otherwise, at any time during the visit)
c
Approximately 24 hours after administration of RO7234292
d
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours after administration of RO7234292
e
On Study Day 197:  samples collected pre-dose and 0.5, 1, 2, 3, 4 and 5 hours after administration of 
RO7234292.  On all other Study Days (57, 85, … 421):  1 sample collected pre-dose (if RO7234292 will 
be administered at the visit) or anytime during the visit (if RO7234292 will not be administered at the 
visit)


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
79
Appendix B
List of Laboratory Analytes


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
80
Appendix B
List of Laboratory Analytes
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of RO7234292 or other similar 
oligonucleotides.
Clinical Chemistry
Sodium
Potassium
Chloride
Total protein
Albumin
Calcium
Magnesium
Phosphorus
Bicarbonate
Glucose
BUN
Creatinine
Total serum Bilirubin
Uric acid
Alkaline phosphatase
AST (SGOT)
ALT (SGPT)
GGT
CPK
Hematology
Red blood cells
Hemoglobin
Hematocrit
Platelets
MCV, MCH, MCHC
White blood cells
(WBC)
WBC Differential 
(% and absolute)

Neutrophils

Eosinophils

Basophils

Lymphocytes

Monocytes
Urinalysis
Specific gravity
pH
Protein
P/C ratio
Glucose
Ketones
Urobilinogen
Leukocyte 
esterase
Nitrite
Bilirubin
Blood
Red blood cells
WBC
Epithelial cells
Bacteria
Casts
Crystals
Color
Appearance
Thyroid Panel
TSH
Free T4
Free T3
Coagulation
aPTT
PT
INR
Screening Tests
FSH (women only)
Serum βhCG
PK1
CSF RO7234292
levels
Urine RO7234292
levels
Anti-RO7234292
antibodies
Pregnancy
Urine hCG
 
 
 
 
CSF Biomarker Panel

mu Htt
 


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
81
Appendix B
List of Laboratory Analytes Continued
1
Any of the collected PK 
, CSF and urine samples from the study patients may also be used by 
Sponsor for investigation of possible biomarkers of disease or the pharmacodynamic effects of 
RO7234292 or for profiling of drug binding proteins, bioanalytical method validation purposes, stability 
assessments, metabolite assessments, immunogenicity assessments (including assay development 
and validation purposes) or to assess other actions of RO7234292 with 
 CSF or urine 
constituents.  Also, if a relationship between genetic markers and disease progression becomes 
apparent during the study or within 5 years after the end of the study, the genetic markers may be 
identified in archived samples for investigation of association with drug effect.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
82
Appendix C
PK Sampling Schedule


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
83
Appendix C
PK Sampling Schedule
Study Period
Treatment Period
(62 weeks)
Post-Treatment
Period or Early 
Termination 
Visit**
(12 Weeks)
Loading Period
(6 weeks)
Maintenance Period
(56 Weeks)
Study Week
1
5
9-28
29
30-62
74
Study Day
1
2
29
57, 85, 113, 
141, 169
197
225, 253, 281, 
309, 337, 365, 
393, 421
519
CSF Sampling
Pre-dose
--
Pre-dose
Pre-dose †
Pre-dose
Pre-dose †
Anytime
Urine Sampling
24-hour collection
--
--
--
--
--
--
† 
Pre-dose at dosing visits only.  (See tables in Appendix A, Footnote 1.)
‡ 
Pre-dose at dosing visits; otherwise, sample to be collected at any time during the visit.
**
Only patients who do not enter the open-label label extension study (Study BN40955) will attend the Post-Treatment/End-of-Study visit.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
84
Appendix D
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
85
Appendix D
Grading Scale for Adverse Events Relating to Laboratory Abnormalities
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010.


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
86
Appendix D
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued


BN40697 (ISIS 443139-CS2)
CONFIDENTIAL
Amendment 4 (Version 5)
Protocol
87
Appendix D
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued