Conditions: Huntington's Disease
Keywords: Huntington's Disease HTTRx Early Manifest Huntington's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This study tested the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of ISIS 443139 administered intrathecally to adult participants with early manifest Huntington's Disease.

Detailed description:

Arms:
arm 1: Participants received ISIS 443139, 10 milligrams (mg), by intrathecal injection, on Study Days 1, 29, 57, and 85. arm 2: Participants received ISIS 443139, 30 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. arm 3: Participants received ISIS 443139, 60 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. arm 4: Participants received ISIS 443139, 90 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. arm 5: Participants received ISIS 443139, 120 mg, by intrathecal injection, on Study Days 1, 29, 57, and 85. arm 6: Participants received placebo, by intrathecal injection, on Study Days 1, 29, 57, and 85.

Interventions: intervention 1: ISIS 443139 10 mg intervention 2: ISIS 443139 30 mg intervention 3: ISIS 443139 60 mg intervention 4: ISIS 443139 90 mg intervention 5: ISIS 443139 120 mg intervention 6: Placebo
Intervention descriptions: intervention 1: ISIS 443139, 10 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85. intervention 2: ISIS 443139, 30 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85. intervention 3: ISIS 443139, 60 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85. intervention 4: ISIS 443139, 90 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85. intervention 5: ISIS 443139, 120 mg, was administered by intrathecal injection, on Study Days 1, 29, 57, and 85. intervention 6: Placebo was administered by intrathecal injection, on Study Days 1, 29, 57, and 85.

Protocol document:
Prot_SAP_000.pdf: 
This supplement contains the following items: 
1. Original protocol, final protocol, summary of changes. 
2. Original statistical analysis plan, final statistical analysis plan, summary of changes. 
 
 
Original Protocol…………………………………………………………………………………………..2 
 
Final Protocol……………..…………………………………………………………………..…………78 
 
Summary of Changes to Protocol……………………………………………………………………162 
 
Original Statistical Analysis Plan…….…………………………………………….………….....…..164 
 
Final Statistical Analysis Plan….....………………………………………………………………….199 
 
Summary of Changes to Statistical Analysis Plan…...…………………………………………….235 


ISIS PHARMACEUTICALS, INC. 
ISIS 443139-CS1 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Multiple Ascending Doses of Intrathecally Administered 
ISIS 443139 in Patients with Early Manifest Huntington’s Disease 
Original Protocol – 6 March 2015 
EudraCT No:  2015-000381-66 
Sponsor: 
Isis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 


PPD
PPD


ISIS 443139-CS1 
CONFIDENTIAL 
Original  
Protocol 
 
6 March 2015 
 
3 
 
ISIS 443139 
Isis Protocol Number ISIS 443139-CS1 
Original Protocol 
EudraCT No:  2015-000381-66 
 
 
Clinical Phase:  1/2a 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Multiple Ascending Doses of Intrathecally Administered 
ISIS 443139 in Patients with Early Manifest Huntington’s Disease 
Trial Sponsor: 
Isis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
+ 01 760 603 3564 
Key Sponsor Contact: 
 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: 
 
Fax: 
  
Date: 
6 March 2015 
 
Confidentiality Statement 
This document contains confidential information of Isis Pharmaceuticals, Inc. that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Isis Pharmaceuticals, Inc.
PPD
PPD
PPD


ISIS 443139-CS1 
CONFIDENTIAL 
Original  
Protocol 
 
6 March 2015 
 
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Protocol Signature Page 
 
Protocol Number: 
ISIS 443139-CS1 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple 
 
Ascending Doses of Intrathecally Administered ISIS 443139 in Patients 
 
with Early Manifest Huntington’s Disease 
Amendment:  
Original Protocol 
Date:  
 
6 March 2015 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally 
Administered ISIS 443139 in Patients with Early Manifest Huntington’s Disease,” dated 
6 March 2015, and agree to conduct the Study as described herein. 
I agree to comply with the International Conference on Harmonization 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 Isis Pharmaceuticals, Inc. 
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 


ISIS 443139-CS1 
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TABLE OF CONTENTS 
 
Page 
PROTOCOL SYNOPSIS ............................................................................................................10 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................17 
COHORT ENROLLMENT FLOWCHART ............................................................................18 
STUDY GLOSSARY ...................................................................................................................19 
1. 
OBJECTIVES .....................................................................................................................22 
1.1 
Primary Objectives ........................................................................................................22 
1.2 
Secondary Objectives ....................................................................................................22 
1.3 
Exploratory Objectives ..................................................................................................22 
2. 
BACKGROUND AND RATIONALE ..............................................................................22 
2.1 
Overview of Disease ......................................................................................................22 
2.1.1 
Epidemiology .........................................................................................................22 
2.1.2 
Huntingtin Protein ..................................................................................................22 
2.1.3 
Clinical Features and Diagnosis of HD ..................................................................23 
2.1.4 
Treatments for HD ..................................................................................................24 
2.2 
Therapeutic Rationale ....................................................................................................24 
2.3 
ISIS 443139 ...................................................................................................................25 
2.3.1 
Mechanism of Action .............................................................................................25 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................26 
2.3.4 
Clinical Experience ................................................................................................26 
2.4 
Rationale for Study Design ............................................................................................27 
2.4.1 
Rationale for the Study Population ........................................................................27 
2.4.2 
Rationale for a Multiple Ascending Dose Design ..................................................27 
2.4.3 
Rationale for Dose Levels and Dosing Schedule ...................................................28 
3. 
EXPERIMENTAL PLAN ..................................................................................................28 
3.1 
Study Design ..................................................................................................................28 
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 .....................................................................................................29 
3.4.2 
Treatment Period ....................................................................................................30 
3.4.3 
Post-Treatment Period ............................................................................................30 
3.5 
End of Study ..................................................................................................................30 
3.6 
Data and Safety Monitoring Board ................................................................................30 
3.7 
Dose Escalation ..............................................................................................................30 
3.8 
Dose Limiting Toxicity ..................................................................................................31 


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4. 
PATIENT ENROLLMENT ...............................................................................................32 
4.1 
Screening .......................................................................................................................32 
4.2 
Randomization ...............................................................................................................32 
4.3 
Replacement of Patients .................................................................................................32 
4.4 
Unblinding of Treatment Assignment ...........................................................................33 
5. 
PATIENT ELIGIBILITY ..................................................................................................33 
5.1 
Inclusion Criteria ...........................................................................................................33 
5.2 
Exclusion Criteria ..........................................................................................................34 
6. 
STUDY PROCEDURES ....................................................................................................36 
6.1 
Study Schedule ..............................................................................................................36 
6.1.1 
Screening Period (Week -6 to Week -1) ................................................................37 
6.1.2 
Treatment Period (Week 1 to Week 14) .................................................................37 
6.1.3 
Post-Treatment Period (Week 17 to Week 29) or Early Termination ....................37 
6.2 
Study Assessments .........................................................................................................37 
6.2.1 
Capacity to Consent ................................................................................................38 
6.2.2 
International Standard Classification of Education (ISCED) .................................38 
6.2.3 
Columbia Suicide Severity Rating Scale (C-SSRS) ...............................................38 
6.2.4 
Vital Signs Measurement .......................................................................................38 
6.2.4.1 
Seated Blood Pressure Measurement ...............................................................38 
6.2.4.2 
Standing Blood Pressure Measurement for Orthostatic Assessment ...............38 
6.2.5 
Electrocardiogram ..................................................................................................39 
6.2.6 
Physical Measurements (Height and Weight) ........................................................39 
6.2.7 
Physical/Neurological Examination .......................................................................39 
6.2.8 
Electrophysiological Assessments .........................................................................39 
6.2.9 
Neuroimaging Assessments ...................................................................................39 
6.2.10 
Speeded Tapping ....................................................................................................40 
6.2.11 
Unified Huntington’s Disease Rating Scale (UHDRS) ..........................................40 
6.2.11.1 
UHDRS Total Functional Capacity Scale (TFC).............................................41 
6.2.11.2 
UHDRS Independence Scale ...........................................................................41 
6.2.11.3 
UHDRS Total Motor Scale (TMS) ..................................................................41 
6.2.12 
HD Work Function (HDWF) Scale ........................................................................41 
6.2.13 
Montreal Cognitive Assessment (MoCA) ..............................................................41 
6.2.14 
HD Cognitive Battery .............................................................................................41 
6.2.14.1 
Self-Paced Tapping ..........................................................................................42 
6.2.14.2 
Emotion Recognition .......................................................................................42 
6.2.14.3 
CANTAB One Touch Stockings (OTS) ..........................................................42 
6.2.14.4 
Symbol Digit Modalities Test (SDMT) ...........................................................42 
6.2.14.5 
Hopkins Verbal Learning Test – Revised (HVLT-R)......................................42 
6.2.14.6 
Trail-Making Test ............................................................................................43 
6.2.15 
Problems Behavior Assessment for Huntington’s Disease – Short Form (PBA-s)43 


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6.2.16 
Stroop Word Reading Test .....................................................................................43 
6.2.17 
Map Search Test .....................................................................................................43 
6.2.18 
Collection of CSF ...................................................................................................43 
6.2.19 
Laboratory Assessments .........................................................................................43 
6.2.19.1 
Plasma and Serum Laboratory Assessments....................................................44 
6.2.19.2 
CSF Laboratory Assessments ..........................................................................44 
6.2.20 
Pregnancy Testing ..................................................................................................44 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................44 
6.3.1 
Contraception Requirements ..................................................................................44 
6.3.2 
Other Requirements ................................................................................................45 
7. 
STUDY DRUG ....................................................................................................................45 
7.1 
Study Drug Description .................................................................................................45 
7.2 
Packaging and Labeling .................................................................................................46 
7.3 
Study Drug Accountability ............................................................................................46 
8. 
TREATMENT OF PATIENTS .........................................................................................46 
8.1 
Study Drug Administration ............................................................................................46 
8.2 
Other Protocol-Required Drugs .....................................................................................47 
8.3 
Other Protocol-Required Treatment Procedures ............................................................47 
8.4 
Treatment Precautions ...................................................................................................47 
8.5 
Safety Monitoring Rules ................................................................................................47 
8.6 
Stopping Rules ...............................................................................................................47 
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 ..........................................................................48 
8.10 
Concomitant Therapy and Procedures ...........................................................................49 
8.10.1 
Concomitant Therapy .............................................................................................49 
8.10.2 
Concomitant Procedures .........................................................................................51 
8.11 
Treatment Compliance ...................................................................................................51 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................51 
9.1 
Sponsor Review of Safety Information .........................................................................51 
9.2 
Regulatory Requirements ..............................................................................................51 
9.3 
Definitions .....................................................................................................................51 
9.3.1 
Adverse Event ........................................................................................................51 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................51 
9.3.3 
Serious Adverse Event (SAE) ................................................................................52 
9.4 
Monitoring and Recording Adverse Events ...................................................................52 
9.4.1 
Serious Adverse Events ..........................................................................................52 
9.4.2 
Non-Serious Adverse Events ..................................................................................53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................53 
9.4.3.1 
Relationship to the Study Drug ........................................................................53 


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9.4.3.2 
Severity ............................................................................................................53 
9.4.3.3 
Action Taken with Study Drug ........................................................................54 
9.4.3.4 
Treatment Given for Adverse Event ................................................................54 
9.4.3.5 
Outcome of the Adverse Event ........................................................................54 
9.5 
Procedures for Handling Special Situations ..................................................................55 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................55 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............55 
9.5.3 
Dosing Errors .........................................................................................................55 
9.5.4 
Contraception and Pregnancy .................................................................................56 
10. STATISTICAL CONSIDERATIONS ..............................................................................56 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................56 
10.1.1 
Safety and Tolerability Endpoints ..........................................................................56 
10.1.2 
Pharmacokinetic Endpoints ....................................................................................57 
10.1.3 
Exploratory Endpoints ............................................................................................57 
10.2 
Sample Size Considerations ...........................................................................................58 
10.3 
Populations .....................................................................................................................59 
10.4 
Definition of Baseline ....................................................................................................59 
10.5 
Interim Analysis .............................................................................................................59 
10.6 
Planned Methods of Analysis ........................................................................................59 
10.6.1 
Demographic and Baseline Characteristics ............................................................59 
10.6.2 
Safety Analysis .......................................................................................................60 
10.6.3 
Pharmacokinetic Analysis ......................................................................................60 
10.6.4 
Exploratory Analysis ..............................................................................................61 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................61 
11.1 
Informed Consent ..........................................................................................................61 
11.2 
Ethical Conduct of the Study .........................................................................................61 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................62 
11.4 
Patient Confidentiality ...................................................................................................62 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................62 
12.1 
Protocol Amendments ....................................................................................................62 
12.2 
Study Termination .........................................................................................................63 
12.3 
Study Documentation and Storage ................................................................................63 
12.4 
Study Monitoring ...........................................................................................................63 
12.5 
Language ........................................................................................................................64 
12.6 
Compensation for Injury ................................................................................................64 
13. REFERENCES ....................................................................................................................65 
14. APPENDICES .....................................................................................................................68 
Appendix A 
Schedule of Procedures ....................................................................................69 
Appendix B 
List of Laboratory Analytes .............................................................................74 
Appendix C 
PK Sampling Schedule ....................................................................................76 


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TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ................................................................................... 46 
Table 2 
Study Drug Dosing Information ........................................................................... 47 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of ISIS 443139 .......................................................................................... 26 
 
 
 


ISIS 443139-CS1 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of 
Intrathecally Administered ISIS 443139 in Patients with Early Manifest Huntington’s 
Disease 
Study Phase 
Phase 1/2a 
Primary Objectives 
To evaluate the safety and tolerability of ascending dose-levels of multiple intrathecal 
(IT) bolus administrations of ISIS 443139 to patients with Huntington’s disease (HD) 
Secondary Objectives 
To characterize the cerebrospinal fluid (CSF) pharmacokinetics of ascending dose-
levels of multiple IT administrations of ISIS 443139 
Exploratory Objectives 
To explore effects of multiple doses of ISIS 443139 on pharmacodynamic biomarkers 
and clinical endpoints relevant to HD.  Plasma pharmacokinetic properties will also be 
assessed. 
Study Design 
ISIS 443139-CS1 is a multi-center, Phase 1/2a, randomized, double-blind, placebo-
controlled study of ascending dose levels of multiple IT administrations of ISIS 443139 
(“slow push” IT bolus) in patients with early manifest HD aged 25-65 years, inclusive. 
Four dose level cohorts (A, B, C and D) will be enrolled sequentially, with patients 
randomized to Study Drug or to placebo in a 3 to 1 ratio.  Cohort A will comprise 
4 patients, Cohorts B and C will comprise 8 patients and Cohort D will comprise 
16 patients.  All patients will be disease “Stage 1” out of a possible five stages, where 
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.  These stages also correlate with scores on the 
13-point UHDRS Total Functional Capacity (TFC) Scale, with Stage 1 corresponding to 
TFC scores of 11-13.  Randomization in Cohort D will be stratified by early Stage 1 
(TFC ≥ 12) or late Stage 1 (TFC = 11) disease. 
Each patient will receive 4 doses of Study Drug with a 28-day interval between doses.  
Patients not completing a course of 4 IT bolus injections may be replaced up to a limit 
of 25% of the cohort sample and only if the reason for premature discontinuation from 
the Treatment Period does not involve a dose-limiting toxicity (DLT). 
Following the 3-month Treatment Period, there will be a 4-month Post-treatment 
Period.  After study completion, an open-label extension study of ISIS 443139 will be 
implemented if this is warranted based on review of safety, tolerability, pharmacokinetic 
and exploratory pharmacodynamic findings. 
Number of Patients 
Approximately 36 patients will be enrolled in this study. 
The number of patients enrolled may be higher if some patients need to be replaced 
and/or if the sizes of certain cohorts are expanded to obtain further experience with 
particular dose levels.  A maximum of 48 patients may be enrolled. 
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 
2. 
Must be capable of giving informed consent (in the opinion of the Investigator) 
Target Population 
3. 
Early manifest, Stage 1 HD (defined as TFC of 11-13, inclusive), aged 25 to 
65 years, inclusive, at the time of informed consent, with genetically confirmed 
disease (CAG repeat length ≥ 36 in huntingtin gene by direct DNA testing) 
4. 
Body Mass Index (BMI) ≥ 18 and ≤ 32 kg/m2; total body weight > 50 kg (110 lbs) 
 
 


ISIS 443139-CS1 
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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
5. 
Able and willing to meet all study requirements in the opinion of the Investigator, 
including travel to Study Center, procedures, measurements and visits, 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 and at the time of enrollment 
f. 
Patients must reside in a proximity to the Study Center that permits prompt 
appearance at the facility if requested by the Investigator (maximum of 
4-hour travel to Study Center) 
Reproductive Status 
6. 
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 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of 
signing the informed consent form until at least 13 weeks after the last dose 
of Study Drug (ISIS 443139 or placebo) 
If not surgically sterile, must have a negative β-HCG pregnancy test at 
Screening and prior to each dose administration 
7. 
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 13 weeks after the last dose of Study Drug (ISIS 443139 or 
placebo) 
Exclusion Criteria: 
Target Disease-Related Exclusions 
1. 
Any condition, including severe chorea, that would prevent either writing or 
performing rapid computer tasks 
Physical, Mental and Laboratory Test Findings 
2. 
Attempted suicide, suicidal ideation with a plan that required hospital admission 
and/or change in level of care within 12 months prior to Screening.  For patients 
with (i) a suicide ideation score ≥ 4 on the Columbia Suicide Severity Rating 
Scale (C-SSRS) within the last 12 months, (ii) a score of 3 or 4 on question 2 of 
the Problems Behavior Assessment for Huntington’s Disease – short form or 
(iii) suicidal behaviors within the last 12 months (as measured by the answer 
“Yes” on any of the C-SSRS Suicidal Behavior Items), a risk assessment should 
be done by an appropriately-qualified mental health professional (e.g., a 
Psychiatrist or licensed Clinical Psychologist) to assess whether it is safe for the 
patient to participate in the study.  In addition, patients deemed by the 
Investigator to be at significant risk of suicide, major depressive episode, 
psychosis, confusional state or violent behavior should be excluded 


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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
3. 
Clinically significant laboratory, vital sign or ECG abnormalities at Screening 
(including heart rate (HR) < 45 bpm; SBP < 90 mmHg; confirmed BP readings 
> 170/105 mmHg) 
4. 
Positive test for human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B at Screening 
Prohibited and Restricted Medications and Procedures 
5. 
Treatment with another investigational drug, biological agent, or device within one 
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 
6. 
Current or recent (within the last 6 months) use of antipsychotics (prescribed for 
psychosis), cholinesterase inhibitors, memantine, amantadine or riluzole.  Stable 
use of antipsychotics (prescribed for treatment of motor symptoms) and/or 
tetrabenazine is not permitted 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 
7. 
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 
8. 
Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for 
6 weeks prior to Screening and with a dose regimen that is not anticipated to 
change during the study 
9. 
Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or 
anticipated use during the study, including but not limited to aspirin (unless 
≤ 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and 
apixaban 
10. Active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed at least 3 days prior to the first day Study Drug is administered to 
the patient (Study Day 1) 
11. Prior treatment with an antisense oligonucleotide (including siRNA) 
12. Any history of gene therapy or cell transplantation or any other experimental brain 
surgery 
13. Presence of an implanted shunt for the drainage of CSF or an implanted CNS 
catheter 
Medical History and Concurrent Disease 
14. Significant history of alcoholism or drug/chemical abuse 
15. Clinically relevant hematological, hepatic, cardiac or renal disease or event (e.g., 
previous acute coronary syndrome within 6 months of Screening).  Abnormal 
hepatic, renal or hematology lab tests must be discussed with the Sponsor 
Medical Monitor 
16. Known history of human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
17. Any condition that increases risk of meningitis unless patient is receiving 
appropriate prophylactic treatment 
18. History of bleeding diathesis or coagulopathy, platelet count < LLN 
19. A medical history of brain or spinal disease that would interfere with the LP 
process, CSF circulation or safety assessment, including tumors or abnormalities 
by MRI or computed tomography (CT), subarachnoid hemorrhage, suggestion of 
raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or 
curvature, chiari malformation, hydrocephalus, syringomyelia, tethered spinal 
cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome 
and Marfan syndrome 
 
 


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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
20. History of post-lumbar-puncture headache of moderate or severe intensity 
and/or blood patch 
21. 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 
22. Hospitalization for any major medical or surgical procedure involving general 
anesthesia within 12 weeks of Screening or planned during the study 
23. Have any other conditions which, in the opinion of the Investigator, would 
make the patient unsuitable for inclusion or could interfere with the patient 
participating in or completing the study 
Treatment Groups 
ISIS 443139, Placebo 
There will be 4 multiple-dose cohorts (n = 4, 8 or 16 per cohort, randomized 3 active: 
1 placebo).  Patients will receive 4 IT bolus doses of Study Drug at 4 week intervals 
during the 3 month Treatment Period (Days 1, 29, 57, 85).  For patients who receive 
ISIS 443139, planned total dose is shown in the table below. 
Planned Dose of Active Study Drug 
# of doses 
Total ISIS 443139 
Cohort A:  10 mg ISIS 443139 
4 
40 mg 
Cohort B:  30 mg ISIS 443139 
4 
120 mg 
Cohort C:  50 mg ISIS 443139 
4 
200 mg 
Cohort D:  70 mg ISIS 443139 
4 
280 mg 
 
Study Drug Dosage and 
Administration 
Each dose of ISIS 443139 or placebo 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. 
Dosing instructions and details regarding administration will be provided in the Study 
Drug manual.  The site pharmacist will be blinded to treatment assignment. 
Dose Escalation 
Four dose level cohorts (Cohorts A, B, C and D) will be enrolled sequentially, with 
patients each receiving 4 doses of Study Drug at 28-day intervals.  The progression of 
the study from one cohort to the next will be determined by the Sponsor in collaboration 
with the Data and Safety Monitoring Board (DSMB) and will generally be based on the 
number of DLTs observed in patients treated with ISIS 443139. 
Beginning with Cohort B, dose administration in a cohort may commence only after 
(1) all patients in the prior cohort have been enrolled, (2) at least 4 patients in the prior 
cohort have received a cumulative dose that is equal to or greater than the initial dose 
planned for the cohort and safety in these patients has been monitored for at least 
7 days post-treatment after reaching that cumulative dose, and (3) safety results for all 
patients enrolled in the prior cohorts have been reviewed by the DSMB.  The 
occurrence of DLTs in 2 patients in a cohort will result in the dose tested in the cohort 
being dose limiting in this study. 
If a single DLT is encountered in Cohort A, the cohort may be expanded up to 
8 patients to assess safety at that dose.  Other dose cohorts (Cohorts B, C and D) may 
also be expanded up to 100% if a single DLT is encountered in those cohorts.  If dosing 
in higher dose cohort(s) is ongoing at the time a single DLT is encountered in a lower 
dose cohort, further enrollment in the higher dose cohort(s) will stop until all current 
patients have completed dosing and at least 7 days of post-dose safety evaluations.  In 
addition, the DSMB will convene to decide if further measures are required such as 
pausing or reducing dosing in ongoing patients in the higher dose cohort(s). 
 
 


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PROTOCOL SYNOPSIS Continued 
Dose Escalation 
Continued 
The occurrence of DLTs in (i) 2 patients in a cohort or (ii) a single SAE that is life 
threatening and that is evaluated by the Sponsor as related to Study Drug in a cohort 
will result in termination of further dosing in that cohort and any higher dose cohort that 
is also ongoing. 
Rationale for Dose and 
Schedule Selection 
ISIS 443139 dose levels and dose interval for ISIS 443139-CS1 were selected based 
on preclinical toxicology and pharmacokinetic observations.  
 
 
  Monthly dosing is expected to achieve ISIS 443139 brain cortex tissue 
levels at steady state by Day 92, and is expected to be safe and well-tolerated by 
patients. 
Study Visit Schedule 
and Procedures 
After informed consent is obtained, patients will undergo a screening evaluation during 
a 6-week period prior to baseline.  Patients who meet the eligibility criteria will visit the 
Study Center on Study Day -1 to undergo baseline clinical, blood, and 
electrophysiological evaluations and for re-assessment of eligibility.  On Study Day 1, 
patients will be admitted to the Study Center, undergo pre-dose evaluations of vital 
signs and then receive an IT bolus injection (slow push) of ISIS 443139 or placebo 
(3:1).  Following the initial LP injection on Day 1, patients will be kept at the Study 
Center for at least 24 hours and carefully monitored for any adverse clinical symptoms 
or signs.  This inpatient post-dose assessment may be reduced to a minimum of 
6 hours following the 2nd, 3rd and 4th dose administrations provided a visit is made to 
the Study Center the next day.  Assessments during these admission periods include 
neurological, electrophysiological and physical examination, vital signs, ECGs, blood 
sampling and clinical laboratory analyses.  Full standard neurological assessment 
(including fundi) will be performed 3 hours post-dosing with Study Drug and prior to 
discharge from the Study Center. 
Study Drug administration will take place on Study Days 1, 29, 57 and 85.  In the 
Treatment Period, Study Center visits are held on Study Days 1, 2, 8, 28, 29, 30, 36, 
56, 57, 58, 84, 85 and 86. 
During the Post-Treatment Period, patients will visit the Study Center on Study 
Days 113, 169 and 197 (study completion visit). 
In addition, the Study Center will monitor the patient’s condition through telephone 
contact on Study Day 3, 31, 59, 64, 87 and 92. 
CSF samples will be taken pre-dose on each Study Drug IT injection day (Days 1, 29, 
57, 85) and on Day 113 or 169.  These samples will be utilized for PK, Htt protein and 
other biomarker and laboratory analyses. 
If a patient terminates early from the Treatment Period of the study, he/she will be 
encouraged to return for the near-term follow-up visits associated with the most recent 
dose of Study Drug and for the Post-Treatment Period (Days 113-197). 
Safety and Tolerability 
Evaluations 
Safety and tolerability evaluations will 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 
• 
Clinical and neuroimaging (including safety sequences) assessments 
 
 
CCI


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PROTOCOL SYNOPSIS Continued 
Safety and Tolerability 
Evaluations Continued 
The safety and tolerability of ISIS 443139 will be assessed by determining the 
incidence, severity and dose-relationships of AEs and changes in laboratory 
parameters by dose.  In addition, clinical, electrophysiological and volumetric 
neuroimaging assessments will be used to monitor for unexpected deterioration.  
Safety results in patients dosed with ISIS 443139 will be compared with those from 
patients dosed with placebo.  Placebo-treated patients will be pooled for analysis. 
Pharmacokinetic 
Evaluations 
A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and 
at one Post-Treatment Period visit (either Study Day 113 or 169) for PK analyses.  The 
CSF concentrations will be summarized using descriptive statistics and the 
ISIS 443139 half-life in CSF will be calculated, if possible.  Analysis of the levels of 
ISIS 443139 in CSF is of key importance. 
In addition, plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and 
at each Post-Treatment Period visit for PK analyses.  Plasma maximum concentration 
(Cmax), area under the curve (AUC), elimination half-life and trough and post-distribution 
drug levels will be assessed, where appropriate. 
Exploratory Evaluations Exploratory evaluations will include: 
• 
Biochemical 
o 
CSF levels of mutant Htt* and total Htt 
o 
Potential biomarkers of HD disease progression 
 
CSF:  neurofilament light chain*, proenkephalin, clusterin, factor H (FH), 
C3, interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1 
beta (IL-1β), MCP-1, chitinase-3-like protein 1 (YKL-40), visinin-like 
protein 1 (VILIP1), apolipoprotein, chromogranin B, neurogranin, 
SNAP25, S100B and tau 
 
Plasma:  IL-6, TNFα and 24S-hydroxycholesterol 
• 
Neuroimaging 
o 
Structural MRI volumes, including but not limited to: 
 
Caudate  
 
Whole brain  
 
Ventricular* 
o 
MRS spectroscopy for frontal lobe myoinositol and N-Acetylaspartic acid 
(NAA) 
o 
Resting state functional MRI 
o 
Neurite orientation dispersion and density imaging (NODDI) 
• 
Electrophysiological 
o 
qEEG 
• 
Clinical 
o 
Functioning/ability to perform activities of daily living 
 
UHDRS Total Functional Capacity Scale (TFC) 
 
UHDRS Independence Scale 
 
HD Work Function Scale 
o 
Cognitive and motor tests: 
 
HD Cognitive Battery* 
• 
Self-Paced Tapping 
• 
Emotion Recognition 
• 
CANTAB One Touch Stockings 
• 
Symbol Digit Modalities Test  
• 
Hopkins Verbal Learning Test Revised 
• 
Trail Making Test Part B 
 
UHDRS Total Motor Scale 
 
Map Search Test 
 
Stroop Word Reading Test 
 
Speeded Tapping 
o 
Neuropsychiatric evaluation  
 
Problems Behavior Assessment for Huntington’s disease-short form 
(PBA-s) 


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PROTOCOL SYNOPSIS Continued 
Exploratory Evaluations 
Continued 
Evaluations will include comparisons between ISIS 443139-treated patients and 
placebo-treated patients of the above biomarkers and clinical evaluations.  If CSF Htt 
protein level is reflective of target engagement, exploratory evaluations will be 
conducted to relate dose and PK to CSF Htt protein level.  Placebo-treated patients will 
be pooled for analysis. 
* 
Key exploratory biochemical, neuroimaging, electrophysiological and clinical 
assessments 
Statistical 
Considerations 
While there is no statistical basis for the sample size, it has been selected based on 
prior experience with generation 2 ASOs given by IT injection to ensure that the safety, 
tolerability, pharmacokinetics and exploratory pharmacodynamics will be adequately 
assessed while minimizing unnecessary patient exposure. 
Sponsor 
Isis Pharmaceuticals, Inc. 
 
 


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STUDY DESIGN AND TREATMENT SCHEMA
 
END-OF-STUDY PROCEDURES 
or Early Termination from Post-
Treatment 
Day 197 
(Week 29) 
SCREENING PERIOD 
 
Days -43 to -2 
 
(Weeks -6 to -1) 
•
Assess capacity to consent, collect 
informed consent 
•
Assess eligibility 
POST-TREATMENT PERIOD 
Days 113 to 197 
(Weeks 17 to 29) 
DOSE TREATMENT PERIOD 
Days -1 to 92 
(Weeks 1 to 14) 
 
Monthly Study Drug Administration 
(ISIS 443139: placebo, 3:1) 
•
Cohorts of patients will be enrolled sequentially 
•
Each patient will receive 4 doses of study 
medication 
•
Cohort enrollment will be staggered.  Initiation 
of dosing in a new cohort will occur after 
(1) enrollment of the prior cohort is complete 
and (2) review of prior cohort data has been 
conducted as depicted in the Cohort 
Enrollment Flowchart below 
EARLY TREATMENT 
TERMINATION 
• If patient is willing to continue with 
the study: 
o complete the block of visits 
associated with the last dose 
received (see * in Appendix A) 
o complete the visit scheduled for 
7 days after the last dose received 
o conduct the Week 17 visit 
approximately 4 weeks after last 
dose and proceed with the Post-
treatment Period 
• If patient is not willing to continue 
with the study, conduct Week 29 as 
an Early Termination Visit 


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COHORT ENROLLMENT FLOWCHART 
 
*  DSMB and Sponsor review of data to permit initiation of dosing in a new cohort will occur when:  
•
at least 4 patients in the current cohort have received multiple doses of Study Drug such that 
the cumulative dose received by each of these patients meets or exceeds the initial dose 
planned for the new cohort and 
•
safety data have been collected in these patients through at least 7 days after receipt of the 
necessary cumulative dose. 
Prior to initiating dosing in a new cohort, the DSMB will review the safety data described above (at 
minimum) and make a recommendation regarding initiation of the new cohort. 
Additionally, the Sponsor may conduct a blinded review (or reviews) of accumulating 
pharmacokinetic data and compare those data to the ISIS 443139 levels that are expected to 
produce a pharmacologic effect (according to the preclinical PK/PD model).  Based on this review, 
the dose level(s) for future cohort(s) may be adjusted.  The maximum dose level tested in a cohort 
will not exceed 70 mg. 
10 
mg 
10 
mg 
10 
mg 
10 
mg 
Post-treatment Period 
Cohort 
A 
(N = 4) 
30 
mg 
30 
mg 
30 
mg 
30 
mg 
Post-treatment Period 
Cohort 
B 
(N = 8) 
50 
mg 
50 
mg 
50 
mg 
50 
mg 
Post-treatment Period 
Cohort 
C 
(N = 8) 
70 
mg 
70 
mg 
70 
mg 
70 
mg 
Post-treatment Period 
Cohort 
D 
(N = 16) 
screen 
screen 
screen 
screen 
Note:  Each         represents one dose followed by a 28-day observation period.   
The Post-treatment Period is 15 weeks. 
Review* 
Review* 
Review* 


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STUDY GLOSSARY  
Abbreviation 
Definition 
2ʹMOE 
2ʹ-O-(2-methoxyethyl) 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AP 
Anterior-posterior 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
AUCt 
Area under the plasma concentration-time curve from time zero to time t 
βhCG 
Beta-subunit of human chorionic gonadotropin (pregnancy test) 
BCHE-K 
Butyrylcholinesterase K variant 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Cmax 
Maximum concentration 
cl 
Clinic 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia suicide severity rating scale 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
DLT 
Dose-limiting toxicity 
DSMB 
Data And Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
FH 
Factor H 
FSE 
Fast spin echo 
GCP 
Good Clinical Practice 
1H-MRS 
Proton magnetic resonance spectroscopy 
HD 
Huntington’s disease 
HDWF 
Huntington’s disease work function 


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Htt 
Huntingtin protein 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HVLT-R 
Hopkins verbal learning test - revised 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-1β 
Interleukin-1 beta 
IL-6 
Interleukin-6 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISIS 443139 
Antisense inhibitor of Htt 
IT 
Intrathecal(ly) 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP-1 
Monocyte chemoattractant protein-1 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
mI 
Myo-inositol 
MoCA 
Montreal cognitive assessment 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MRS 
Magnetic resonance spectroscopy 
MTD 
Maximum tolerated dose 
NAA 
N-Acetyl-aspartate 
NCS 
Not clinically significant  
NODDI 
Neurite orientation dispersion and density imaging 
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 
PK 
Pharmacokinetic(s) 


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PBA-s 
Problems behavior assessment for Huntington’s disease – short form 
PT 
Prothrombin time 
qEEG 
Quantitative EEG 
rsfMRI 
Resting state functional MRI 
RNase H 
Ribonuclease H (a non-specific endonuclease and catalyzes the cleavage 
of RNA via a hydrolytic mechanism) 
S100B 
S100 calcium binding protein B 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
siRNA 
Small interfering ribonucleic acid 
SAP 
Statistical Analysis Plan 
SNAP25 
Synaptosomal-associated protein 25 
Study Day 1 
Defined as the first day Study Drug is administered to the patient 
Study Drug 
ISIS 443139 or placebo 
SUSAR 
Suspected unexpected serious adverse reaction 
SDMT 
Symbol digit modalities test 
TEAE 
Treatment-emergent adverse event 
TFC 
Total functional capacity 
Tmax 
Time to maximal concentration 
TMS 
Total motor scale 
TMT-A 
Trail-making test part A 
TMT-B 
Trail-making test part B 
TNFα 
Tumor necrosis factor alpha 
TSE 
Turbo spin echo 
UHDRS 
Unified Huntington’s disease rating scale 
VILIP1 
Visinin-like protein 1 
WBC 
White blood cell 
YKL-40 
Chitinase-3-like protein 1 


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1. 
OBJECTIVES 
1.1 
Primary Objectives 
To evaluate the safety and tolerability of ascending dose-levels of multiple intrathecal (IT) bolus 
administrations of an antisense inhibitor of Htt (ISIS 443139) to patients with Huntington’s 
disease (HD) 
1.2 
Secondary Objectives 
To characterize the cerebrospinal fluid (CSF) pharmacokinetics (PK) of ascending dose-levels of 
multiple IT administrations of ISIS 443139. 
1.3 
Exploratory Objectives 
To explore effects of multiple doses of ISIS 443139 on potential target engagement and disease 
progression biomarkers and clinical endpoints relevant to HD.  Plasma pharmacokinetic 
properties of ISIS 443139 will also be assessed.  Disease progression markers are included 
primarily as a safety measure to document any marked worsening.  A lesser objective is to gain 
experience with these measures in an ISIS 443139 clinical study as preparation for subsequent, 
longer-term clinical studies.  It is not expected that the majority of biomarkers and clinical 
measures will be impacted significantly by the 3 months of dosing planned for this study.  For 
the current study, select disease progression markers are considered to be key exploratory target 
engagement, biochemical, neuroimaging and cognitive assessments based on their potential to 
evidence changes in disease progression in early HD.  These key exploratory endpoints are 
mutant Htt in CSF, neurofilament light chain in CSF, ventricular volume as assessed by 
structural MRI and the composite cognitive score resulting from assessment of the components 
of the HD Cognitive Battery. 
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). 
2.1.2 
Huntingtin Protein 
While the exact function of Htt has been elusive, studies suggest that Htt 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, 


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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 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 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.  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 
the illness until death.  The manifest disease period can be subdivided into five 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 five stages also correlate with score on the UHDRS Total 
Functional Capacity (TFC) Scale, with Stage 1 corresponding to TFC scores of 11-13, Stage 2 to 
scores of 7-10, Stage 3 to scores of 3-6, Stage 4 to scores of 1-2 and Stage 5 to a score of 0 
(Shoulson et al. 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 


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cognitive disturbances (Folstein et al. 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), a vesicular monoamine transporter 2 inhibitor, is the 
only drug currently approved for HD, and its label is specific for hyperkinetic motor disorders 
with Huntington’s chorea.  Tetrabenazine is approved in the United States, New Zealand, 
Australia, Canada, Israel and some European countries.  However, the drug has been linked to 
many significant adverse events (AEs), including Parkinsonism, akathisia, sedation, depression 
and suicidal thoughts (Xenazine label 2011).  Tetrabenazine is contraindicated in patients who 
are actively suicidal and in patients with untreated or inadequately treated depression 
(Xenazine label 2011), a population that includes approximately > 40% of HD patients 
(Chen et al. 2012).  Additionally, tetrabenazine 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 (muHtt) (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 


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mechanism.  Because the genetic origin of HD is localized to just one gene, inhibiting HTT 
expression is a promising therapeutic option (Stanek et al. 2013). 
ISIS 443139 is being developed to reduce the synthesis of Htt by targeting HTT mRNA and 
directing its catalytic degradation through the action of ribonuclease H (RNase H), 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 muHtt 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 ISIS 443139 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. 
2.3 
ISIS 443139 
2.3.1 
Mechanism of Action 
ISIS 443139 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 
ISIS 443139 to the cognate mRNA results in the RNase H-mediated degradation of the HTT 
mRNA, thus preventing production of the Htt protein.  Both wild-type and mutant HTT mRNA 
are targeted by ISIS 443139. 
2.3.2 
Chemistry 
Chemically, ISIS 443139 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer). 
 
.  The nucleotide sequence of ISIS 443139 (Figure 1) is 
complementary to a 20-nucleotide stretch 
 of the HTT mRNA. 
 
.  These 
MOE-modified nucleotides confer (1) increased affinity to the target mRNA  
(Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003) and (3) amelioration of 
some high dose toxicities resulting in an improved safety profile compared to first generation 
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antisense drugs containing phosphorothioate-modified oligodeoxynucleotides (DNA)  
(Henry et al. 2000).  The central portion of the oligonucleotide is composed of 
  ISIS 443139 employs this chimeric structure to enable use of the RNase H-
mechanism for antisense activity.  While the 2′-MOE modification confers increased stability 
and affinity, it does not support RNase H catalysis of RNA hybridized to 2′-MOE-modified 
nucleotides (McKay et al. 1999) because conformational changes induced in the heteroduplex by 
2′-alkoxy:RNA hybrids are not recognized by RNase H enzymes (Inoue et al. 1987; Monia et al. 
1993).  By limiting the 2′-MOE modification to nucleotides flanking the phosphorothioate 
oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry are preserved while 
also retaining RNase H recognition. 
Figure 1 
Design of ISIS 443139 
 
2.3.3 
Preclinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.4 
Clinical Experience 
ISIS 443139 has not been evaluated in any clinical setting. 
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2.4 
Rationale for Study Design 
2.4.1 
Rationale for the Study Population 
This is the first study of ISIS 443139 in humans, and it will be conducted in patients with early 
manifest HD.  Early manifest HD patients are generally active and independent in most areas of 
functioning (often still working or driving).  These patients are fully capable of informed 
consent.  It is necessary to conduct this study in patients, rather than in healthy volunteers, for 
two reasons.  First, a better understanding of the safety of ISIS 443139 in its intended target 
population will be achieved in patients since the intended target of the Study Drug (i.e., mutant 
HTT mRNA transcripts) is not present in healthy volunteers.  Second, ISIS 443139 must be 
administered via intrathecal (IT) administration, and consideration of the balance between risk 
and benefit justifies investigation in a patient population only.  Although assessment of safety is 
the primary objective of this study, HD patients who enroll in this study will be relatively early 
in the manifest disease process and may experience benefit from the investigational treatment if 
it addresses the primary pathogenesis of the disease. 
Eligible patients will be aged ≥ 25 years of age to avoid very high CAG repeats associated with 
early disease onset (e.g., > 55 repeats) as such patients are considered to have a somewhat 
different, rapidly-progressing phenotype.  Eligible patients will also be ≤ 65 years of age to avoid 
undesirable comorbidity that is more common above this age. 
2.4.2 
Rationale for a Multiple Ascending Dose Design 
This is a first-in-man, multiple ascending dose (MAD) study in patients with HD.  This design is 
rational given the prolonged time between doses and the rarity of the patient population.  Also, 
the study is designed with a focus on patient safety. 
The study is designed to capture the information that would ordinarily be obtained in two 
separate studies – a single ascending dose (SAD) study and a MAD study.  The length of the 
dosing interval makes this design feasible.  With Study Drug dosing at 28-day intervals, 
comprehensive safety, tolerability and pharmacokinetic evaluations can be conducted in each 
patient for 28 days after the first dose.  This is comparable to the evaluation that would be 
conducted in a SAD study.  At the conclusion of this 28-day period, monthly dosing will 
continue (in the absence of significant safety issues related to Study Drug) for three additional 
doses, allowing for evaluation of safety, tolerability and pharmacokinetics during a multiple-dose 
regimen. 
This design, which eliminates the need for a SAD study, is appropriate because of the nature of 
the patients under investigation.  These are rare patients with a devastating disease, and Study 
Drug has to be administered by IT injection.  Therefore, it is important to obtain a maximum 
amount of information from each patient enrolled in each study conducted in this population. 
Patient safety is paramount with this study design.  For example, only clinical research facilities 
with capabilities for 24-hour in-patient monitoring will be utilized, and patients will be required 
to live close enough to the facility to permit prompt appearance at the facility if requested.  Each 
patient will be required to have a trial partner (i.e., a reliable and competent individual with a 
close relationship with the patient), and the Investigator will seek supplemental information 
about the patient’s condition from the trial partner using validated assessment tools.  In addition, 


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patient safety during the study will be monitored closely and on an ongoing basis by an 
independent, unblinded Data Safety Monitoring Board (DSMB). 
2.4.3 
Rationale for Dose Levels and Dosing Schedule 
The proposed study will test the safety, tolerability, and PK of multiple doses of ISIS 443139 
administered as IT injections.  Four dose levels will be evaluated .  The doses are predicted to 
produce a range of pharmacologic effect but are not intended to elicit dose-limiting toxicities. 
ISIS 443139 dose levels and dose interval for ISIS 443139-CS1 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.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
.  The dose 
interval (administration every 28 days) was selected based on the nonclinical pharmacokinetic 
and pharmacodynamic (HTT mRNA reduction) data required to achieve ISIS 443139 brain 
cortex tissue levels that are predicted to be at steady state by Day 92 and to achieve reduction in 
HTT mRNA levels.  Also, monthly dosing is expected to be safe and well-tolerated by patients. 
Additional details on dose scaling and expected CSF and tissue concentrations are summarized 
in the Investigator’s Brochure. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 1/2a, multi-center, double-blind, randomized, placebo-controlled, dose-escalation 
study conducted in patients with early manifest HD.  The study consists of four cohorts (n = 4-16 
per cohort, randomized 3 active:1 placebo).  The doses planned for the study are shown below.  
Based on emerging safety data from this study, one or more cohorts may be expanded by 
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enrolling additional patients.  Additionally, pharmacokinetic and pharmacodynamic measures 
will be collected at each dose level and compared to the results that are predicted by models 
constructed from preclinical data.  The doses utilized in remaining cohorts may be adjusted, or 
an additional cohort may be added, if necessary to achieve pharmacologically relevant levels.  
The maximum dose tested in a cohort will not exceed 70 mg. 
Cohort A: 
N = 4, 10 mg ISIS 443139 or placebo (3:1) 
Cohort B: 
N = 8, 30 mg ISIS 443139 or placebo (6:2) 
Cohort C: 
N = 8, 50 mg ISIS 443139 or placebo (6:2) 
Cohort D: 
N = 16, 70 mg ISIS 443139 or placebo (12:4) 
Randomization in Cohort D will be stratified by early Stage 1 (TFC ≥ 12) or late Stage 1 
(TFC = 11) disease, where Stage 1 represents the highest level of capacity of the 5 stages of 
manifest disease. 
Patients will receive 4 monthly IT doses of Study Drug (ISIS 443139 or placebo).  Cohorts will 
be enrolled sequentially.  Initiation of dosing in a new cohort may begin after three conditions 
have been met:  (1) all patients in the lower-dose cohorts have been enrolled; (2) at least four 
patients in the lower-dose cohort have been followed for 7 days after receipt of a cumulative 
dose that meets or exceeds the initial dose for the next higher dose level cohort; and (3) a review 
of data collected in the lower-dose cohorts has been conducted by the DSMB and a decision has 
been made to proceed with the next cohort (see Section 3.7). 
After study completion, an open-label extension study of ISIS 443139 may be implemented if 
warranted based on review of safety, tolerability, pharmacokinetic and exploratory 
pharmacodynamic findings and subject to approval by the relevant Competent Authorities and 
Ethics Committees. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Approximately 36 patients are planned to be enrolled in this study.  The number of patients 
enrolled may be higher if some patients need to be replaced and/or if the sizes of the cohorts are 
expanded to obtain further experience with particular dose levels.  A maximum of 48 patients 
may be enrolled. 
3.4 
Overall Study Duration and Follow-up 
The overall study duration will be approximately 7-8 months.  The study will consist of a 
Screening Period of up to 6 weeks, a 13-week Treatment Period and a 15-week Post-Treatment 
Period.  Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Screening Period 
Patient eligibility for the study will be determined within 6 weeks prior to patient entry into the 
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3.4.2 
Treatment Period 
Eligible patients will report to the Study Center for monthly administration of Study Drug and 
for additional, non-dosing visits as described in the Schedule of Procedures in Appendix A. 
In Cohorts A and B, no more than one patient may begin the Treatment Period on a given day.  
In later cohorts, the first two patients in the cohort may not begin the Treatment Period on a 
given day. 
3.4.3 
Post-Treatment Period 
Patients will return to the Study Center for follow-up visits 4, 12 and 16 weeks after the last dose 
of Study Drug.  The final study visit will be Study Day 197/Week 29. 
3.5 
End of Study 
The end of study is defined as last patient, last study visit. 
3.6 
Data and Safety Monitoring Board  
An independent and unblinded DSMB will be assembled to review data collected on 
ISIS 443139 during this study.  Based on its ongoing assessment of the safety and tolerability of 
ISIS 443139, the DSMB will provide recommendations to the Sponsor for modifying, stopping 
or continuing the study as planned.  The progression of the study from the one cohort to the next 
will be determined by the Sponsor and the DSMB, and this determination will generally be based 
on the number of dose-limiting toxicities (DLTs) observed in patients treated with ISIS 443139. 
Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data will be outlined in the DSMB Charter.  The DSMB will consist of at least three 
voting members, all medical doctors experienced in the conduct of clinical studies in patients 
with neurodegenerative diseases and otherwise independent from the conduct of the study.  
Additional non-voting members may join the DSMB as required.  A majority of voting members 
must agree before escalation dose can proceed.  The decisions of the DSMB will be recorded in 
minutes of the meeting. 
3.7 
Dose Escalation 
Four dose level cohorts (Cohorts A, B, C and D) will be enrolled sequentially, with patients each 
receiving 4 doses of Study Drug at 28-day intervals.  In Cohorts A and B, no more than one 
patient may begin the Treatment Period on a given day.  In later cohorts, the first two patients in 
the cohort may not begin the Treatment Period on a given day.  The progression of the study 
from initiation of dosing in one cohort to the next will be determined by the Sponsor and the 
DSMB. 
Beginning with Cohort B, dose administration in the cohort may commence only after the 
following minimum requirements are met in the prior cohort: 
• All patients in the prior cohort have been enrolled 
• At least 4 patients in the prior cohort have received multiple doses of Study Drug 
(ISIS 443139 or placebo) such that the cumulative dose received by each patient is equal 
to or greater than the dose level planned for patients in the new cohort.  This corresponds 


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to a requirement for multiple dose administration in all patients in Cohort A (when 
considering escalation to Cohort B) and multiple dose administration in at least 50% of 
patients in Cohorts B or C (when considering escalation to Cohort C or D, respectively). 
• Patient safety in the prior cohort has been monitored for at least 7 days post-treatment 
after receipt of the cumulative dose that meets or exceeds the dose planned for the new 
cohort, and those data are available for review. 
• Safety data in the prior cohort have been reviewed by the DSMB and the DSMB has 
recommended initiation of the new cohort. 
Additionally, the Sponsor may conduct a blinded review (or reviews) of accumulating CSF 
pharmacokinetic data and compare those data to the ISIS 443139 levels that are expected to 
produce a pharmacologic effect (according to the preclinical PK/PD model).  This review will be 
conducted in a manner that does not associate individual data with particular patients for those 
involved in the conduct of the study.  Based on this review, the dose level(s) for future cohort(s) 
may be adjusted.  The maximum single and cumulative doses administered in a cohort will not 
exceed 70 and 280 mg, respectively. 
If a single DLT is encountered in Cohort A, the cohort may be expanded from to up to 8 patients 
to assess safety at that dose.  Other dose cohorts (Cohorts B, C and D) may also be expanded by 
up to 100% if a single DLT is encountered in those cohorts.  If dosing in higher dose cohort(s) is 
ongoing at the time a single DLT is encountered in a lower dose cohort, further enrollment in the 
higher dose cohort(s) will stop until all current patients have completed dosing and at least 
7 days of post-treatment safety evaluations.  In addition, the DSMB will convene to decide if 
further measures are required such as pausing or reducing dose in ongoing patients in the higher 
dose cohort(s). 
The occurrence of DLTs in (i) 2 patients in a cohort or (ii) a single SAE that is life threatening 
and that is evaluated by the Sponsor as related to Study Drug in a cohort will result in 
termination of further dosing in that cohort and any higher dose cohort that is also ongoing.  In 
this situation, the DSMB will determine if the previous (lower) tolerated dose is the maximum 
tolerated dose (MTD).  The Sponsor and DSMB will determine if enrollment of additional 
patients at the previous (lower) tolerated dose is required to confirm that there is an acceptable 
toxicity profile at the lower dose prior to its designation as the MTD. 
3.8 
Dose Limiting Toxicity 
A DLT is defined as an adverse event (AE) that, in the judgment of the Investigator, is of 
sufficient significance to be dose limiting, is possibly or definitely related to Study Drug (i.e., the 
AE is substantially less likely to occur in patients not administered the Study Drug) and that it is 
not a known sign or symptom of HD or effect of any study procedure (e.g., LP, venipuncture, 
MRI scan). 
If a suspected DLT occurs during IT injection of the Study Drug, administration of Study Drug 
to the patient should be stopped (i.e., the injection should be discontinued immediately and no 
further Study Drug injections should be administered in this patient).  The Investigator should 
contact the Isis Medical Monitor as soon as possible to discuss the case.  The DSMB should 


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convene and determine (based on unblinded data review, if necessary) if any relevant findings 
have been observed in other patients in the study. 
Patients that experience a DLT will discontinue study treatment but should complete any 
follow-up visits associated with the most recent dose (see Section 8.9) and should complete the 
Post-Treatment Period. 
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 or their legally acceptable representatives 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 procedures, are performed.  At the time of randomization, 
patients will 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.  The screening number and patient identification number must remain constant 
throughout the entire study.  In the event the patient is re-consented and re-screened, the patient 
must be given a new screening number.  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 ISIS 443139 or 
placebo.  Within each cohort, randomization will be 3:1 ISIS 443139:placebo as outlined in 
Section 3.1. 
The Sponsor or designee will prepare the randomization list. 
4.3 
Replacement of Patients 
Patients withdrawn early from the Study who do not complete all scheduled doses of Study Drug 
(ISIS 443139 or placebo) may be replaced at the discretion of the Sponsor unless the Investigator 
and Sponsor Medical Monitor agree that this should not be done for reasons of safety.  
Replacement patients will be assigned to the same Study Drug (ISIS 443139 or placebo) as the 
patients who are being replaced without unblinding any study personnel.  No more than 
48 patients may be enrolled. 
Patients whose randomization code has been broken will not be replaced. 


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4.4 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors and Study Center personnel related to the study will be 
blinded throughout the Study.  However, if a patient has suffered a Serious Adverse Event (SAE) 
(as defined in Section 9.3.3), and/or when knowledge of the treatment assignment will impact the 
clinical management of the patient, the Investigator will have the ability to unblind the treatment 
assignment for that patient through an automated system.  The Sponsor or designee will be 
informed of the unblinding of a patient within 24 hours.  An unblinded randomization schema 
will be maintained securely at the Sponsor’s (or designee’s) Quality Assurance Department.  In 
addition, all SUSARs will be unblinded by the Sponsor’s or designee’s Drug Safety and Quality 
Assurance personnel for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendices A and B) prior to unblinding, as knowledge of the treatment arm 
could influence patient assessment. 
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. Early manifest, Stage 1 HD (defined as TFC of 11-13, inclusive), aged 25 to 65 years, 
inclusive, at the time of informed consent, with genetically confirmed disease (CAG 
repeat length ≥ 36 in huntingtin gene by direct DNA testing) 
4. Body Mass Index (BMI) ≥ 18 and ≤ 32 kg/m2; total body weight > 50 kg (110 lbs) 
5. Able and willing to meet all study requirements in the opinion of the Investigator, 
including travel to Study Center, procedures, measurements and visits, 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 
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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 and at the time of enrollment 
f. Patients must reside in a proximity to the Study Center that permits prompt 
appearance at the facility if requested by the Investigator (maximum of 4-hour travel 
to Study Center) 
Reproductive Status 
6. 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 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of signing the 
informed consent form until at least 13 weeks after the last dose of Study Drug 
(ISIS 443139 or placebo) 
If not surgically sterile, must have a negative β-HCG pregnancy test at Screening and 
prior to each dose administration. 
7. Males must be surgically sterile, abstinent or, if engaged in sexual relations with a female 
of child-bearing potential, the patient must be using an acceptable contraceptive method 
(refer to Section 6.3.1) from the time of signing the informed consent form until at least 
13 weeks after the last dose of Study Drug (ISIS 443139 or placebo) 
5.2 
Exclusion Criteria 
Target Disease-Related Exclusions  
1. Any condition, including severe chorea, that would prevent either writing or performing 
rapid computer tasks 
Physical, Mental and Laboratory Test Findings 
2. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or 
change in level of care within 12 months prior to Screening.  For patients with (i) a 
suicide ideation score ≥ 4 on the Columbia Suicide Severity Rating Scale (C-SSRS) 


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within the last 12 months, (ii) a score of 3 or 4 on question 2 of the Problems Behavior 
Assessment for Huntington’s Disease – short form or (iii) suicidal behaviors within the 
last 12 months (as measured by the answer “Yes” on any of the C-SSRS Suicidal 
Behavior Items), a risk assessment should be done by an appropriately-qualified mental 
health professional (e.g., a Psychiatrist or licensed Clinical Psychologist) to assess 
whether it is safe for the patient to participate in the study.  In addition, patients deemed 
by the Investigator to be at significant risk of suicide, major depressive episode, 
psychosis, confusional state or violent behavior should be excluded 
3. Clinically significant laboratory, vital sign or ECG abnormalities at Screening (including 
heart rate (HR) < 45 bpm; SBP < 90 mmHg; confirmed BP readings > 170/105 mmHg) 
4. Positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B 
at Screening 
Prohibited and Restricted Medications and Procedures 
5. Treatment with another investigational drug, biological agent, or device within one 
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 
6. Current or recent (within the last 6 months) use of antipsychotics (prescribed for 
psychosis), cholinesterase inhibitors, memantine, amantadine or riluzole.  Stable use of 
antipsychotics (prescribed for treatment of motor symptoms) and/or tetrabenazine is not 
permitted 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 
7. 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 
8. Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for 6 weeks 
prior to Screening and with a dose regimen that is not anticipated to change during the 
study 
9. Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or anticipated 
use during the study, including but not limited to aspirin (unless ≤ 81 mg/day), 
clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban 
10. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed at least 3 days prior to the first day Study Drug is administered to the patient 
(Study Day 1) 
11. Prior treatment with an antisense oligonucleotide (including siRNA) 
12. Any history of gene therapy or cell transplantation or any other experimental brain 
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13. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter 
Medical History and Concurrent Disease 
14. Significant history of alcoholism or drug/chemical abuse  
15. Clinically relevant hematological, hepatic, cardiac or renal disease or event (e.g., 
previous acute coronary syndrome within 6 months of Screening).  Abnormal hepatic, 
renal or hematology lab tests must be discussed with the Sponsor Medical Monitor 
16. Known history of human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
17. Any condition that increases risk of meningitis unless patient is receiving appropriate 
prophylactic treatment 
18. History of bleeding diathesis or coagulopathy, platelet count < LLN 
19. A medical history of brain or spinal disease that would interfere with the LP process, CSF 
circulation or safety assessment, including tumors or abnormalities by MRI or computed 
tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure 
on MRI or ophthalmic examination, spinal stenosis or curvature, chiari malformation, 
hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue 
disorders such as Ehlers-Danlos syndrome and Marfan syndrome 
20. History of post-lumbar-puncture headache of moderate or severe intensity and/or blood 
patch 
21. 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 
22. Hospitalization for any major medical or surgical procedure involving general anesthesia 
within 12 weeks of Screening or planned during the study 
23. Have any other conditions which, in the opinion of the Investigator, 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 
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. 


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6.1.1 
Screening Period (Week -6 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.  
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 14) 
Study Drug will be administered four times, with doses separated by 28 days (Section 8.1). 
Eligible patients will report to the Study Center on Study Day -1 (the day prior to first Study 
Drug 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 Study Drug 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 adverse events 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. 
Each subsequent Study Drug administration will be conducted in the same manner, with most 
pre-dose assessments conducted on the day before Study Drug administration; post-dose, in-
clinic observation of at least 6 hours after Study Drug administration (longer or overnight if 
necessary for safety reasons); in-clinic assessments on the day after Study Drug administration; 
telephonic contact with patients two days after Study Drug administration and in-clinic 
assessments one week after Study Drug administration. 
6.1.3 
Post-Treatment Period (Week 17 to Week 29) or Early Termination 
After completion of the Treatment Period, patients will enter the 15-week Post- Treatment 
Period.  This period consists of three Study Center visits on Weeks 17, 21 and 29, as outlined in 
the Schedule of Procedures in Appendix A. 
Patients who terminate early from the Treatment or Post-Treatment Periods (for reasons other 
than withdrawal of consent) should be encouraged to submit to additional visit(s) as described in 
detail in Section 8.9.  (Also see Appendices A and C and Study Design and Treatment Schema.) 
6.2 
Study Assessments 
The order of study assessments will be defined in the Study Manual.  All efforts should be made 
to adhere to a consistent order of assessments throughout the study.  Rest periods will be 
scheduled during the testing, and the patient should be permitted additional rest periods as 
needed to minimize testing fatigue. 


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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 
International Standard Classification of Education (ISCED) 
The ISCED is used to capture each patient’s level of education based on categories ranging from 
pre-primary education through advanced degree programs. 
6.2.3 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a structured tool to assess suicidal ideation and behavior.  Four constructs are 
measured:  severity of ideation, intensity of ideation, behavior and lethality of actual suicide 
attempts.  Binary (yes/no) data are collected for 10 categories, and composite endpoints based on 
the categories are followed over time to monitor patient safety (Posner et al. 2011).  It maps to 
the Columbia-Classification Algorithm for Suicide Assessment (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. 
A referral for psychiatric evaluation is required for any increase in the most severe suicidal 
ideation score from baseline.  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. 
6.2.4 
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. 
6.2.4.1 
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 heart.  
The patient must rest for at least 10 minutes in the seated position prior to measuring blood 
pressure (BP). 
6.2.4.2 
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 two minutes of standing, BP and pulse rate will be measured three times, with each test 
separated by at least 1 minute from the prior test.  If the diastolic BP readings from the three tests 


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are not all within 5 mm Hg, two 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. 
6.2.5 
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 Study Day -1 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. 
6.2.6 
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). 
6.2.7 
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). 
6.2.8 
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.  HD 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). 
6.2.9 
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 at Screening and during the Post-Treatment Period.  Ventricular volume 
as assessed by structural MRI is a key exploratory endpoint for the study. 
Ventricular expansion as assessed by structural MRI is a key exploratory endpoint for the study. 
At the Screening and Study Day 197/Week 29 visits, the following scans will be performed to 
characterize the patients’ pre-treatment and end-of-study state:  T2 flair, T2 star and T2 Fast Spin 
Echo (FSE)/Turbo Spin Echo (TSE). 
Additionally, at the Study Day 113/Week 17 visit, MRI will be used to image the CSF space. 


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Metabolic disturbances in the frontal lobe of the brain will be assessed using proton magnetic 
resonance spectroscopy (1H-MRS).  Using 1H-MRS, the concentrations of particular metabolites, 
N-Acetyl-aspartate (NAA) and myo-inositol (mI), can be measured relative to the signal of 
unsuppressed water.  Normal, healthy tissues present a constant proton spectrum, and relative 
changes in metabolites may be reflective of aberrant biochemical transformations (Walecki et al. 
2011).  NAA serves as a marker or neuronal health, as it is found only in mature neurons, and 
has been shown to decline in patients with cognitive impairment (Kantarci et al. 2003).  
Myo-inositol serves as a marker of glial cells, and elevated levels are associated with regional 
gliosis (Walecki et al. 2011).  A recent study demonstrated elevated mI and decreased NAA in 
HD (Sturrock and Leavitt 2010) suggesting that these metabolites might serve as endpoints in 
HD clinical trials. 
Corticostriatal connectivity loss occurs early in Huntington’s disease.  The functional and 
effective connectivity between brain regions will be examined using resting state functional MRI 
(rsfMRI).  Seed connectivity will be used to identify brain regions which are simultaneously 
activated at rest.  Dynamic causal modelling will be used to explore causal interactions between 
the brain and these regions.  Brain cellular microstructure and structural connectivity will be 
examined using volumetric MRI combined with neurite orientation dispersion and density 
imaging (NODDI).  Computational approaches will be applied to visualize neural tracts and to 
determine the relative strength of anatomical connections between brain regions.  Graph theory 
will be used to detect changes in the organization of brain networks such as integration and 
efficiency.  The rsfMRI and NODDI scans require approximately 25 minutes in the scanner.  It is 
recognized that some patients may be unwilling to submit to this additional burden; therefore, 
while patients will be encouraged to receive these scans, they will not be required. 
6.2.10 
Speeded Tapping 
The speeded tapping test is a measure of psychomotor speed and has been used as a longitudinal 
marker of disease severity in manifest and pre-manifest HD.  For the test, the patient taps the 
index finger of his/her non-dominant hand as quickly as possible.  A brief rest period is held 
between trials. 
6.2.11 
Unified Huntington’s Disease Rating Scale (UHDRS) 
The UHDRS, developed by the Huntington Study Group to provide a uniform assessment of the 
clinical features and course of HD has undergone reliability and validity testing that support its 
use in longitudinal studies (Huntington Study Group 1996).  The scale assesses four domains 
associated with HD:  motor function, cognitive function, behavioral abnormalities and functional 
capacity. 
For this study, only the UHDRS components required to calculate the total functional capacity 
scale, the independence scale and the total motor scale will be collected.  These components are 
simple, multiple-choice questions based on patient interview, physical exam and observation 
during motor activities, such as speeded tapping (Section 6.2.10) and walking.  The components 
are described further below. 


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6.2.11.1 
UHDRS Total Functional Capacity Scale (TFC) 
The TFC represents the Investigator’s assessment of the patient’s capacity to perform a wide 
range of activities of daily living including working, chores, managing finances, eating, dressing 
and bathing.  It is based on a brief interview with the patient and the study partner.  Scores range 
from 0 to 13, and higher scores represent better functioning. 
6.2.11.2 
UHDRS Independence Scale 
The patient’s independence scale is the Investigator’s assessment of the patient’s degree of 
independence.  The scale consists of 19 discrete levels ranging from 10 to 100 (by 5) where no 
special care needed corresponds to a scale of 100 and tube fed and total bed care corresponds to a 
scale of 10. 
6.2.11.3 
UHDRS Total Motor Scale (TMS) 
The TMS is the sum of the individual motor ratings obtained during administration of the motor 
assessment portion of the UHDRS.  Scores range from 0 to 124, and higher scores represent 
more severe impairment. 
6.2.12 
HD Work Function (HDWF) Scale 
The HDWF scale is a measure of work role limitations and effort, which are areas that may be 
affected by the cognitive, behavioral and motor changes associated with HD (Brossman et al. 
2012).  It was developed for prodromal HD, the stage prior to overt motor impairment and HD 
diagnosis in which structural and functional brain changes lead to subtle changes in cognition 
and motor function.   Patients complete the questionnaire consisting of 20 questions, where the 
response to each is based on a 7-point Likert scale ranging from “not at all like me” to “very 
much like me”.  Scores range from 20 to 140, and higher scores represent higher work function 
ability. 
A companion scale was developed as a proxy indicator of the patient’s work function, 
acknowledging that insight may diminish in some individuals in the prodromal or early stages of 
HD.  During for development of the HDWF scale, correlation between the patient and 
companion scores were statistically significant (Brossman et al. 2012).  If the patient suffers 
from diminished insight, information from the companion, i.e., trial partner, may provide 
important supporting information. 
6.2.13 
Montreal Cognitive Assessment (MoCA) 
The MoCA is a screening test for cognitive impairment that spans the visuospatial/executive, 
naming, memory, attention, language, abstraction, delayed recall and orientation domains that 
has been shown to be sensitive in HD (Nasreddine et al. 2005; Videnovic et al. 2010).  The test 
administrator prompts the patient through a series of tests and follows a simple algorithm to 
document the patient’s score.  Total scores range from 0 to 30 points, with lower numbers 
representative of more cognitive impairment.  This test will be performed at Screening only to 
characterize the patient population relative to published populations. 
6.2.14 
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 six tests that comprise the 


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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 six individual tests.  This composite cognitive score is a 
key exploratory endpoint for the study.  The individual tests that comprise the battery are 
described below. 
6.2.14.1 
Self-Paced Tapping 
Self-paced tapping measures cognitive and motor timing.  The patient listens to a repeating tone 
at 3Hz and taps in time with the tone, alternating between left and right thumbs.  The patient 
continues to tap after the tone stops, attempting to maintain the same rate of tapping.  Four trials 
are conducted. 
Scoring of each effort is based on the precision of taps, which is directly estimated, and timing 
precision, which is calculated as the reciprocal of the standard deviation of the intertap interval. 
6.2.14.2 
Emotion Recognition 
For this test, patients view faces depicting a neutral expression or an emotion (anger, disgust, 
fear, sadness, surprise, happiness).  After a practice trial for each category, the patient views 
70 test trials and categorizes each face by emotion.  The number of correct responses for 
negative emotions (anger, disgust, fear, sadness) are tallied (Johnson et al. 2007). 
6.2.14.3 
CANTAB One Touch Stockings (OTS) 
The OTS test measures executive function, spatial planning and working memory.  On a 
computer or tablet screen, the patient is shown two stacks of colored balls, which can be 
perceived balls stacked in hanging socks or stockings.  The patient must move the balls between 
the stockings to achieve a particular color pattern.  Rearranging the balls to make the target 
pattern may take one, two, three or four moves.  Then, the patient is shown two stacks of colored 
balls and must determine, without moving the balls, the minimum number of moves necessary to 
achieve the target pattern. 
Tests are scored based on accuracy in determining minimum number of moves and time to 
correct solution. 
6.2.14.4 
Symbol Digit Modalities Test (SDMT) 
The SDMT is used to assess attention, visuoperceptual processing, working memory and 
psychomotor speed.  It has been shown to have strong reliability and validity (Smith 1982; 
Hinton-Bayre et al. 1999).  The patient must pair abstract symbols with specific numbers 
according to a translation key.  The test measures the number of items correctly paired 
(maximum of 110) in 90 seconds. 
6.2.14.5 
Hopkins Verbal Learning Test – Revised (HVLT-R) 
The HVLT-R is used to assess verbal memory through tests of recall and recognition.  Patients 
must recall a series of 12 words over three immediate trials (learning), free recall after a 
25-minute delay and a recognition trial. 


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6.2.14.6 
Trail-Making Test  
The Trail-Making Test Part B (TMT-B) is a test of executive functioning.  Patients are presented 
with a picture of 25 circles, each labeled with a number (1 – 13) or a letter (A – L).  The patient 
must draws lines to connect the circles in an ascending pattern that alternates between the 
numbers and letters (i.e., 1-A-2-B-3-C … ).  The patient is instructed to connect the circles as 
quickly as possible, and the time to complete the task is recorded.   
The Trail-Making Test Part A (TMT-A) is also administered, but the results of the TMT-A are 
not considered to be part of the battery.  For the TMT-A, patients are presented with 25 circles, 
each labeled with a number (1-25) and are asked to connect the numbers.  Administration of 
TMT-A prior to TMT-B provides practice to aid in administering TMT-B. 
6.2.15 
Problems Behavior Assessment for Huntington’s Disease – Short Form (PBA-s) 
The PBA-s assesses common behavioral and psychiatric manifestations of HD, including affect, 
irritability, loss of motivation, perseverative phenomena and psychotic symptoms.  The test 
administrator interviews the patient and trial partner and rates the patient’s behavior over the 
prior four weeks according to the guidelines for the test. 
6.2.16 
Stroop Word Reading Test 
The Stroop Word Reading Test is a measure of processing and psychomotor speed.  Patients are 
presented with a page of color names printed in black ink and are asked to read aloud as many 
words as possible within a given amount of time.  The number of words read correctly is 
counted. 
6.2.17 
Map Search Test 
The Map Search Test is a test of sustained visual attention.  Patients are presented with a visually 
cluttered map and asked to circle as many target symbols on the map as possible within a fixed 
period of time.  Scoring is based on the number of correctly identified symbols. 
6.2.18 
Collection of CSF 
Patients will have CSF collected pre-dose during the LP procedure on Study Days 1, 29, 57 and 
85 for safety and PK analyses.  A sample will also be collected during the Post Treatment Period 
on either Study Day 113 or Study Day 169.  Prior to the injection, 20 mL of CSF fluid is to be 
collected for analyses, using a standard LP collection kit.  If there are difficulties in collecting 
20 mL of CSF fluid, a minimum of 15 mL should be collected.  A 24G Whitacre (atraumatic) 
needle 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.  Fluoroscopy guidance should be used if attempts at 
lumbar puncture without imaging are unsuccessful. 
6.2.19 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 


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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).  Pharmacokinetic analysis of ISIS 443139 in plasma will be 
conducted using samples collected as described in Appendices A and C. 
In addition, assessments of exploratory biomarkers will include interleukin-6 (IL-6), TNF and 
24S-hydroxycholesterol. 
6.2.19.2 
CSF Laboratory Assessments 
CSF will be used for standard laboratory measurement of cells, glucose, protein and ISIS 443139 
pharmacokinetic analyses.   
Key exploratory CSF biomarkers are muHtt level and neurofilament light chain.  Additional CSF 
assessments are total Htt, proenkephalin, clusterin, factor H (FH), C3, IL-6, TNF, IL-1, 
monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (YKL-40), visinin-like 
protein 1 (VILIP1), apolipoprotein E, chromogranin B, neurogranin, synaptosomal-associated 
protein 25 (SNAP25), S100 calcium binding protein B (S100B) and tau. 
Extra CSF will be stored for investigation of possible biomarkers of HD or the 
pharmacodynamic effects of ISIS 443139 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 
ISIS 443139 with CSF constituents. 
6.2.20 
Pregnancy Testing 
Pregnancy tests will be conducted in all female patients who are not surgically sterile, as 
described 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 13 weeks after the last dose of study drug (ISIS 443139 or placebo). 
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. 
For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche and does not meet one 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 


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• 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 Study Drug 
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 13 weeks after the last dose of Study Drug.  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 two can result in either or both products failing. 
6.3.2 
Other Requirements 
Patients should be encouraged to maintain consistency throughout the study with respect to 
smoking, caffeine consumption and alcoholic beverage consumption. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
ISIS 443139 Study Drug and artificial CSF diluent are manufactured by Isis Pharmaceuticals, 
Inc., Carlsbad, CA, USA.  The Study Drug is supplied as a 5 mL fill volume in a 6 mL clear 
glass vial.  The diluent (artificial CSF) is supplied as a 20 mL fill volume in a 20 mL clear glass 
vial.  These configurations allow for various clinical doses by using different dilution procedures 
between the Study Drug and diluent vials.  Study Drug characteristics are described in Table 1.  
More details are provided in the Study Drug Manual. 


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Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 443139 
Placebo 
Diluent 
(artificial CSF) 
Strength 
20 mg/mL 
NA 
NA 
Volume/vial 
5 mL solution per vial 
5 mL solution per vial 
20 mL solution per vial 
Route of Administration 
IT injection 
IT injection 
IT injection 
 
ISIS 443139 Study Drug and the diluent (artificial CSF) must be stored securely at 2° C to 8° C.  
ISIS 443139 Study Drug must be protected from light. 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 443139 or placebo) 
and diluent labeled in accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 443139 or placebo) and diluent supplies provided by the Sponsor.  The Study Center must 
return all used and unused Study Drug and diluent vials to the Sponsor or designee. 
8. 
TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
Study Drug dosing will occur at the Study Center on Study Days 1, 29, 57 and 85.  On each of 
these Study 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 Study Drug.  A 24G 
Whitacre (atraumatic) needle 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.  Fluoroscopy guidance should be 
used if attempts at lumbar puncture without imaging are unsuccessful. 
Table 2 outlines the dose equivalent and ISIS 443139 concentration for delivery.  See Section 3.1 
for a description of adjustments that might be made to doses and the maximum dose that will be 
tested. 


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Table 2 
Study Drug Dosing Information 
Cohort 
Volume to Administer 
Nominal ISIS 443139 Concentration  
ISIS 443139 Per Dose 
Cohort A 
20 mL  
0.50 mg/mL 
10 mg or placebo 
Cohort B 
20 mL  
1.5 mg/mL 
30 mg or placebo 
Cohort C 
20 mL  
2.5 mg/mL 
50 mg or placebo 
Cohort D 
20 mL  
3.5 mg/mL 
70 mg or placebo 
 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug preparation and administration.  These instructions must be followed 
for each Study Drug 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. 
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.  There are no additional specific stopping rules for this study but the 
Investigator should discuss significant concerns relating to individual patients with the 
Isis Medical Monitor to ensure that it is appropriate for the patient to continue Study Drug. 


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8.7 
Adjustment of Dose and/or Treatment Schedule 
For a given patient, no adjustment of dose is permitted.  In the event of a concurrent illness that 
would prevent the dosing procedure from being performed safely, an adjustment in the dose 
schedule may be permitted at the discretion of the Sponsor Medical Monitor. 
8.8 
Discontinuation of Study Drug 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an adverse event that necessitates permanent discontinuation of 
Study Drug 
• The patient experiences a DLT as defined in Section 3.7 
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 Treatment or Post-Treatment Periods (for reasons other 
than withdrawal of consent) should be encouraged to submit to additional visit(s) as described in 
detail in Section 8.9.  (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. 


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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 (a) conduct the 
full block of visits associated with the last dose received (see description of “visit blocks” 
below), (b) conduct the visit scheduled for 7 days after the last dose received, (c) and proceed to 
the Week 17 visit approximately 4 weeks after last dose and conduct all visits in the 
Post-Treatment Period (see Appendix A). 
“Visit blocks”:  Each dose of Study Drug is associated with a series of visits that are 
timed to assess acute safety and tolerability of ISIS 443139.  There are four “visit blocks” 
in this study:  Study Days -1, 1, 2 and 3; Study Days 28, 29, 30 and 31; Study Days 56, 
57, 58 and 59 and Study Days 84, 85, 86 and 87. 
For patients who terminate early from the Treatment Period for reasons other than withdrawal of 
consent every effort and are not willing to participate in the Post-Treatment Period, every effort 
should be made to (a) conduct the full block of visits associated with the last dose received (see 
description of “visit blocks” above), (b) conduct the visit scheduled for 7 days after the last dose 
received and (c) conduct the Week 29 visit as an Early Termination Visit. 
For patients who terminate early from the Post-Treatment Period for reasons other than 
withdrawal of consent, every effort should be made to conduct the Week 29 visit as an Early 
Termination Visit. 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.10.1 
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 study medication and end of study. 
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 adverse events 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 


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• Antipsychotics (only if prescribed for motor symptoms) and/or tetrabenazine 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 (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 
• Tetrabenazine 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 


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8.10.2 
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 study medication and end of study. 
8.11 
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 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 DSMB will be notified of any SAE as specified in 
the DSMB charter. 
The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that the Study Drug (ISIS 443139 or placebo) caused the AE and, 
therefore, meets the definition of a SUSAR. 
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 adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 


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9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event 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 one 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 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 197.  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. 


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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 Study Day 197.  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: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 443139 or placebo) is characterized by one 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 Study Drug (ISIS 443139 or placebo) 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 
Study Drug (ISIS 443139 or placebo) 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 asymptomatic adverse events, the toxicity grading system and toxicity grade should be 
indicated according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) guidelines, version 4.0 or higher (available at 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
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• 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 Study Drug (ISIS 443139 or placebo) due to the event is characterized by one 
of the following. 
• None:  No changes were made to Study Drug (ISIS 443139 or placebo) administration 
and dose 
• Permanently Discontinued:  Study drug 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 
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 one 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 one 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) 


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• 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. 
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 
Study Drug (ISIS 443139 or placebo) 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 Study Drug (ISIS 443139 or placebo) 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. 


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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. 
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 Study Drug.  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 


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• 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 
• Clinical assessments 
• Volumetric and safety neuroimaging assessments 
10.1.2 
Pharmacokinetic Endpoints 
A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and at one 
Post-Treatment Period visit for PK analyses. 
Plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and at each 
Post-Treatment Period visit for PK analyses. 
Plasma Cmax, AUC, elimination half-life and trough and post-distribution drug levels will be 
assessed, where appropriate. 
10.1.3 
Exploratory Endpoints 
• Biochemical 
o CSF levels of mutant Htt* and total Htt 
o CSF levels of neurofilament light chain*, proenkephalin, clusterin, FH, C3, IL-6, 
TNFα, IL-1β, MCP-1, YKL-40, VILIP1, apolipoprotein, chromogranin B, 
neurogranin, SNAP25, S100B and tau 
o Plasma levels of IL-6, TNFα and 24S-hydroxycholesterol 
• Neuroimaging volumes, including but not limited to: 
o Structural MRI  
 Caudate  
 Whole brain  
 Ventricular* 
o MRS spectroscopy for frontal lobe myoinositol and N-Acetylaspartic acid (NAA) 
o Resting state functional MRI 


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o Neurite orientation dispersion and density imaging (NODDI) 
• Electrophysiological 
o qEEG  
• Clinical 
o Functioning/ability to perform activities of daily living 
 UHDRS Total Functional Capacity Scale (TFC) 
 UHDRS Independence Scale 
 HD Work Function Scale 
o Cognitive and motor tests: 
 HD Cognitive Battery* 
• Self-Paced Tapping 
• Emotion Recognition 
• CANTAB One Touch Stockings 
• Symbol Digit Modalities Test 
• Hopkins Verbal Learning Test Revised 
• Trail Making Test Part B 
 UHDRS Total Motor Scale 
 Stroop Word Reading Test 
 Map Search Test 
 Speeded Tapping 
o Neuropsychiatric evaluation 
 Problems Behavior Assessment for Huntington’s disease-short form (PBA-s) 
* Key exploratory biochemical, neuroimaging, electrophysiological and clinical assessments 
10.2 
Sample Size Considerations 
While there is no statistical rationale for the sample size, it has been selected based on prior 
experience with generation 2.0 ASOs given by IT injection to ensure that the safety, tolerability, 
pharmacokinetics and exploratory pharmacodynamics will be adequately assessed while 
minimizing unnecessary patient exposure. 


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10.3 
Populations 
Safety Population:  All patients who are randomized and receive at least one dose of Study Drug. 
Per Protocol Population: All patients who are randomized and receive all doses of the 
protocol-specified Study Drug (ISIS 443139 or placebo). 
PK Population:  All patients who are randomized to ISIS 443139 and receive at least one dose of 
ISIS 443139 and have sufficient sampling to permit pharmacokinetic evaluation. 
10.4 
Definition of Baseline 
For vital signs (BP, heart rate, respiration rate and temperature), baseline will be defined as the 
average of the three values collected prior to first dose (Screening, Study Day -1 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. 
10.5 
Interim Analysis  
An unblinded interim analysis may be performed and the results summarized by treatment group 
at the end of each cohort upon completion of dosing for that cohort or at any time if needed to 
address a safety concern.  The results of an analysis of this type will not be shared with patients 
or Investigators. 
A DSMB will be assembled to review safety, tolerability, pharmacokinetic and target 
engagement/pharmacodynamic (as needed) data collected on ISIS 443139 during this study.  
Unblinded statisticians or designees who will not be involved in the study conduct will generate 
and distribute the data to DSMB prior to each DSMB meeting.  Based on its ongoing assessment 
of the safety and tolerability of ISIS 443139, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping or continuing the study as planned.  Details on the safety 
assessments, frequency of review, meeting schedules and controlled access to unblinded data are 
outlined in the DSMB charter and/or the statistical analysis plan (SAP). 
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, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rate unless otherwise stated. 
Since there are limited placebo-treated patients within each dose cohort, the placebo-treated 
patients will be pooled for analysis. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Patient disposition will be summarized by treatment group.  All patients 
enrolled will be included in a summary of patient disposition. 


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10.6.2 
Safety Analysis 
The safety analysis will be conducted on the Safety Population. 
Treatment duration and amount of Study Drug received will be summarized by treatment group. 
All treatment-emergent adverse events (TEAEs) and SAEs will be summarized for each 
treatment group 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, etc., will be summarized by study visit 
for each treatment group.  These safety variables will also be presented as change and percent 
change from baseline over time after Study Drug administration, as appropriate. 
Vital sign and ECG measures will be tabulated by treatment group.  In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
Columbia – Suicide Severity Rating Scale will be summarized by study visit for each treatment 
group.  Physical examination, standard neurological assessment (including fundi), and clinical 
and neuroimaging results will be summarized, if appropriate, and listed. 
10.6.3 
Pharmacokinetic Analysis 
The pharmacokinetic analysis will be conducted on the PK Population. 
A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and at one 
Post-Treatment Period visit for PK analyses.  The CSF concentrations will be summarized using 
descriptive statistics and the ISIS 443139 half-life in CSF will be calculated, if possible. 
Plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and at each 
Post-Treatment Period visit for PK analyses.  Plasma PK parameters will be summarized using 
descriptive statistics. 
Non-compartmental PK analysis of ISIS 443139 in plasma will be carried out on each individual 
patient data set.  Cmax and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  The plasma half-life (t1/2λz) associated with the apparent terminal 
elimination phase will be calculated, if appropriate using available data, from the equation, 
t1/2λz = 0.693/λz, where λz is the rate constant associated with the apparent terminal elimination 
phase.  Partial areas under the plasma concentration-time curve from zero time (predose) to 
selected times (t) after the administration (AUCt) will be calculated using the linear trapezoidal 
rule. 
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 Statistical 
Analysis Plan. 


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10.6.4 
Exploratory Analysis 
The exploratory analyses will be conducted on the Per Protocol and Safety Populations. 
Exploratory evaluations (Section 10.1.3) will be summarized using descriptive statistics by study 
visit and treatment group.  Change and percent change from baseline over time will be 
summarized as appropriate.  Comparison between ISIS 443139 group and the pooled placebo 
group will be performed in an exploratory manner.  Details will be described in the Statistical 
Analysis Plan. 
Additional exploratory 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 exploratory endpoints may be performed as where deemed appropriate. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
HD 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).  A prospective patient’s consent will be sought only if 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 any Study Drug (ISIS 443139 or placebo) are 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. 


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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 patient s 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. 
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. 
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. 


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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. 
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. 


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64 
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.  
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. 
 
 
 


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REFERENCES 
Altmann KH, Dean NM, Fabbro D, Freier SM, Geiger T, Häner R, Hüsken D, Martin P, Monia BP, Müller M, 
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nuclease resistance to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bañez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L, Ferrer I, Guzmán M, Estivill X, Martí E. A 
pathogenic mechanism in Huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS 
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Brossman B, Williams JK, Downing N, Mills JA, Paulsen JS. Development of the Huntington disease work function 
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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: 
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Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington’s Disease. Neuropsychiatry 
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Crooke ST and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol Toxicol 1996; 
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DeRenzo EG, Conley RR, Love R. Assessment of capacity to give consent to research participation: state-of-the-art 
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Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, 
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Srinidhi J, Barnes G, Gusella J, MacDonald M. Trinucleotide repeat instability and age of onset in Huntington’s 
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Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel JP, Gusella JF, 
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407-410. 
FDA: DRAFT Guidance for Industry Suicidality: Prospective Assessment of Occurrence in Clinical Trials, 
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Folstein SE. The psychopathology of Huntington’s disease. J Nerv Ment Dis 1989; 177: 645. 
Geary RS, Yu RZ, Watanabe T, Henry SP, Hardee GE, Chappell A, Matson J, Sasmor H, Cummins L, Levin AL. 
Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-methoxyethyl) modified antisense 
oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 1419–1428. 
Henry SP, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
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293-297. 
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Oct 25; 2: RRN1192. 
Huntington G. On chorea. Med Surg Reporter 1872; 26: 320–321. 


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Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996; 
11: 136-142. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Letters 1987; 215: 327-330. 
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mitochondrial metabolism, bioenergetics and structure in murin embryonic stem cells. Dev Biol 2014; 391: 230-240. 
Johnson SA, Stout JC, Solomon AC, Langbehn DR, Aylward EH, Cruce CB, Ross CA, Nance M, Kayson E, 
Julian-Baros E, Hayden MR, Kieburtz K, Guttman M, Oakes D, Shoulson I, Beglinger L, Duff K, Penziner E, 
Paulsen JS, 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. 
Kantarci K, Reynolds G, Petersen RC, Boeve BF, Knopman DS, Edland SD, Smith GE, Ivnik RJ, Tangalos EG, 
Jack Jr CR. Proton MR spectroscopy in mild cognitive impairment and Alzheimer disease: comparison of 1.5 and 
3T. Am J Neuroradiol 2003; 24: 843–849. 
Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pyrel KA, Artates JW, Weiss A, 
Cheng SH, Shihabuddin LS, Hung G, Bennett CF, Cleveland DW. Sustained therapeutic reversal of Huntington’s 
disease by transient repression of huntingtin synthesis. Neuron 2012; 74: 1031-1044. 
Kuermmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, Beal MF, Hersch SM, Ferrante RJ. Huntingtin aggregates 
may not predict neuronal death in Huntington’s disease. Ann Neurol 1999; 46: 842-843. 
Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR, 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. 
McKay RA, Miraglia LJ, Cummins LL, Owens SR, Sasmor H, Dean NM. Characterization of a potent and specific 
class of antisense oligonucleotide inhibitor of human protein kinase C-α expression. J of Biol Chem 1999; 274: 
1715-1722. 
Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, Kawasaki AM, Cook PD, Freier SM. 
Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. 
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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, 
Third Edition, Huntington’s Disease Society of America 2011. 
Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, 
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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. 
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Neurosugery and Psychiatry 2001; 97: 310-314. 
Paulsen JS, Smith MM, Long JD, PREDICT HD Investigators and Coordinators of the Huntington Study Group. 
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Paulson HL and Albin RL. Huntington’s Disease. Clinical Features and Routes to Therapy. In: Lo DC, Hughes, RE, 
editors. Neurobiology of Huntington’s disease: Applications to drug discovery. Boca Raton, FL. CRC Press 2011. 
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14(1): 39-47. 
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Stanek LM, Yang W, Angus S, Sardi PS, Hayden MR, Hung GH, Bennett CF, Cheng SH, Shihabuddin LS. 
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Stout JC, Queller S, Baker KN, Cowlishaw S, Sampaio C, Fitzer-Attas C, Borowsky B, 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 and 
Neurology 2010; 23: 243-259. 
Videnovic A, Bernard B, Fan W, Jaglin J, Leurgans S, Shannon KM. The Montreal cognitive assessment as a 
screening tool for cognitive dysfunction in Huntington's disease. Mov Disord 2010; 25(3): 401-404. 
Walecki J, Barcikowska M, Cwikla JB, Gabryelewicz T. N-acetylaspartate, choline, myoinositol, glutamine and 
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Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein, Penney JB, Snodgrass SR, Shoulson I, Gomez F, 
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14. 
APPENDICES 
 


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Appendix A 
Schedule of Procedures 
 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Screen 
Treatment Evaluation Period  
(13 Weeks) 
Post-Treatment 
Period 
(15 Weeks) 
Study Week 
-6 to -1 
1 
2 
5 
6 
9 
10 
13 
14 
17/ 
ET 2 
21 
29/ 
ET2 
Study Day 
-43 to -2 
-1 
1 
2 
3 
8 
28 
29 
30 31 36 56 
57 
58 59 64 84 
85 
86 87 92 
113 
141 
197 
Visit Window (days) * 
- 
* 
0 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
±2 
±7 
±7 
Visit Type 1 
cl 
cl 
cl 
cl 
ph 
cl 
cl 
cl 
cl ph cl 
cl 
cl 
cl ph ph cl 
cl 
cl ph ph 
cl 
cl 
cl 
Overnight Stay 3 
X 
 
 
X 
X 
X 
 
 
 
Capacity to Consent 
Assessment and Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical History and ISCED 
X 
 
 
 
 
 
 
 
 
 
MoCA  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, T) 
X 
X 
X a 
 
 
X 
Xa 
X 
Xa 
 
X 
Xa 
X 
X 
X 
Orthostasis  
X 
X b 
 
 
 
 
 
Xb 
 
X 
X 
Physical& Neurological Exam4 
X 
X 
X c 
Xd 
 
X 
X 
Xc 
Xd 
X 
X 
Xc 
Xd 
 
X 
Xc 
Xd 
X 
X 
X 
Body Weight and Height 5 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Functional, Cognitive, Motor 
and Neuropsychiatric 
assessments 6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
C-SSRS 7 
X 
X 
Xb 
X 
 
X 
X 
Xb 
X 
X 
X 
Xb 
X 
 
X 
Xb 
X 
X 
X 
X 
qEEG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Structural MRI 8 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
T2 flair, T2 star, T2 FSE/TSE 
MRI8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
rsfMRI and NODDI8, 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI of the CSF space8 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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Appendix A Schedule of Procedures Continued 
Study Period 
Screen 
Treatment Evaluation Period  
(13 Weeks) 
Post-Treatment 
Period 
(15 Weeks) 
Study Week 
-6 to -1 
1 
2 
5 
6 
9 
10 
13 
14 
17/ 
ET 2 
21 
29/ 
ET2 
Study Day 
-43 to -2 
-1 
1 
2 
3 
8 
28 
29 
30 31 36 56 
57 
58 59 64 84 
85 
86 87 92 
113 
141 
197 
Visit Window (days) * 
- 
* 
0 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
±2 
±7 
±7 
Visit Type 1 
cl 
cl 
cl 
cl 
ph 
cl 
cl 
cl 
cl ph cl 
cl 
cl 
cl ph ph cl 
cl 
cl ph ph 
cl 
cl 
cl 
1H-MRS 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ECG (12-Lead) 10 
X 
X 
 
X 
 
 
 
 
X 
 
X 
Chemistry Panel 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Hematology 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Urinalysis 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Genetic Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
FSH 11 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 12 
X 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Serum Biomarker Sample 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Thyroid Panel 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
PT, INR, aPTT 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
Plasma Sampling for PK 
 
X e 
Xd 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
X f 
Xd 
 
 
X 
X 
X 
Archived Serum Sample 13 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
CSF Sample for 
PK/Safety/Biomarkers 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X g 
Xg 
X h 
Archived CSF Sample 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
Xg 
Xg 
Xh 
Study Drug Administration 
X 
 
 
X 
 
 
 
 
X 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Appendix A Schedule of Procedures Continued 
 
Note:  If not specifically labeled, “X” means anytime; ET = early termination 
* 
Visit windows are calculated relative to Study Day 1.  Note that within each block of visits associated with dose 
administration, the visits must occur on 4 consecutive days.  There are four “visit blocks” in this study:  
(Study Days -1, 1, 2 and 3), (Study Days 28, 29, 30 and 31), (Study Days 56, 57, 58 and 59) and 
(Study Days 84, 85, 86 and 87). 
 
1 
cl = clinic visit; ph = phone visit 
2 
If the patient terminates early from the Treatment Period but is willing to participate in the Post-Treatment Period, 
(a) conduct the full block of visits associated with the last dose received (see asterisk above), (b) conduct the 
visit scheduled for 7 days after the last dose received, (c) proceed to the Week 17 visit approximately 4 weeks 
after last dose and conduct all visits in the Post-Treatment Period.  If the patient terminates early from the 
Treatment Period and is not willing to participate in the Post-Treatment Period, (a) conduct the full block of visits 
associated with the last dose received (see asterisk above), (b) conduct the visit scheduled for 7 days after the 
last dose received and (c) conduct the Week 29 visit as an Early Termination Visit.  If the patient terminates early 
from the Post-Treatment Period, conduct the Week 29 visit as an Early Termination Visit. 
3 
On Study Day 1, the patient must stay in the clinic overnight and undergo safety monitoring follow-up as 
scheduled on Study Day 2.  On Study Days 29, 57 and 85, the patient may either stay in the clinic overnight or 
be discharged (after a minimum observation period of 6 hours after Study Drug administration), provided the 
patient returns to the clinic on the following day (Day 30, 58 or 86) for all required assessments. 
4 
Full physical and neurological exam (including fundi) to be given at Screening and abbreviated physical (but full 
neurological) exam to be given during Treatment and Post-treatment Periods as indicated to assess changes 
from Screening. 
5 
Height is measured at Screening only. 
6 
Functional, Cognitive, Motor and Neuropsychiatric Tests are speeded tapping, UHDRS total functional capacity 
scale, UHDRS independence scale, UHDRS total motor scale, HD work function scale, HD Cognitive Battery 
(self-paced tapping, emotion recognition, CANTAB one-touch stockings, symbol-digit modalities test, Hopkins 
verbal learning test – revised and trail making tests), Problems Behavior Assessment for Huntington’s disease-
short form, Stroop Word Reading test and Map Search test. 
7 
The C-SSRS must be administered on the study days shown.  It may also be administered at any time that the 
Investigator feels is necessary. 
8 
For imaging during the Screening period, the scans should be conducted sufficiently early in the Screening 
Period to allow for repeat scanning if necessary.  For imaging at post-Screening visits, efforts should be made to 
conduct the imaging within the visit window.  If re-scanning at a post-Screening visit is necessary because the 
original scan is not usable, the re-scanning should be conducted within one week of the original scan if at all 
possible. 
9 
rsfMRI and NODDI scans are conducted only in patients who have consented for these assessments. 
10 Measured in triplicate at the Study Day -1 visit only. 
11 Women who are not surgically sterile as confirmation of menopause. 
12 Women who are not surgically sterile.  Serum test at Screen visit; dipstick at post-screen visits. 
13 Stored at -80º C for follow-up exploration of laboratory findings and/or adverse events (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 ISIS 443139. 
 
 


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Appendix A Schedule of Procedures Continued 
 
Time (in reference to time of Study Drug administration): 
a 
Predose, 3 and 6 hours post IT injection 
b 
Predose 
c 
Predose and 3 hours post IT injection; also conduct at 6 hours post IT injection on any dosing day that the 
patient does not stay in the clinic overnight (overnight stays are optional on Study Days 29, 57 and 85) 
d 
24 hours after prior dose of Study Drug 
e 
Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post IT injection 
f 
Predose, 0.5, 1, 2, 3, 4 and 5 hours post IT injection 
g 
All patients in Cohort A will have CSF collected on Study Day 113 (Week 17) and not on Study Day 141 
(Week 21).  For all other cohorts, CSF sampling will be conducted in approximately 50% of patients on Study 
Day 113 (Week 17) and in the remaining 50% of patients on Study Day 141 (Week 21), as assigned by the 
Sponsor according to a predetermined, randomized assignment. 
h 
CSF sampling will be conducted at Study Day 197 (Week 29) in only those patients who attend the visit as an 
early termination visit and did not undergo CSF sampling on either Study Day 113 (Week 17) or Study Day 141 
(Week 21).  If CSF sampling was conducted on Study Day 113 (Week 17) or Study Day 141 (Week 21), do not 
collect CSF at Study Day 197 (Week 29) 
 


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Appendix B 
List of Laboratory Analytes 
 
 


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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 ISIS 443139 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 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 
White blood cells 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Color 
Appearance 
 
Thyroid Panel 
TSH 
Free T4 
Free T3 
 
Coagulation 
aPTT 
PT 
INR 
Screening Tests 
Hepatitis B surface 
antigen 
Hepatitis C antibody 
HIV antibody 
FSH (women only) 
Serum βhCG 
Drug/Alcohol screen2 
 
Genetics 
CAG repeat length 
apoE isoform genotype 
BCHE-K 
 
PK1 
Plasma ISIS 443139 
levels 
CSF ISIS 443139 levels 
 
Pregnancy 
Urine hCG 
CSF Safety Panel 
(Minimum Requirements) 
Red blood cells 
White blood cells 
Glucose 
Protein 
 
Exploratory CSF 
Biomarker Panel 
mu Htt 
total Htt 
Proenkephalin 
Clusterin 
FH 
C3 
IL-6 
TNFα 
IL-1β 
MCP-1 
YKL-40 
VILIP1 
ApoE 
Chromogranin B 
Neurogranin 
SNAP25 
S100B 
Tau 
Neurofilament light chain 
 
Exploratory Serum 
Biomarker Panel 
IL-6 
TNFα 
24S-hydroxycholesterol 
1 
Any of the collected PK plasma and CSF samples from the study patients may also be used by Isis for 
investigation of possible biomarkers of disease or the pharmacodynamic effects of ISIS 443139 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 ISIS 443139 with plasma and CSF 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. 
2 
Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, opiates


ISIS 443139-CS1 
CONFIDENTIAL 
Original  
Protocol 
 
6 March 2015 
 
76 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Original 
Protocol 
 
6 March 2015 
 
77 
Appendix C PK Sampling Schedule 
Study Period 
Treatment Evaluation Period 
(13 Weeks) 
Post-Treatment 
Period or Early 
Termination Visit 
(15 Weeks) 
Study Week 
1 
5 
9 
13 
17 
21 
29 
Study Day 
1 
2 
29 
57 
85 
86 
113 
141 
197 
CSF sampling 
predose 
 
predose 
predose 
predose 
 
anytime1 
Plasma sampling 
Predose, 0.5, 1, 2, 3, 
4, 5, 6, 8,12 hours 
post IT injection 
24 hours post Day 1 
IT injection 
predose 
predose 
Predose, 0.5, 1, 
2, 3, 4, 5 hours 
post IT injection 
24 hours post 
Day 85 
IT injection 
any-
time 
any-
time 
any-
time 
1 
All patients in Cohort A will have CSF sampling on Study Day 113 (Week 17) and not on Study Day 141 (Week 21).  For all other cohorts, CSF sampling will 
be conducted in approximately 50% of patients in the cohort on Study Day 113 (Week 17) and in the remaining 50% of patients in the cohort on 
Study Day 141 (Week 21), as assigned by the Sponsor.  CSF sampling will be conducted on Study Day 197 (Week 29) in only those patients who attend the 
visit as an early termination visit and did not undergo CSF sampling on either Study Day 113 (Week 17) or Study Day 141 (Week 21).  If CSF sampling was 
conducted on Study Day 113 (Week 17) or Study Day 141 (Week 21), do not collect CSF on Study Day 197 (Week 29). 


 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 443139-CS1 
 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Multiple Ascending Doses of Intrathecally Administered 
ISIS 443139 in Patients with Early Manifest Huntington’s Disease 
 
Protocol Amendment 3 – 5 April 2017 
 
EudraCT No:  2015-000381-66 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
2 
 
 
ISIS 443139-CS1 
 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Multiple Ascending Doses of Intrathecally Administered 
ISIS 443139 in Patients with Early Manifest Huntington’s Disease 
 
Protocol Amendment 3 – 5 April 2017 
 
 
Protocol History: 
Original Protocol: 
 
6 March 2015 
Protocol Amendment 1: 
   
7 May 2015 
Protocol Amendment 2: 
 
25 May 2016 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
 MD 
Vice President, Clinical Development 
 
CCI
CCI


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
3 
 
ISIS 443139 
Ionis Protocol Number ISIS 443139-CS1 
Protocol Amendment 3 
EudraCT No:  2015-000381-66 
 
Clinical Phase:  1/2a 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Multiple Ascending Doses of Intrathecally Administered 
ISIS 443139 in Patients with Early Manifest Huntington’s Disease 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 01 760 931 9200 
Fax: 
+ 01 760 603 3564 
Key Sponsor Contact: 
 
2855 Gazelle Court 
Carlsbad, CA 92010 
Phone: + 
 
Fax: 
+ 
  
 
 
Date: 
5 April 2017 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulatory agencies.  This information 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 
 
PPD
PPD
PPD


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 443139-CS1 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple 
Ascending Doses of Intrathecally Administered ISIS 443139 in Patients 
with Early Manifest Huntington’s Disease 
Amendment: 
Amendment 3 
Date: 
5 April 2017 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally 
Administered ISIS 443139 in Patients with Early Manifest Huntington’s Disease,” dated 5 April 
2017, and agree to conduct the Study as described herein. 
I agree to comply with the International Conference on Harmonization 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 Ionis Pharmaceuticals, Inc. 
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
5 
TABLE OF CONTENTS 
 
Page 
PROTOCOL AMENDMENT.....................................................................................................10 
PROTOCOL SYNOPSIS ............................................................................................................11 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................19 
COHORT ENROLLMENT FLOWCHART ............................................................................20 
STUDY GLOSSARY ...................................................................................................................21 
1. 
OBJECTIVES .....................................................................................................................24 
1.1 
Primary Objectives ........................................................................................................24 
1.2 
Secondary Objectives ....................................................................................................24 
1.3 
Exploratory Objectives ..................................................................................................24 
2. 
BACKGROUND AND RATIONALE ..............................................................................24 
2.1 
Overview of Disease ......................................................................................................24 
2.1.1 
Epidemiology .........................................................................................................24 
2.1.2 
Huntingtin Protein ..................................................................................................24 
2.1.3 
Clinical Features and Diagnosis of HD ..................................................................25 
2.1.4 
Treatments for HD ..................................................................................................26 
2.2 
Therapeutic Rationale ....................................................................................................26 
2.3 
ISIS 443139 ...................................................................................................................27 
2.3.1 
Mechanism of Action .............................................................................................27 
2.3.2 
Chemistry ...............................................................................................................27 
2.3.3 
Preclinical Experience ............................................................................................28 
2.3.4 
Clinical Experience ................................................................................................28 
2.4 
Rationale for Study Design ............................................................................................29 
2.4.1 
Rationale for the Study Population ........................................................................29 
2.4.2 
Rationale for a Multiple Ascending Dose Design ..................................................29 
2.4.3 
Rationale for Dose Levels and Dosing Schedule ...................................................30 
3. 
EXPERIMENTAL PLAN ..................................................................................................31 
3.1 
Study Design ..................................................................................................................31 
3.2 
Number of Study Centers ..............................................................................................31 
3.3 
Number of Patients ........................................................................................................31 
3.4 
Overall Study Duration and Follow-up .........................................................................32 
3.4.1 
Screening Period .....................................................................................................32 
3.4.2 
Treatment Period ....................................................................................................32 
3.4.3 
Post-Treatment Period ............................................................................................32 
3.5 
End-of-Study ..................................................................................................................32 
3.6 
Data and Safety Monitoring Board ................................................................................32 
3.7 
Dose Escalation ..............................................................................................................32 
3.8 
Dose Limiting Toxicity ..................................................................................................34 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
6 
4. 
PATIENT ENROLLMENT ...............................................................................................34 
4.1 
Screening .......................................................................................................................34 
4.2 
Randomization ...............................................................................................................34 
4.3 
Replacement of Patients .................................................................................................35 
4.4 
Unblinding of Treatment Assignment ...........................................................................35 
5. 
PATIENT ELIGIBILITY ..................................................................................................35 
5.1 
Inclusion Criteria ...........................................................................................................35 
5.2 
Exclusion Criteria ..........................................................................................................37 
6. 
STUDY PROCEDURES ....................................................................................................39 
6.1 
Study Schedule ..............................................................................................................39 
6.1.1 
Screening Period (Week -6 to Week -1) ................................................................39 
6.1.2 
Treatment Period (Week 1 to Week 14) .................................................................39 
6.1.3 
Post-Treatment Period (Week 17 to Week 29) or Early Termination ....................40 
6.2 
Study Assessments .........................................................................................................40 
6.2.1 
Capacity to Consent ................................................................................................40 
6.2.2 
International Standard Classification of Education (ISCED) .................................40 
6.2.3 
Columbia Suicide Severity Rating Scale (C-SSRS) ...............................................40 
6.2.4 
Vital Signs Measurement .......................................................................................40 
6.2.4.1 
Seated Blood Pressure Measurement ...............................................................41 
6.2.4.2 
Standing Blood Pressure Measurement for Orthostatic Assessment ...............41 
6.2.5 
Electrocardiogram ..................................................................................................41 
6.2.6 
Physical Measurements (Height and Weight) ........................................................41 
6.2.7 
Physical/Neurological Examination .......................................................................41 
6.2.8 
Electrophysiological Assessments .........................................................................41 
6.2.9 
Neuroimaging Assessments ...................................................................................42 
6.2.10 
Speeded Tapping ....................................................................................................42 
6.2.11 
Unified Huntington’s Disease Rating Scale (UHDRS) ..........................................43 
6.2.11.1 
UHDRS Total Functional Capacity Scale (TFC).............................................43 
6.2.11.2 
UHDRS Independence Scale ...........................................................................43 
6.2.11.3 
UHDRS Total Motor Scale (TMS) ..................................................................43 
6.2.12 
HD Work Function (HDWF) Scale ........................................................................43 
6.2.13 
Montreal Cognitive Assessment (MoCA) ..............................................................44 
6.2.14 
HD Cognitive Battery .............................................................................................44 
6.2.14.1 
Self-Paced Tapping ..........................................................................................44 
6.2.14.2 
Emotion Recognition .......................................................................................44 
6.2.14.3 
CANTAB One Touch Stockings (OTS) ..........................................................44 
6.2.14.4 
Symbol Digit Modalities Test (SDMT) ...........................................................45 
6.2.14.5 
Hopkins Verbal Learning Test – Revised (HVLT-R)......................................45 
6.2.14.6 
Trail-Making Test ............................................................................................45 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
7 
6.2.15 
Problems Behavior Assessment for Huntington’s Disease – Short Form (PBA-s)
 ................................................................................................................................45 
6.2.16 
Stroop Word Reading Test .....................................................................................45 
6.2.17 
Map Search Test .....................................................................................................45 
6.2.18 
Collection of CSF ...................................................................................................45 
6.2.19 
Laboratory Assessments .........................................................................................46 
6.2.19.1 
Plasma and Serum Laboratory Assessments....................................................46 
6.2.19.2 
CSF Laboratory Assessments ..........................................................................46 
6.2.20 
Pregnancy Testing ..................................................................................................47 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................47 
6.3.1 
Contraception Requirements ..................................................................................47 
6.3.2 
Other Requirements ................................................................................................48 
7. 
STUDY DRUG ....................................................................................................................48 
7.1 
Study Drug Description .................................................................................................48 
7.2 
Packaging and Labeling .................................................................................................48 
7.3 
Study Drug Accountability ............................................................................................48 
8. 
TREATMENT OF PATIENTS .........................................................................................49 
8.1 
Study Drug Administration ............................................................................................49 
8.2 
Other Protocol-Required Drugs .....................................................................................49 
8.3 
Other Protocol-Required Treatment Procedures ............................................................49 
8.4 
Treatment Precautions ...................................................................................................49 
8.5 
Safety Monitoring Rules ................................................................................................50 
8.6 
Stopping Rules ...............................................................................................................50 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................50 
8.8 
Discontinuation of Study Drug ......................................................................................50 
8.9 
Withdrawal of Patients from the Study ..........................................................................50 
8.10 
Concomitant Therapy and Procedures ...........................................................................51 
8.10.1 
Concomitant Therapy .............................................................................................52 
8.10.2 
Concomitant Procedures .........................................................................................53 
8.11 
Treatment Compliance ...................................................................................................53 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ..........................53 
9.1 
Sponsor Review of Safety Information .........................................................................53 
9.2 
Regulatory Requirements ..............................................................................................53 
9.3 
Definitions .....................................................................................................................54 
9.3.1 
Adverse Event ........................................................................................................54 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................54 
9.3.3 
Serious Adverse Event (SAE) ................................................................................54 
9.4 
Monitoring and Recording Adverse Events ...................................................................55 
9.4.1 
Serious Adverse Events ..........................................................................................55 
9.4.2 
Non-Serious Adverse Events ..................................................................................55 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
8 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................55 
9.4.3.1 
Relationship to the Study Drug ........................................................................55 
9.4.3.2 
Severity ............................................................................................................56 
9.4.3.3 
Action Taken with Study Drug ........................................................................56 
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 ..................................................................57 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................57 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............57 
9.5.3 
Dosing Errors .........................................................................................................58 
9.5.4 
Contraception and Pregnancy .................................................................................58 
10. STATISTICAL CONSIDERATIONS ..............................................................................59 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................59 
10.1.1 
Safety and Tolerability Endpoints ..........................................................................59 
10.1.2 
Pharmacokinetic Endpoints ....................................................................................59 
10.1.3 
Exploratory Endpoints ............................................................................................59 
10.2 
Sample Size Considerations ...........................................................................................61 
10.3 
Populations .....................................................................................................................61 
10.4 
Definition of Baseline ....................................................................................................61 
10.5 
Interim Analysis .............................................................................................................61 
10.6 
Planned Methods of Analysis ........................................................................................62 
10.6.1 
Demographic and Baseline Characteristics ............................................................62 
10.6.2 
Safety Analysis .......................................................................................................62 
10.6.3 
Pharmacokinetic Analysis ......................................................................................62 
10.6.4 
Exploratory Analysis ..............................................................................................63 
11. INVESTIGATOR’S REGULATORY OBLIGATIONS .................................................63 
11.1 
Informed Consent ..........................................................................................................63 
11.2 
Ethical Conduct of the Study .........................................................................................64 
11.3 
Independent Ethics Committee/Institutional Review Board .........................................64 
11.4 
Patient Confidentiality ...................................................................................................64 
12. ADMINISTRATIVE AND LEGAL OBLIGATIONS ....................................................65 
12.1 
Protocol Amendments ....................................................................................................65 
12.2 
Study Termination .........................................................................................................65 
12.3 
Study Documentation and Storage ................................................................................65 
12.4 
Study Monitoring ...........................................................................................................66 
12.5 
Language ........................................................................................................................67 
12.6 
Compensation for Injury ................................................................................................67 
13. REFERENCES ....................................................................................................................68 
14. APPENDICES .....................................................................................................................71 
Appendix A 
Schedule of Procedures ....................................................................................72 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
9 
Appendix B 
List of Laboratory Analytes .............................................................................77 
Appendix C 
PK Sampling Schedule ....................................................................................79 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......81 
 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................48 
Table 2 
Study Drug Dosing Information ............................................................................49 
 
 
TABLE OF FIGURES 
Page 
Figure 1 
Design of ISIS 443139 ...........................................................................................28 
 
 


See Protocol Changes Section


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
11 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of 
Intrathecally Administered ISIS 443139 in Patients with Early Manifest Huntington’s 
Disease 
Study Phase 
Phase 1/2a 
Primary Objectives 
To evaluate the safety and tolerability of ascending dose-levels of multiple intrathecal 
(IT) bolus administrations of ISIS 443139 to patients with Huntington’s disease (HD) 
Secondary Objectives 
To characterize the cerebrospinal fluid (CSF) pharmacokinetics of ascending dose-
levels of multiple IT administrations of ISIS 443139 
Exploratory Objectives 
To explore effects of multiple doses of ISIS 443139 on pharmacodynamic biomarkers 
and clinical endpoints relevant to HD.  Plasma pharmacokinetic properties will also be 
assessed. 
Study Design 
ISIS 443139-CS1 is a multi-center, Phase 1/2a, randomized, double-blind, placebo-
controlled study of ascending dose levels of multiple IT administrations of ISIS 443139 
(“slow push” IT bolus) in patients with early manifest HD aged 25-65 years, inclusive. 
Five (5) dose level cohorts (A, B, C, D and E) will be enrolled sequentially, with patients 
randomized to Study Drug or to placebo in a 3 to 1 ratio.  Cohort A will comprise 
4 patients, Cohorts B and C will comprise 8 patients and Cohorts D and E will comprise 
12 patients.  All patients will be disease “Stage 1” out of a possible 5 stages, where 
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.  These stages also correlate with scores on the 
13-point UHDRS Total Functional Capacity (TFC) Scale, with Stage 1 corresponding to 
TFC scores of 11-13.  Randomization in Cohort D will be stratified by early Stage 1 
(TFC ≥ 12) or late Stage 1 (TFC = 11) disease. 
Each patient will receive 4 doses of Study Drug with a 28-day interval between doses.  
Patients not completing a course of 4 IT bolus injections may be replaced up to a limit 
of 25% of the cohort sample and only if the reason for premature discontinuation from 
the Treatment Period does not involve a dose-limiting toxicity (DLT). 
Following the 3-month Treatment Period, there will be a 4-month Post-treatment 
Period.  After study completion, an open-label extension study of ISIS 443139 will be 
implemented if this is warranted based on review of safety, tolerability, pharmacokinetic 
and exploratory pharmacodynamic findings. 
Number of Patients 
Approximately 44 patients will be enrolled in this study. 
The number of patients enrolled may be higher if some patients need to be replaced 
and/or if the sizes of certain cohorts are expanded to obtain further experience with 
particular dose levels.  A maximum of 48 patients may be enrolled. 
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 
2. 
Must be capable of giving informed consent (in the opinion of the Investigator) 
Target Population 
3. 
Early manifest, Stage 1 HD (defined as TFC of 11-13, inclusive), aged 25 to 
65 years, inclusive, at the time of informed consent, with genetically confirmed 
disease (CAG repeat length ≥ 36 in huntingtin gene by direct DNA testing) 
4. 
Body Mass Index (BMI) ≥ 18 and ≤ 32 kg/m2; total body weight > 50 kg (110 lbs) 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
12 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
 
Inclusion Criteria Continued 
5. 
Able and willing to meet all study requirements in the opinion of the Investigator, 
including travel to Study Center, procedures, measurements and visits, 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 and at the time of enrollment 
f. Patients must reside in a proximity to the Study Center that permits prompt 
appearance at the facility if requested by the Investigator (maximum of 4-hour 
travel to Study Center) 
Reproductive Status 
6. 
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 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of 
signing the informed consent form until at least 13 weeks after the last dose of 
Study Drug (ISIS 443139 or placebo) 
If not surgically sterile, must have a negative HCG pregnancy test at 
Screening and prior to each dose administration 
7. 
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 13 weeks after the last dose of Study Drug 
(ISIS 443139 or placebo) 
* 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: 
Target Disease-Related Exclusions 
1. 
Any condition, including severe chorea, that would prevent either writing or 
performing rapid computer tasks 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
13 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria: Continued 
Physical, Mental and Laboratory Test Findings 
2. 
Attempted suicide, suicidal ideation with a plan that required hospital admission 
and/or change in level of care within 12 months prior to Screening.  For patients 
with (i) a suicide ideation score ≥ 4 on the Columbia Suicide Severity Rating 
Scale (C-SSRS) within the last 12 months, (ii) a score of 3 or 4 on question 2 of 
the Problems Behavior Assessment for Huntington’s Disease – short form or 
(iii) suicidal behaviors within the last 12 months (as measured by the answer 
“Yes” on any of the C-SSRS Suicidal Behavior Items), a risk assessment should 
be done by an appropriately-qualified mental health professional (e.g., a 
Psychiatrist or licensed Clinical Psychologist) to assess whether it is safe for the 
patient to participate in the study.  In addition, patients deemed by the 
Investigator to be at significant risk of suicide, major depressive episode, 
psychosis, confusional state or violent behavior should be excluded 
3. Clinically significant laboratory, vital sign or ECG abnormalities at Screening 
(including heart rate (HR) < 45 bpm; SBP < 90 mmHg; confirmed BP readings 
> 170/105 mmHg) 
4. Positive test for human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B at Screening 
Prohibited and Restricted Medications and Procedures 
5. Treatment with another investigational drug, 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 
6. Current or recent (within the last 6 months) use of antipsychotics (prescribed for 
psychosis), cholinesterase inhibitors, memantine, amantadine or riluzole.  Stable 
use of antipsychotics (prescribed for treatment of motor symptoms) and/or 
tetrabenazine is not permitted 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 
7. 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 
8. Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for 
6 weeks prior to Screening and with a dose regimen that is not anticipated to 
change during the study 
9. Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or 
anticipated use during the study, including but not limited to aspirin (unless 
≤ 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and 
apixaban 
10. Active infection requiring systemic antiviral or antimicrobial therapy that will not 
be completed at least 3 days prior to the first day Study Drug is administered to 
the patient (Study Day 1) 
11. Prior treatment with an antisense oligonucleotide (including siRNA) 
12. Any history of gene therapy or cell transplantation or any other experimental brain 
surgery 
13. Presence of an implanted shunt for the drainage of CSF or an implanted CNS 
catheter 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
14 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria: Continued 
Medical History and Concurrent Disease 
14. Significant history of alcoholism or drug/chemical abuse 
15. Clinically relevant hematological, hepatic, cardiac or renal disease or event (e.g., 
previous acute coronary syndrome within 6 months of Screening).  Abnormal 
hepatic, renal or hematology lab tests must be discussed with the Sponsor 
Medical Monitor 
16. Known history of human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
17. Any condition that increases risk of meningitis unless patient is receiving 
appropriate prophylactic treatment 
18. History of bleeding diathesis or coagulopathy, platelet count < LLN 
19. A medical history of brain or spinal disease that would interfere with the LP 
process, CSF circulation or safety assessment, including tumors or abnormalities 
by MRI or computed tomography (CT), subarachnoid hemorrhage, suggestion of 
raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or 
curvature, chiari malformation, hydrocephalus, syringomyelia, tethered spinal 
cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome 
and Marfan syndrome 
20. History of post-lumbar-puncture headache of moderate or severe intensity and/or 
blood patch 
21. 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 
22. Hospitalization for any major medical or surgical procedure involving general 
anesthesia within 12 weeks of Screening or planned during the study 
23. Have any other conditions which, in the opinion of the Investigator, would make 
the patient unsuitable for inclusion or could interfere with the patient participating 
in or completing the study 
Treatment Groups 
ISIS 443139, Placebo 
There will be 5 multiple-dose cohorts (n = 4, 8 or 12 per cohort, randomized 3 active: 
1 placebo).  Patients will receive 4 IT bolus doses of Study Drug at 4-week intervals 
during the 3-month Treatment Period (Days 1, 29, 57, 85).  For patients who receive 
ISIS 443139, planned total dose is shown in the table below. 
Planned Dose of Active Study Drug 
# of doses 
Total ISIS 443139 
Cohort A:  10 mg ISIS 443139 
4 
40 mg 
Cohort B:  30 mg ISIS 443139 
4 
120 mg 
Cohort C:  60 mg ISIS 443139 
4 
240 mg 
Cohort D:  90 mg ISIS 443139 
4 
360 mg 
Cohort E:  120 mg ISIS 443139 
4 
480 mg 
Study Drug Dosage and 
Administration 
Each dose of ISIS 443139 or placebo 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. 
Dosing instructions and details regarding administration will be provided in the Study 
Drug manual.  The site pharmacist will be blinded to treatment assignment. 


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PROTOCOL SYNOPSIS Continued 
Dose Escalation 
Five (5) dose level cohorts (Cohorts A, B, C, D and E) will be enrolled sequentially, with 
patients each receiving 4 doses of Study Drug at 28-day intervals.  The progression of 
the study from one cohort to the next will be determined by the Sponsor in collaboration 
with the Data and Safety Monitoring Board (DSMB) and will generally be based on the 
number of DLTs observed in patients treated with ISIS 443139. 
Beginning with Cohort B, dose administration in a cohort may commence only after 
(1) all patients in the prior cohort have been enrolled, (2) at least 4 patients in the prior 
cohort have received a cumulative dose that is equal to or greater than the initial dose 
planned for the cohort and safety in these patients has been monitored for at least 
7 days post-treatment after reaching that cumulative dose, and (3) safety results for all 
patients enrolled in the prior cohorts have been reviewed by the DSMB.  The 
occurrence of DLTs in 2 patients in a cohort will result in the dose tested in the cohort 
being dose limiting in this study. 
If a single DLT is encountered in Cohort A, the cohort may be expanded up to 
8 patients to assess safety at that dose.  Other dose cohorts (Cohorts B, C, D and E) 
may also be expanded up to 100% if a single DLT is encountered in those cohorts.  If 
dosing in higher dose cohort(s) is ongoing at the time a single DLT is encountered in a 
lower-dose cohort, further enrollment in the higher dose cohort(s) will stop until all 
current patients have completed dosing and at least 7 days of post-dose safety 
evaluations.  In addition, the DSMB will convene to decide if further measures are 
required such as pausing or reducing dosing in ongoing patients in the higher dose 
cohort(s). 
The occurrence of (i) DLTs in 2 patients in a cohort or (ii) a single SAE (excluding those 
attributable to the lumbar puncture, other study procedure or HD) that is evaluated by 
the Sponsor as related to Study Drug and is of sufficient significance to be dose limiting 
will result in termination of further dosing in that cohort and any higher dose cohort that 
is also ongoing. 
Rationale for Dose and 
Schedule Selection 
ISIS 443139 dose levels and dose interval for ISIS 443139-CS1 were selected based 
on preclinical toxicology and pharmacokinetic observations. 
 
 
  Monthly dosing is 
expected to achieve ISIS 443139 brain cortex tissue levels at steady state by Day 92, 
and is expected to be safe and well-tolerated by patients. 
Study Visit Schedule 
and Procedures 
After informed consent is obtained, patients will undergo a screening evaluation during 
a 6-week period prior to baseline.  Patients who meet the eligibility criteria will visit the 
Study Center on Study Day -1 to undergo baseline clinical, blood, and 
electrophysiological evaluations and for re-assessment of eligibility.  On Study Day 1, 
patients will be admitted to the Study Center, undergo pre-dose evaluations of vital 
signs and then receive an IT bolus injection (slow push) of ISIS 443139 or placebo 
(3:1).  Following the initial LP injection on Day 1, patients will be kept at the Study 
Center for at least 24 hours and carefully monitored for any adverse clinical symptoms 
or signs.  This inpatient post-dose assessment may be reduced to a minimum of 
6 hours following the 2nd, 3rd and 4th dose administrations provided a visit is made to 
the Study Center the next day.  Assessments during these admission periods include 
neurological, electrophysiological and physical examination, vital signs, ECGs, blood 
sampling and clinical laboratory analyses.  Full standard neurological assessment 
(including fundi) will be performed 3 hours post-dosing with Study Drug and prior to 
discharge from the Study Center. 
Study Drug administration will take place on Study Days 1, 29, 57 and 85.  In the 
Treatment Period, Study Center visits are held on Study Days 1, 2, 8, 28, 29, 30, 36, 
56, 57, 58, 84, 85 and 86. 
 
 
CCI


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PROTOCOL SYNOPSIS Continued 
Study Visit Schedule 
and Procedures 
Continued 
During the Post-Treatment Period, patients will visit the Study Center on Study 
Days 113, 141 and 197 (study completion visit). 
In addition, the Study Center will monitor the patient’s condition through telephone 
contact on Study Day 3, 31, 59, 64, 87 and 92. 
CSF samples will be taken pre-dose on each Study Drug IT injection day (Days 1, 29, 
57, 85) and on Day 113 or 141.  These samples will be utilized for PK, Htt protein and 
other biomarker and laboratory analyses. 
If a patient terminates early from the Treatment Period of the study, he/she will be 
encouraged to return for the near-term follow-up visits associated with the most recent 
dose of Study Drug and for the Post-Treatment Period (Days 113-197). 
Safety and Tolerability 
Evaluations 
Safety and tolerability evaluations will 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 
• 
Clinical and neuroimaging (including safety sequences) assessments 
The safety and tolerability of ISIS 443139 will be assessed by determining the 
incidence, severity and dose-relationships of AEs and changes in laboratory 
parameters by dose.  In addition, clinical, electrophysiological and volumetric 
neuroimaging assessments will be used to monitor for unexpected deterioration.  
Safety results in patients dosed with ISIS 443139 will be compared with those from 
patients dosed with placebo.  Placebo-treated patients will be pooled for analysis. 
Pharmacokinetic 
Evaluations 
A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and 
at 1 Post-Treatment Period visit (either Study Day 113 or 141) for PK analyses.  The 
CSF concentrations will be summarized using descriptive statistics and the 
ISIS 443139 half-life in CSF will be calculated, if possible.  Analysis of the levels of 
ISIS 443139 in CSF is of key importance. 
In addition, plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and 
at each Post-Treatment Period visit for PK analyses.  Plasma maximum concentration 
(Cmax), area under the curve (AUC), elimination half-life and trough and post-distribution 
drug levels will be assessed, where appropriate. 
Exploratory Evaluations Exploratory evaluations will include: 
• 
Biochemical 
o 
CSF levels of mutant Htt* and total Htt 
o 
Potential biomarkers of HD disease progression 
• 
CSF:  neurofilament light chain*, proenkephalin, clusterin, factor H (FH), C3, 
interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), 
MCP-1, chitinase-3-like protein 1 (YKL-40), visinin-like protein 1 (VILIP1), 
apolipoprotein, chromogranin B, neurogranin, SNAP25, S100B and tau 


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PROTOCOL SYNOPSIS Continued 
Exploratory Evaluations 
Continued 
 
Exploratory evaluations will include: Continued 
• 
Plasma or Serum:  IL-6, TNFα and 24S-hydroxycholesterol 
• 
Neuroimaging 
o 
Structural MRI volumes, including but not limited to: 
 
Caudate  
 
Whole brain 
 
Ventricular* 
o 
MRS spectroscopy for frontal lobe myoinositol and N-Acetylaspartic acid 
(NAA) 
o 
Resting state functional MRI 
o 
Neurite orientation dispersion and density imaging (NODDI) 
• 
Electrophysiological 
o 
qEEG 
• 
Clinical 
o 
Functioning/ability to perform activities of daily living 
 
UHDRS Total Functional Capacity Scale (TFC) 
 
UHDRS Independence Scale 
 
HD Work Function Scale 
o 
Cognitive and motor tests: 
 
HD Cognitive Battery* 
• 
Self-Paced Tapping 
• 
Emotion Recognition 
• 
CANTAB One Touch Stockings 
• 
Symbol Digit Modalities Test  
• 
Hopkins Verbal Learning Test Revised 
• 
Trail Making Test Part B 
 
UHDRS Total Motor Scale 
 
Map Search Test 
 
Stroop Word Reading Test 
 
Speeded Tapping 
o 
Neuropsychiatric evaluation  
 
Problems Behavior Assessment for Huntington’s disease-short form 
(PBA-s) 
Evaluations will include comparisons between ISIS 443139-treated patients and 
placebo-treated patients of the above biomarkers and clinical evaluations.  If CSF Htt 
protein level is reflective of target engagement, exploratory evaluations will be 
conducted to relate dose and PK to CSF Htt protein level.  Placebo-treated patients will 
be pooled for analysis. 
* Key exploratory biochemical, neuroimaging, electrophysiological and clinical 
assessments 
 
 


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PROTOCOL SYNOPSIS Continued 
Statistical 
Considerations 
While there is no statistical basis for the sample size, it has been selected based on 
prior experience with generation 2 ASOs given by IT injection to ensure that the safety, 
tolerability, pharmacokinetics and exploratory pharmacodynamics will be adequately 
assessed while minimizing unnecessary patient exposure. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
 
 


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STUDY DESIGN AND TREATMENT SCHEMA 
 
 
 
END-OF-STUDY PROCEDURES 
or Early Termination from Post-
Treatment 
Day 197 
(Week 29) 
SCREENING PERIOD 
 
Days -43 to -2 
 
(Weeks -6 to -1) 
•
Assess capacity to consent, collect 
informed consent 
•
Assess eligibility 
POST-TREATMENT PERIOD 
Days 113 to 197 
(Weeks 17 to 29) 
DOSE TREATMENT PERIOD 
Days -1 to 92 
(Weeks 1 to 14) 
 
Monthly Study Drug Administration 
(ISIS 443139: placebo, 3:1) 
•
Cohorts of patients will be enrolled sequentially 
•
Each patient will receive 4 doses of study 
medication 
•
Cohort enrollment will be staggered.  Initiation 
of dosing in a new cohort will occur after 
(1) enrollment of the prior cohort is complete 
and (2) review of prior cohort data has been 
conducted as depicted in the Cohort 
Enrollment Flowchart below 
EARLY TREATMENT 
TERMINATION 
• If patient is willing to continue with 
the study: 
o complete the block of visits 
associated with the last dose 
received (see * in Appendix A) 
o complete the visit scheduled for 
7 days after the last dose received 
o conduct the Week 17 visit 
approximately 4 weeks after last 
dose and proceed with the Post-
treatment Period 
• If patient is not willing to continue 
with the study, conduct Week 29 as 
an Early Termination Visit 


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COHORT ENROLLMENT FLOWCHART 
 
 
 
*  DSMB and Sponsor review of data to permit initiation of dosing in a new cohort will occur when:  
•
at least 4 patients in the current cohort have received multiple doses of Study Drug such that 
the cumulative dose received by each of these patients meets or exceeds the initial dose 
planned for the new cohort and 
•
safety data have been collected in these patients through at least 7 days after receipt of the 
necessary cumulative dose. 
Prior to initiating dosing in a new cohort, the DSMB will review the safety data described above (at 
minimum) and make a recommendation regarding initiation of the new cohort. 
Additionally, the Sponsor may conduct a blinded review (or reviews) of accumulating 
pharmacokinetic data and compare those data to the ISIS 443139 levels that are expected to 
produce a pharmacologic effect (according to the preclinical PK/PD model).  Based on this review, 
the dose level(s) for future cohort(s) may be adjusted.  The maximum dose level tested in a cohort 
will not exceed 120 mg.  Beginning with Cohort C, the dose level for a cohort will not exceed 
2 times the dose tested in the prior cohort. 
10 
mg 
10 
mg 
10 
mg 
10 
mg 
Post-treatment Period 
Cohort 
A 
(N = 4) 
30 
mg 
30 
mg 
30 
mg 
30 
mg 
Post-treatment Period 
Cohort 
B 
(N = 8) 
60 
mg 
60 
mg 
60 
mg 
60 
mg 
Post-treatment Period 
Cohort 
C 
(N = 8) 
90 
mg 
90 
mg 
90 
mg 
90 
mg 
Post-treatment Period 
Cohort 
D 
(N = 12) 
screen 
screen 
screen 
screen 
Cohort 
E 
(N = 12) 
120 
mg 
120 
mg 
120 
mg 
120 
mg 
Post-treatment Period 
screen 
Review* 
Note:  Each         represents 1-dose followed by a 28-day observation period.   
The Post-treatment Period is 15 weeks. 
Review* 
Review* 
Review* 


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STUDY GLOSSARY  
Abbreviation 
Definition 
2ʹMOE 
2ʹ-O-(2-methoxyethyl) 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AP 
Anterior-posterior 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the curve 
AUCt 
Area under the plasma concentration-time curve from time zero to time t 
βhCG 
Beta-subunit of human chorionic gonadotropin (pregnancy test) 
BCHE-K 
Butyrylcholinesterase K variant 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Cmax 
Maximum concentration 
cl 
Clinic 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia suicide severity rating scale 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
DLT 
Dose-limiting toxicity 
DSMB 
Data And Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
FH 
Factor H 
FSE 
Fast spin echo 
GCP 
Good Clinical Practice 
1H-MRS 
Proton magnetic resonance spectroscopy 
HD 
Huntington’s disease 
HDWF 
Huntington’s disease work function 


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Htt 
Huntingtin protein 
HIV 
Human Immunodeficiency Virus 
HR 
Heart rate 
HVLT-R 
Hopkins verbal learning test - revised 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-1β 
Interleukin-1 beta 
IL-6 
Interleukin-6 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISIS 443139 
Antisense inhibitor of Htt 
IT 
Intrathecal(ly) 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCP-1 
Monocyte chemoattractant protein-1 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities  
mI 
Myo-inositol 
MoCA 
Montreal cognitive assessment 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MRS 
Magnetic resonance spectroscopy 
MTD 
Maximum tolerated dose 
NAA 
N-Acetyl-aspartate 
NCS 
Not clinically-significant  
NODDI 
Neurite orientation dispersion and density imaging 
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 
PK 
Pharmacokinetic(s) 


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PBA-s 
Problems behavior assessment for Huntington’s disease – short form 
PT 
Prothrombin time 
qEEG 
Quantitative EEG 
rsfMRI 
Resting state functional MRI 
RNase H 
Ribonuclease H (a non-specific endonuclease and catalyzes the cleavage 
of RNA via a hydrolytic mechanism) 
S100B 
S100 calcium binding protein B 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
siRNA 
Small interfering ribonucleic acid 
SAP 
Statistical Analysis Plan 
SNAP25 
Synaptosomal-associated protein 25 
Study Day 1 
Defined as the first day Study Drug is administered to the patient 
Study Drug 
ISIS 443139 or placebo 
SUSAR 
Suspected unexpected serious adverse reaction 
SDMT 
Symbol digit modalities test 
TEAE 
Treatment-emergent adverse event 
TFC 
Total functional capacity 
Tmax 
Time to maximal concentration 
TMS 
Total motor scale 
TMT-A 
Trail-making test part A 
TMT-B 
Trail-making test part B 
TNFα 
Tumor necrosis factor alpha 
TSE 
Turbo spin echo 
UHDRS 
Unified Huntington’s disease rating scale 
VILIP1 
Visinin-like protein 1 
WBC 
White blood cell 
YKL-40 
Chitinase-3-like protein 1 


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1. 
OBJECTIVES 
1.1 
Primary Objectives 
To evaluate the safety and tolerability of ascending dose-levels of multiple intrathecal (IT) bolus 
administrations of an antisense inhibitor of Htt (ISIS 443139) to patients with Huntington’s 
disease (HD) 
1.2 
Secondary Objectives 
To characterize the cerebrospinal fluid (CSF) pharmacokinetics (PK) of ascending dose-levels of 
multiple IT administrations of ISIS 443139. 
1.3 
Exploratory Objectives 
To explore effects of multiple doses of ISIS 443139 on potential target engagement and disease 
progression biomarkers and clinical endpoints relevant to HD.  Plasma pharmacokinetic 
properties of ISIS 443139 will also be assessed.  Disease progression markers are included 
primarily as a safety measure to document any marked worsening.  A lesser objective is to gain 
experience with these measures in an ISIS 443139 clinical study as preparation for subsequent, 
longer-term clinical studies.  It is not expected that the majority of biomarkers and clinical 
measures will be impacted significantly by the 3 months of dosing planned for this study.  For 
the current study, select disease progression markers are considered to be key exploratory target 
engagement, biochemical, neuroimaging and cognitive assessments based on their potential to 
evidence changes in disease progression in early HD.  These key exploratory endpoints are 
mutant Htt in CSF, neurofilament light chain in CSF, ventricular volume as assessed by 
structural MRI and the composite cognitive score resulting from assessment of the components 
of the HD Cognitive Battery. 
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). 
2.1.2 
Huntingtin Protein 
While the exact function of Htt has been elusive, studies suggest that Htt 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, 


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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 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 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.  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 
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 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 


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cognitive disturbances (Folstein et al. 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), a vesicular monoamine transporter 2 inhibitor, is the 
only drug currently approved for HD, and its label is specific for hyperkinetic motor disorders 
with Huntington’s chorea.  Tetrabenazine is approved in the United States, New Zealand, 
Australia, Canada, Israel and some European countries.  However, the drug has been linked to 
many significant adverse events (AEs), including Parkinsonism, akathisia, sedation, depression 
and suicidal thoughts (Xenazine label 2011).  Tetrabenazine is contraindicated in patients who 
are actively suicidal and in patients with untreated or inadequately treated depression 
(Xenazine label 2011), a population that includes approximately > 40% of HD patients 
(Chen et al. 2012).  Additionally, tetrabenazine 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 (muHtt) (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 


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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). 
ISIS 443139 is being developed to reduce the synthesis of Htt by targeting HTT mRNA and 
directing its catalytic degradation through the action of ribonuclease H (RNase H), 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 muHtt 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 ISIS 443139 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. 
2.3 
ISIS 443139 
2.3.1 
Mechanism of Action 
ISIS 443139 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 
ISIS 443139 to the cognate mRNA results in the RNase H-mediated degradation of the HTT 
mRNA, thus preventing production of the Htt protein.  Both wild-type and mutant HTT mRNA 
are targeted by ISIS 443139. 
2.3.2 
Chemistry 
Chemically, ISIS 443139 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer). 
 
 The nucleotide sequence of ISIS 443139 (Figure 1) is 
complementary to a 20-nucleotide stretch 
of the HTT mRNA. 
 
  These MOE-
modified nucleotides confer (1) increased affinity to the target mRNA  
(Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003) and (3) amelioration of 
some high dose toxicities resulting in an improved safety profile compared to first generation 
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antisense drugs containing phosphorothioate-modified oligodeoxynucleotides (DNA)  
(Henry et al. 2000).  The central portion of the oligonucleotide is composed of 
.  ISIS 443139 employs this chimeric structure to enable use of the RNase H-
mechanism for antisense activity.  While the 2′-MOE modification confers increased stability 
and affinity, it does not support RNase H catalysis of RNA hybridized to 2′-MOE-modified 
nucleotides (McKay et al. 1999) because conformational changes induced in the heteroduplex by 
2′-alkoxy:RNA hybrids are not recognized by RNase H enzymes (Inoue et al. 1987; Monia et al. 
1993).  By limiting the 2′-MOE modification to nucleotides flanking the phosphorothioate 
oligodeoxynucleotide core, the beneficial attributes of the 2′-MOE chemistry are preserved while 
also retaining RNase H recognition. 
Figure 1 
Design of ISIS 443139 
 
2.3.3 
Preclinical Experience 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3.4 
Clinical Experience 
ISIS 443139 has not been evaluated in any clinical setting. 
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2.4 
Rationale for Study Design 
2.4.1 
Rationale for the Study Population 
This is the first study of ISIS 443139 in humans, and it will be conducted in patients with early 
manifest HD.  Early manifest HD patients are generally active and independent in most areas of 
functioning (often still working or driving).  These patients are fully capable of informed 
consent.  It is necessary to conduct this study in patients, rather than in healthy volunteers, for 
2 reasons.  First, a better understanding of the safety of ISIS 443139 in its intended target 
population will be achieved in patients since the intended target of the Study Drug (i.e., mutant 
HTT mRNA transcripts) is not present in healthy volunteers.  Second, ISIS 443139 must be 
administered via intrathecal (IT) administration, and consideration of the balance between risk 
and benefit justifies investigation in a patient population only.  Although assessment of safety is 
the primary objective of this study, HD patients who enroll in this study will be relatively early 
in the manifest disease process and may experience benefit from the investigational treatment if 
it addresses the primary pathogenesis of the disease. 
Eligible patients will be aged ≥ 25 years of age to avoid very high CAG repeats associated with 
early disease onset (e.g., > 55 repeats) as such patients are considered to have a somewhat 
different, rapidly-progressing phenotype.  Eligible patients will also be ≤ 65 years of age to avoid 
undesirable comorbidity that is more common above this age. 
2.4.2 
Rationale for a Multiple Ascending Dose Design 
This is a first-in-man, multiple ascending dose (MAD) study in patients with HD.  This design is 
rational given the prolonged time between doses and the rarity of the patient population.  Also, 
the study is designed with a focus on patient safety. 
The study is designed to capture the information that would ordinarily be obtained in 2 separate 
studies – a single ascending dose (SAD) study and a MAD study.  The length of the dosing 
interval makes this design feasible.  With Study Drug dosing at 28-day intervals, comprehensive 
safety, tolerability and pharmacokinetic evaluations can be conducted in each patient for 28 days 
after the first dose.  This is comparable to the evaluation that would be conducted in a SAD 
study.  At the conclusion of this 28-day period, monthly dosing will continue (in the absence of 
significant safety issues related to Study Drug) for 3 additional doses, allowing for evaluation of 
safety, tolerability and pharmacokinetics during a multiple-dose regimen. 
This design, which eliminates the need for a SAD study, is appropriate because of the nature of 
the patients under investigation.  These are rare patients with a devastating disease, and Study 
Drug has to be administered by IT injection.  Therefore, it is important to obtain a maximum 
amount of information from each patient enrolled in each study conducted in this population. 
Patient safety is paramount with this study design.  For example, only clinical research facilities 
with capabilities for 24-hour in-patient monitoring will be utilized, and patients will be required 
to live close enough to the facility to permit prompt appearance at the facility if requested.  Each 
patient will be required to have a trial partner (i.e., a reliable and competent individual with a 
close relationship with the patient), and the Investigator will seek supplemental information 
about the patient’s condition from the trial partner using validated assessment tools.  In addition, 


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patient safety during the study will be monitored closely and on an ongoing basis by an 
independent, unblinded Data Safety Monitoring Board (DSMB). 
2.4.3 
Rationale for Dose Levels and Dosing Schedule 
The proposed study will test the safety, tolerability, and PK of multiple doses of ISIS 443139 
administered as IT injections.  Five (5) dose levels will be evaluated.  The doses are predicted to 
produce a range of pharmacologic effect but are not intended to elicit dose-limiting toxicities. 
ISIS 443139 dose levels and dose interval for ISIS 443139-CS1 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  The dose interval (administration every 
28 days) was selected based on the nonclinical pharmacokinetic and pharmacodynamic 
(HTT mRNA reduction) data required to achieve ISIS 443139 brain cortex tissue levels that are 
predicted to be at steady state by Day 92 and to achieve reduction in HTT mRNA levels.  Also, 
monthly dosing is expected to be safe and well-tolerated by patients. 
Additional details on dose scaling and expected CSF and tissue concentrations are summarized 
in the Investigator’s Brochure. 
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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 1/2a, multi-center, double-blind, randomized, placebo-controlled, dose-escalation 
study conducted in patients with early manifest HD.  The study consists of 5 cohorts (n = 4-12 
per cohort, randomized 3 active:1 placebo).  The doses planned for the study are shown below.  
Based on emerging safety data from this study, 1 or more cohorts may be expanded by enrolling 
additional patients.  Additionally, pharmacokinetic and pharmacodynamic measures will be 
collected at each dose level and compared to the results that are predicted by models constructed 
from preclinical data.  The doses utilized in remaining cohorts may be adjusted, or an additional 
cohort may be added, if necessary to achieve pharmacologically relevant levels.  The maximum 
dose tested in a cohort will not exceed 120 mg.  Beginning with Cohort C, the dose level for a 
cohort will not exceed 2 times the dose tested in the prior cohort. 
Cohort A: 
N = 4, 10 mg ISIS 443139 or placebo (3:1) 
Cohort B: 
N = 8, 30 mg ISIS 443139 or placebo (6:2) 
Cohort C: 
N = 8, 60 mg ISIS 443139 or placebo (6:2) 
Cohort D: 
N = 12, 90 mg ISIS 443139 or placebo (9:3) 
Cohort E: 
N = 12, 120 mg ISIS 443139 or placebo (9:3) 
Randomization in Cohort D will be stratified by early Stage 1 (TFC ≥ 12) or late Stage 1 
(TFC = 11) disease, where Stage 1 represents the highest level of capacity of the 5 stages of 
manifest disease. 
Patients will receive 4 monthly IT doses of Study Drug (ISIS 443139 or placebo).  Cohorts will 
be enrolled sequentially.  Initiation of dosing in a new cohort may begin after 3 conditions have 
been met:  (1) all patients in the lower-dose cohorts have been enrolled; (2) at least 4 patients in 
the lower-dose cohort have been followed for 7 days after receipt of a cumulative dose that meets 
or exceeds the initial dose for the next higher dose level cohort; and (3) a review of data 
collected in the lower-dose cohorts has been conducted by the DSMB and a decision has been 
made to proceed with the next cohort (see Section 3.7). 
After study completion, an open-label extension study of ISIS 443139 may be implemented if 
warranted based on review of safety, tolerability, pharmacokinetic and exploratory 
pharmacodynamic findings and subject to approval by the relevant Competent Authorities and 
Ethics Committees. 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
3.3 
Number of Patients 
Approximately 44 patients are planned to be enrolled in this study.  The number of patients 
enrolled may be higher if some patients need to be replaced and/or if the sizes of the cohorts are 


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expanded to obtain further experience with particular dose levels.  A maximum of 48 patients 
may be enrolled. 
3.4 
Overall Study Duration and Follow-up 
The overall study duration will be approximately 7-8 months.  The study will consist of a 
Screening Period of up to 6 weeks, a 13-week Treatment Period and a 15-week Post-Treatment 
Period.  Please refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Screening Period 
Patient eligibility for the study will be determined within 6 weeks prior to patient entry into the 
Treatment Period. 
3.4.2 
Treatment Period 
Eligible patients will report to the Study Center for monthly administration of Study Drug and 
for additional, non-dosing visits as described in the Schedule of Procedures in Appendix A. 
In Cohorts A and B, no more than 1 patient may begin the Treatment Period on a given day.  In 
later cohorts, the first 2 patients in the cohort may not begin the Treatment Period on a given day. 
3.4.3 
Post-Treatment Period 
Patients will return to the Study Center for follow-up visits 4, 8 and 16 weeks after the last dose 
of Study Drug.  The final study visit will be Study Day 197/Week 29. 
3.5 
End-of-Study 
The End-of-Study is defined as last patient, last study visit. 
3.6 
Data and Safety Monitoring Board  
An independent and unblinded DSMB will be assembled to review data collected on 
ISIS 443139 during this study.  Based on its ongoing assessment of the safety and tolerability of 
ISIS 443139, the DSMB will provide recommendations to the Sponsor for modifying, stopping 
or continuing the study as planned.  The progression of the study from one cohort to the next will 
be determined by the Sponsor and the DSMB, and this determination will generally be based on 
the number of dose-limiting toxicities (DLTs) observed in patients treated with ISIS 443139. 
Details on the safety assessments, frequency of review, meeting schedules and controlled access 
to unblinded data will be outlined in the DSMB Charter.  The DSMB will consist of at least 
3 voting members, all medical doctors experienced in the conduct of clinical studies in patients 
with neurodegenerative diseases and otherwise independent from the conduct of the study.  
Additional non-voting members may join the DSMB as required.  A majority of voting members 
must agree before escalation dose can proceed.  The decisions of the DSMB will be recorded in 
minutes of the meeting. 
3.7 
Dose Escalation 
Five (5) dose level cohorts (Cohorts A, B, C, D and E) will be enrolled sequentially, with 
patients each receiving 4 doses of Study Drug at 28-day intervals.  In Cohorts A and B, no more 
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2 patients in the cohort may not begin the Treatment Period on a given day.  The progression of 
the study from initiation of dosing in one cohort to the next will be determined by the Sponsor 
and the DSMB. 
Beginning with Cohort B, dose administration in the cohort may commence only after the 
following minimum requirements are met in the prior cohort: 
• All patients in the prior cohort have been enrolled 
• At least 4 patients in the prior cohort have received multiple doses of Study Drug 
(ISIS 443139 or placebo) such that the cumulative dose received by each patient is equal 
to or greater than the dose level planned for patients in the new cohort.  This corresponds 
to a requirement for multiple-dose administration in all patients in Cohort A (when 
considering escalation to Cohort B) and multiple-dose administration in at least 50% of 
patients in Cohorts B or C (when considering escalation to Cohort C or D, respectively) 
• Patient safety in the prior cohort has been monitored for at least 7 days post-treatment 
after receipt of the cumulative dose that meets or exceeds the dose planned for the new 
cohort, and those data are available for review 
• Safety data in the prior cohort have been reviewed by the DSMB and the DSMB has 
recommended initiation of the new cohort 
Additionally, the Sponsor may conduct a blinded review (or reviews) of accumulating CSF 
pharmacokinetic data and compare those data to the ISIS 443139 levels that are expected to 
produce a pharmacologic effect (according to the preclinical PK/PD model).  This review will be 
conducted in a manner that does not associate individual data with particular patients for those 
involved in the conduct of the study.  Based on this review, the dose level(s) for future cohort(s) 
may be adjusted.  The maximum single and cumulative doses administered in a cohort will not 
exceed 120 and 480 mg, respectively.  Beginning with Cohort C, the dose level for a cohort will 
not exceed 2 times the dose tested in the prior cohort. 
If a single DLT is encountered in Cohort A, the cohort may be expanded from 4 to up to 
8 patients to assess safety at that dose.  Other dose cohorts (Cohorts B, C, D and E) may also be 
expanded by up to 100% if a single DLT is encountered in those cohorts.  If dosing in higher 
dose cohort(s) is ongoing at the time a single DLT is encountered in a lower-dose cohort, further 
enrollment in the higher dose cohort(s) will stop until all current patients have completed dosing 
and at least 7 days of post-treatment safety evaluations.  In addition, the DSMB will convene to 
decide if further measures are required such as pausing or reducing dose in ongoing patients in 
the higher dose cohort(s). 
The occurrence of (i) DLTs in 2 patients in a cohort or (ii) a single SAE (excluding those 
attributable to the lumbar puncture, other study procedure or HD) that is evaluated by the 
Sponsor as related to Study Drug and is of sufficient significance to be dose limiting will result 
in termination of further dosing in that cohort and any higher dose cohort that is also ongoing.  In 
this situation, the DSMB will determine if the previous (lower) tolerated dose is the maximum 
tolerated dose (MTD).  The Sponsor and DSMB will determine if enrollment of additional 
patients at the previous (lower) tolerated dose is required to confirm that there is an acceptable 


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toxicity profile at the lower-dose or if a cohort of intermediate dose level (between the previous 
(lower) tolerated dose and the terminated dose) should be enrolled. 
3.8 
Dose Limiting Toxicity 
A suspected DLT is defined as an adverse event (AE) that, in the judgment of the Investigator, is 
of sufficient significance to be dose limiting, is possibly or definitely related to Study Drug (i.e., 
the AE is substantially less likely to occur in patients not administered the Study Drug) and that 
it is not a known sign or symptom of HD or effect of any study procedure (e.g., LP, 
venipuncture, MRI scan). 
If an Investigator considers an event to be a suspected DLT, the event will be referred to the 
unblinded DSMB which will determine whether it constitutes a DLT. 
If a suspected DLT occurs during IT injection of the Study Drug, administration of Study Drug 
to the patient must be stopped (i.e., the injection must be discontinued immediately and no 
further Study Drug injections may be administered in this patient).  The Investigator should 
contact the Ionis Medical Monitor as soon as possible to discuss the case.  The DSMB should 
convene and determine (based on unblinded data review, if necessary) if any relevant findings 
have been observed in other patients in the study. 
Patients that experience a DLT will discontinue study treatment but should complete any 
follow-up visits associated with the most recent dose (see Section 8.9) and should complete the 
Post-Treatment Period. 
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 procedures, are 
performed.  At the time of randomization, patients will 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.  The screening number and 
patient identification number must remain constant throughout the entire study.  In the event the 
patient is re-consented and re-screened, the patient must be given a new screening number.  
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 
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Eligible patients will be randomized centrally by an automated system to receive ISIS 443139 or 
placebo.  Within each cohort, randomization will be 3:1 ISIS 443139:placebo as outlined in 
Section 3.1. 
The Sponsor or designee will prepare the randomization list. 
4.3 
Replacement of Patients 
Patients withdrawn early from the Study who do not complete all scheduled doses of Study Drug 
(ISIS 443139 or placebo) may be replaced at the discretion of the Sponsor unless the Investigator 
and Sponsor Medical Monitor agree that this should not be done for reasons of safety.  
Replacement patients will be assigned to the same Study Drug (ISIS 443139 or placebo) as the 
patients who are being replaced without unblinding any study personnel.  No more than 
48 patients may be enrolled. 
Patients whose randomization code has been broken will not be replaced. 
4.4 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors and Study Center personnel related to the study will be 
blinded throughout the Study.  However, if a patient has suffered a Serious Adverse Event (SAE) 
(as defined in Section 9.3.3), and/or when knowledge of the treatment assignment will impact the 
clinical management of the patient, the Investigator will have the ability to unblind the treatment 
assignment for that patient through an automated system.  The Sponsor or designee will be 
informed of the unblinding of a patient within 24 hours.  An unblinded randomization schema 
will be maintained securely at the Sponsor’s (or designee’s) Quality Assurance Department.  In 
addition, all SUSARs will be unblinded by the Sponsor’s or designee’s Drug Safety and Quality 
Assurance personnel for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendices A and B) prior to unblinding, as knowledge of the treatment arm 
could influence patient assessment. 
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. Early manifest, Stage 1 HD (defined as TFC of 11-13, inclusive), aged 25 to 65 years, 
inclusive, at the time of informed consent, with genetically confirmed disease (CAG 
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4. Body Mass Index (BMI) ≥ 18 and ≤ 32 kg/m2; total body weight > 50 kg (110 lbs) 
5. Able and willing to meet all study requirements in the opinion of the Investigator, 
including travel to Study Center, procedures, measurements and visits, 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 and at the time of enrollment 
f. Patients must reside in a proximity to the Study Center that permits prompt 
appearance at the facility if requested by the Investigator (maximum of 4-hour travel 
to Study Center) 
Reproductive Status 
6. 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 2 highly 
effective contraceptive methods (refer to Section 6.3.1) from the time of signing the 
informed consent form until at least 13 weeks after the last dose of Study Drug 
(ISIS 443139 or placebo) 
If not surgically sterile, must have a negative HCG pregnancy test at Screening and 
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7. Males must be surgically sterile, abstinent* or, if engaged in sexual relations with a 
female of child-bearing potential, the patient must be using an acceptable contraceptive 
method (refer to Section 6.3.1) from the time of signing the informed consent form until 
at least 13 weeks after the last dose of Study Drug (ISIS 443139 or placebo) 
* 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. 
5.2 
Exclusion Criteria 
Target Disease-Related Exclusions  
1. Any condition, including severe chorea, that would prevent either writing or performing 
rapid computer tasks 
Physical, Mental and Laboratory Test Findings 
2. Attempted suicide, suicidal ideation with a plan that required hospital admission and/or 
change in level of care within 12 months prior to Screening.  For patients with (i) a 
suicide ideation score ≥ 4 on the Columbia Suicide Severity Rating Scale (C-SSRS) 
within the last 12 months, (ii) a score of 3 or 4 on question 2 of the Problems Behavior 
Assessment for Huntington’s Disease – short form or (iii) suicidal behaviors within the 
last 12 months (as measured by the answer “Yes” on any of the C-SSRS Suicidal 
Behavior Items), a risk assessment should be done by an appropriately-qualified mental 
health professional (e.g., a Psychiatrist or licensed Clinical Psychologist) to assess 
whether it is safe for the patient to participate in the study.  In addition, patients deemed 
by the Investigator to be at significant risk of suicide, major depressive episode, 
psychosis, confusional state or violent behavior should be excluded 
3. Clinically significant laboratory, vital sign or ECG abnormalities at Screening (including 
heart rate (HR) < 45 bpm; SBP < 90 mmHg; confirmed BP readings > 170/105 mmHg) 
4. Positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B 
at Screening 
Prohibited and Restricted Medications and Procedures 
5. Treatment with another investigational drug, 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 
6. Current or recent (within the last 6 months) use of antipsychotics (prescribed for 
psychosis), cholinesterase inhibitors, memantine, amantadine or riluzole.  Stable use of 
antipsychotics (prescribed for treatment of motor symptoms) and/or tetrabenazine is not 
permitted unless stable dose for at least 12 weeks prior to Screening and with a dose 
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7. 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 
8. Supplement use (e.g., coenzyme Q10, vitamins, creatine) unless stable dose for 6 weeks 
prior to Screening and with a dose regimen that is not anticipated to change during the 
study 
9. Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or anticipated 
use during the study, including but not limited to aspirin (unless ≤ 81 mg/day), 
clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban 
10. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed at least 3 days prior to the first day Study Drug is administered to the patient 
(Study Day 1) 
11. Prior treatment with an antisense oligonucleotide (including siRNA) 
12. Any history of gene therapy or cell transplantation or any other experimental brain 
surgery 
13. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter 
Medical History and Concurrent Disease 
14. Significant history of alcoholism or drug/chemical abuse  
15. Clinically relevant hematological, hepatic, cardiac or renal disease or event (e.g., 
previous acute coronary syndrome within 6 months of Screening).  Abnormal hepatic, 
renal or hematology lab tests must be discussed with the Sponsor Medical Monitor 
16. Known history of human immunodeficiency virus (HIV), hepatitis C or chronic 
hepatitis B 
17. Any condition that increases risk of meningitis unless patient is receiving appropriate 
prophylactic treatment 
18. History of bleeding diathesis or coagulopathy, platelet count < LLN 
19. A medical history of brain or spinal disease that would interfere with the LP process, CSF 
circulation or safety assessment, including tumors or abnormalities by MRI or computed 
tomography (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure 
on MRI or ophthalmic examination, spinal stenosis or curvature, chiari malformation, 
hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue 
disorders such as Ehlers-Danlos syndrome and Marfan syndrome 
20. History of post-lumbar-puncture headache of moderate or severe intensity and/or blood 
patch 
21. 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 


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22. Hospitalization for any major medical or surgical procedure involving general anesthesia 
within 12 weeks of Screening or planned during the study 
23. Have any other conditions which, in the opinion of the Investigator, 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 
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 -6 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.  
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 14) 
Study Drug will be administered 4 times, with doses separated by 28 days (Section 8.1). 
Eligible patients will report to the Study Center on Study Day -1 (the day prior to first Study 
Drug 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 Study Drug 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 adverse events 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. 
Each subsequent Study Drug administration will be conducted in the same manner, with most 
pre-dose assessments conducted on the day before Study Drug administration; post-dose, 
in-clinic observation of at least 6 hours after Study Drug administration (longer or overnight if 
necessary for safety reasons); in-clinic assessments on the day after Study Drug administration; 
telephonic contact with patients 2 days after Study Drug administration and in-clinic assessments 
1-week after Study Drug administration. 


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6.1.3 
Post-Treatment Period (Week 17 to Week 29) or Early Termination 
After completion of the Treatment Period, patients will enter the 15-week Post-Treatment Period.  
This period consists of 3 Study Center visits on Weeks 17, 21 and 29, as outlined in the Schedule 
of Procedures in Appendix A. 
Patients who terminate early from the Treatment or Post-Treatment Periods (for reasons other 
than withdrawal of consent) should be encouraged to submit to additional visit(s) as described in 
detail in Section 8.9.  (Also see Appendices A and C and Study Design and Treatment Schema.) 
6.2 
Study Assessments 
The order of study assessments will be defined in the Study Manual.  All efforts should be made 
to adhere to a consistent order of assessments throughout the study.  Rest periods will be 
scheduled during the testing, and the patient should be permitted additional 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 
International Standard Classification of Education (ISCED) 
The ISCED is used to capture each patient’s level of education based on categories ranging from 
pre-primary education through advanced degree programs. 
6.2.3 
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. 
A referral for psychiatric evaluation is required for any increase in the most severe suicidal 
ideation score from baseline.  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. 
6.2.4 
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. 


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For each vital sign measurement, record the patient’s position and the arm used for the 
measurement. 
6.2.4.1 
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 heart.  
The patient must rest for at least 10 minutes in the seated position prior to measuring blood 
pressure (BP). 
6.2.4.2 
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. 
6.2.5 
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 Study Day -1 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. 
6.2.6 
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). 
6.2.7 
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). 
6.2.8 
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.  HD 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). 


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6.2.9 
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 at Screening and during the Post-Treatment Period. 
Ventricular expansion as assessed by structural MRI is a key exploratory endpoint for the study. 
At the Screening and Study Day 197/Week 29 visits, the following scans will be performed to 
characterize the patients’ pre-treatment and end-of-study state:  T2 flair, T2 star and T2 Fast Spin 
Echo (FSE)/Turbo Spin Echo (TSE). 
Additionally, at the Study Day 113/Week 17 visit, MRI will be used to image the CSF space. 
Metabolic disturbances in the frontal lobe of the brain will be assessed using proton magnetic 
resonance spectroscopy (1H-MRS).  Using 1H-MRS, the concentrations of particular metabolites, 
N-Acetyl-aspartate (NAA) and myo-inositol (mI), can be measured relative to the signal of 
unsuppressed water.  Normal, healthy tissues present a constant proton spectrum, and relative 
changes in metabolites may be reflective of aberrant biochemical transformations (Walecki et al. 
2011).  NAA serves as a marker or neuronal health, as it is found only in mature neurons, and 
has been shown to decline in patients with cognitive impairment (Kantarci et al. 2003).  
Myo-inositol serves as a marker of glial cells, and elevated levels are associated with regional 
gliosis (Walecki et al. 2011).  A recent study demonstrated elevated mI and decreased NAA in 
HD (Sturrock and Leavitt 2010) suggesting that these metabolites might serve as endpoints in 
HD clinical trials. 
Corticostriatal connectivity loss occurs early in Huntington’s disease.  The functional and 
effective connectivity between brain regions will be examined using resting state functional MRI 
(rsfMRI).  Seed connectivity will be used to identify brain regions which are simultaneously 
activated at rest.  Dynamic causal modelling will be used to explore causal interactions between 
the brain and these regions.  Brain cellular microstructure and structural connectivity will be 
examined using volumetric MRI combined with neurite orientation dispersion and density 
imaging (NODDI).  Computational approaches will be applied to visualize neural tracts and to 
determine the relative strength of anatomical connections between brain regions.  Graph theory 
will be used to detect changes in the organization of brain networks such as integration and 
efficiency.  The rsfMRI and NODDI scans require approximately 25 minutes in the scanner.  It is 
recognized that some patients may be unwilling to submit to this additional burden; therefore, 
while patients will be encouraged to receive these scans, they will not be required. 
6.2.10 
Speeded Tapping 
The speeded tapping test is a measure of psychomotor speed and has been used as a longitudinal 
marker of disease severity in manifest and pre-manifest HD.  For the test, the patient taps the 
index finger of his/her non-dominant hand as quickly as possible.  A brief rest period is held 
between trials. 


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6.2.11 
Unified Huntington’s Disease Rating Scale (UHDRS) 
The UHDRS, developed by the Huntington Study Group to provide a uniform assessment of the 
clinical features and course of HD has undergone reliability and validity testing that support its 
use in longitudinal studies (Huntington Study Group 1996).  The scale assesses 4 domains 
associated with HD:  motor function, cognitive function, behavioral abnormalities and functional 
capacity. 
For this study, only the UHDRS components required to calculate the total functional capacity 
scale, the independence scale and the total motor scale will be collected.  These components are 
simple, multiple-choice questions based on patient interview, physical exam and observation 
during motor activities, such as speeded tapping (Section 6.2.10) and walking.  The components 
are described further below. 
6.2.11.1 
UHDRS Total Functional Capacity Scale (TFC) 
The TFC represents the Investigator’s assessment of the patient’s capacity to perform a wide 
range of activities of daily living including working, chores, managing finances, eating, dressing 
and bathing.  It is based on a brief interview with the patient and the study partner.  Scores range 
from 0 to 13, and higher scores represent better functioning. 
6.2.11.2 
UHDRS Independence Scale 
The patient’s independence scale is the Investigator’s assessment of the patient’s degree of 
independence.  The scale consists of 19 discrete levels ranging from 10 to 100 (by 5) where no 
special care needed corresponds to a scale of 100 and tube fed and total bed care corresponds to a 
scale of 10. 
6.2.11.3 
UHDRS Total Motor Scale (TMS) 
The TMS is the sum of the individual motor ratings obtained during administration of the motor 
assessment portion of the UHDRS.  Scores range from 0 to 124, and higher scores represent 
more severe impairment. 
6.2.12 
HD Work Function (HDWF) Scale 
The HDWF scale is a measure of work role limitations and effort, which are areas that may be 
affected by the cognitive, behavioral and motor changes associated with HD (Brossman et al. 
2012).  It was developed for prodromal HD, the stage prior to overt motor impairment and HD 
diagnosis in which structural and functional brain changes lead to subtle changes in cognition 
and motor function.  Patients complete the questionnaire consisting of 20 questions, where the 
response to each is based on a 7-point Likert scale ranging from “not at all like me” to “very 
much like me”.  Scores range from 20 to 140, and higher scores represent higher work function 
ability. 
A companion scale was developed as a proxy indicator of the patient’s work function, 
acknowledging that insight may diminish in some individuals in the prodromal or early stages of 
HD.  During for development of the HDWF scale, correlation between the patient and 
companion scores were statistically significant (Brossman et al. 2012).  If the patient suffers 
from diminished insight, information from the companion, i.e., trial partner, may provide 
important supporting information. 


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6.2.13 
Montreal Cognitive Assessment (MoCA) 
The MoCA is a screening test for cognitive impairment that spans the visuospatial/executive, 
naming, memory, attention, language, abstraction, delayed recall and orientation domains that 
has been shown to be sensitive in HD (Nasreddine et al. 2005; Videnovic et al. 2010).  The test 
administrator prompts the patient through a series of tests and follows a simple algorithm to 
document the patient’s score.  Total scores range from 0 to 30 points, with lower numbers 
representative of more cognitive impairment.  This test will be performed at Screening only to 
characterize the patient population relative to published populations. 
6.2.14 
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.  This composite cognitive score is a 
key exploratory endpoint for the study.  The individual tests that comprise the battery are 
described below. 
6.2.14.1 
Self-Paced Tapping 
Self-paced tapping measures cognitive and motor timing.  The patient listens to a repeating tone 
at 3Hz and taps in time with the tone, alternating between left and right thumbs.  The patient 
continues to tap after the tone stops, attempting to maintain the same rate of tapping.  Four (4) 
trials are conducted. 
Scoring of each effort is based on the precision of taps, which is directly estimated, and timing 
precision, which is calculated as the reciprocal of the standard deviation of the intertap interval. 
6.2.14.2 
Emotion Recognition 
For this test, patients view faces depicting a neutral expression or an emotion (anger, disgust, 
fear, sadness, surprise, happiness).  After a practice trial for each category, the patient views 
70 test trials and categorizes each face by emotion.  The number of correct responses for 
negative emotions (anger, disgust, fear, sadness) are tallied (Johnson et al. 2007). 
6.2.14.3 
CANTAB One Touch Stockings (OTS) 
The OTS test measures executive function, spatial planning and working memory.  On a 
computer or tablet screen, the patient is shown 2 stacks of colored balls, which can be perceived 
balls stacked in hanging socks or stockings.  The patient must move the balls between the 
stockings to achieve a particular color pattern.  Rearranging the balls to make the target pattern 
may take 1, 2, 3 or 4 moves.  Then, the patient is shown 2 stacks of colored balls and must 
determine, without moving the balls, the minimum number of moves necessary to achieve the 
target pattern. 
Tests are scored based on accuracy in determining minimum number of moves and time to 
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6.2.14.4 
Symbol Digit Modalities Test (SDMT) 
The SDMT is used to assess attention, visuoperceptual processing, working memory and 
psychomotor speed.  It has been shown to have strong reliability and validity (Smith 1982; 
Hinton-Bayre et al. 1999).  The patient must pair abstract symbols with specific numbers 
according to a translation key.  The test measures the number of items correctly paired 
(maximum of 110) in 90 seconds. 
6.2.14.5 
Hopkins Verbal Learning Test – Revised (HVLT-R) 
The HVLT-R is used to assess verbal memory through tests of recall and recognition.  Patients 
must recall a series of 12 words over 3 immediate trials (learning), free recall after a 25-minute 
delay and a recognition trial. 
6.2.14.6 
Trail-Making Test  
The Trail-Making Test Part B (TMT-B) is a test of executive functioning.  Patients are presented 
with a picture of 25 circles, each labeled with a number (1 – 13) or a letter (A – L).  The patient 
must draw lines to connect the circles in an ascending pattern that alternates between the 
numbers and letters (i.e., 1-A-2-B-3-C …).  The patient is instructed to connect the circles as 
quickly as possible, and the time to complete the task is recorded.   
The Trail-Making Test Part A (TMT-A) is also administered, but the results of the TMT-A are 
not considered to be part of the battery.  For the TMT-A, patients are presented with 25 circles, 
each labeled with a number (1-25) and are asked to connect the numbers.  Administration of 
TMT-A prior to TMT-B provides practice to aid in administering TMT-B. 
6.2.15 
Problems Behavior Assessment for Huntington’s Disease – Short Form (PBA-s) 
The PBA-s assesses common behavioral and psychiatric manifestations of HD, including affect, 
irritability, loss of motivation, perseverative phenomena and psychotic symptoms.  The test 
administrator interviews the patient and trial partner and rates the patient’s behavior over the 
prior 4 weeks according to the guidelines for the test. 
6.2.16 
Stroop Word Reading Test 
The Stroop Word Reading Test is a measure of processing and psychomotor speed.  Patients are 
presented with a page of color names printed in black ink and are asked to read aloud as many 
words as possible within a given amount of time.  The number of words read correctly is 
counted. 
6.2.17 
Map Search Test 
The Map Search Test is a test of sustained visual attention.  Patients are presented with a visually 
cluttered map and asked to circle as many target symbols on the map as possible within a fixed 
period of time.  Scoring is based on the number of correctly identified symbols. 
6.2.18 
Collection of CSF 
Patients will have CSF collected pre-dose during the LP procedure on Study Days 1, 29, 57 and 
85 for safety and PK analyses.  A sample will also be collected during the Post Treatment Period 
on either Study Day 113 or Study Day 141.  Prior to the injection, 20 mL of CSF fluid is to be 


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collected for analyses, using a standard LP collection kit.  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.  
Fluoroscopy guidance should be used if attempts at lumbar puncture without imaging are 
unsuccessful. 
6.2.19 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
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).  Pharmacokinetic analysis of ISIS 443139 in plasma will be 
conducted using samples collected as described in Appendices A and C. 
In addition, assessments of exploratory biomarkers will include interleukin-6 (IL-6), TNFα and 
24S-hydroxycholesterol. 
For each scheduled lumbar puncture, local laboratory analysis of coagulation factors (PT, INR 
and aPTT) and platelets must be conducted and results reviewed prior to performing the lumbar 
puncture.   
• For dosing visits (Days 1, 29, 57 and 85), collection for local labs may occur on the day 
prior to dosing at the same time that samples are collected for analysis at the central 
laboratory. 
• For the lumbar puncture in the Post-Treatment Period (Day 113 or Day 141 or Day 197), 
collection for local labs may occur on the day of the lumbar puncture provided results can 
be obtained and reviewed prior to performing the lumbar puncture.  
6.2.19.2 
CSF Laboratory Assessments 
CSF will be used for standard laboratory measurement of cells, glucose, protein and ISIS 443139 
pharmacokinetic analyses.   
Key exploratory CSF biomarkers are muHtt level and neurofilament light chain.  Additional CSF 
assessments are total Htt, proenkephalin, clusterin, factor H (FH), C3, IL-6, TNFα, IL-1β, 
monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (YKL-40), visinin-like 
protein 1 (VILIP1), apolipoprotein E, chromogranin B, neurogranin, synaptosomal-associated 
protein 25 (SNAP25), S100 calcium binding protein B (S100B) and tau. 
Extra CSF will be stored for investigation of possible biomarkers of HD or the 
pharmacodynamic effects of ISIS 443139 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 
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6.2.20 
Pregnancy Testing 
Pregnancy tests will be conducted in all female patients who are not surgically sterile, as 
described 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 13 weeks after the last dose of Study Drug (ISIS 443139 or placebo). 
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. 
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 Study Drug 
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 13 weeks after the last dose of Study Drug.  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). 


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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. 
6.3.2 
Other Requirements 
Patients should be encouraged to maintain consistency throughout the study with respect to 
smoking, caffeine consumption and alcoholic beverage consumption. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
ISIS 443139 Study Drug and artificial CSF diluent are manufactured by Ionis Pharmaceuticals, 
Inc., Carlsbad, CA, USA.  The Study Drug is supplied as a 5 mL fill volume in a 6 mL clear 
glass vial.  The diluent (artificial CSF) is supplied as a 20 mL fill volume in a 20 mL clear glass 
vial.  These configurations allow for various clinical doses by using different dilution procedures 
between the Study Drug and diluent vials.  Study Drug characteristics are described in Table 1.  
More details are provided in the Study Drug Manual. 
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 443139 
Placebo 
Diluent 
(artificial CSF) 
Strength 
20 mg/mL 
NA 
NA 
Volume/Vial 
5 mL solution per vial 
5 mL solution per vial 
20 mL solution per vial 
Route of Administration 
IT injection 
IT injection 
IT injection 
 
ISIS 443139 Study Drug and the diluent (artificial CSF) must be stored securely at 2° C to 8° C.  
ISIS 443139 Study Drug must be protected from light. 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 443139 or placebo) 
and diluent labeled in accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 443139 or placebo) and diluent supplies provided by the Sponsor.  The Study Center must 
return all used and unused Study Drug and diluent vials to the Sponsor or designee. 


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8. 
TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
Study Drug dosing will occur at the Study Center on Study Days 1, 29, 57 and 85.  On each of 
these Study 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 Study Drug.  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.  Fluoroscopy guidance should be used if attempts at lumbar 
puncture without imaging are unsuccessful. 
Table 2 outlines the dose equivalent and ISIS 443139 concentration for delivery.  See Section 3.1 
for a description of adjustments that might be made to doses and the maximum dose that will be 
tested. 
Table 2 
Study Drug Dosing Information 
Cohort 
Volume to Administer 
Nominal ISIS 443139 Concentration  
ISIS 443139 Per Dose 
Cohort A 
20 mL  
0.50 mg/mL 
10 mg or placebo 
Cohort B 
20 mL  
1.5 mg/mL 
30 mg or placebo 
Cohort C 
20 mL  
3.0 mg/mL 
60 mg or placebo 
Cohort D 
20 mL  
4.5 mg/mL 
90 mg or placebo 
Cohort E 
20 mL  
6.0 mg/mL 
120 mg or placebo 
 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug preparation and administration.  These instructions must be followed 
for each Study Drug 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. 
8.4 
Treatment Precautions 
Patients will be discouraged from resting supine after the lumbar puncture procedure and will be 
encouraged to mobilize immediately. 


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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.  There are no additional specific stopping rules for this study but the 
Investigator should discuss significant concerns relating to individual patients with the 
Ionis Medical Monitor to ensure that it is appropriate for the patient to continue Study Drug. 
8.7 
Adjustment of Dose and/or Treatment Schedule 
For a given patient, no adjustment of dose is permitted except as mandated by the DSMB as 
described in Section 3.7.  In the event of a concurrent illness that would prevent the dosing 
procedure from being performed safely, an adjustment in the dose schedule may be permitted at 
the discretion of the Sponsor Medical Monitor. 
8.8 
Discontinuation of Study Drug 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an adverse event that necessitates permanent discontinuation of 
Study Drug 
• The patient experiences a DLT as defined in Section 3.8 
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 Treatment or Post-Treatment Periods (for reasons other 
than withdrawal of consent) should be encouraged to submit to additional visit(s) as described in 
detail in Section 8.9.  (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 


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• 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 (a) conduct the 
full block of visits associated with the last dose received (see description of “visit blocks” 
below), (b) conduct the visit scheduled for 7 days after the last dose received, (c) and proceed to 
the Week 17 visit approximately 4 weeks after last dose and conduct all visits in the 
Post-Treatment Period (see Appendix A). 
“Visit blocks”:  Each dose of Study Drug is associated with a series of visits that are 
timed to assess acute safety and tolerability of ISIS 443139.  There are 4 “visit blocks” in 
this study:  Study Days -1, 1, 2 and 3; Study Days 28, 29, 30 and 31; Study Days 56, 57, 
58 and 59 and Study Days 84, 85, 86 and 87. 
For patients who terminate early from the Treatment Period for reasons other than withdrawal of 
consent every effort and are not willing to participate in the Post-Treatment Period, every effort 
should be made to (a) conduct the full block of visits associated with the last dose received (see 
description of “visit blocks” above), (b) conduct the visit scheduled for 7 days after the last dose 
received and (c) conduct the Week 29 visit as an Early Termination Visit. 
For patients who terminate early from the Post-Treatment Period for reasons other than 
withdrawal of consent, every effort should be made to conduct the Week 29 visit as an Early 
Termination Visit. 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
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8.10.1 
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 study medication and end of study. 
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 adverse events 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) and/or tetrabenazine 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 (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 


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• Cholinesterase inhibitors 
• Memantine 
• Amantadine 
• Tetrabenazine 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 
8.10.2 
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 study medication and end of study. 
8.11 
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 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 DSMB will be notified of any SAE as specified in 
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The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that the Study Drug (ISIS 443139 or placebo) caused the AE and, 
therefore, meets the definition of a SUSAR. 
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 adverse event.  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 adverse event 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 not result in 
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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 197.  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 Study Day 197.  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: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 443139 or placebo) 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 Study Drug (ISIS 443139 or placebo) administration 
 
 


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• 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 
Study Drug (ISIS 443139 or placebo) 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 adverse events, 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 adverse events 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 Study Drug (ISIS 443139 or placebo) due to the event is characterized by 1 of 
the following: 
• None:  No changes were made to Study Drug (ISIS 443139 or placebo) administration 
and dose 
• Permanently Discontinued:  Study Drug 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 
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 


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• 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. 
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 
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• 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 
Study Drug (ISIS 443139 or placebo) 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 Study Drug (ISIS 443139 or placebo) 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. 
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 Study Drug.  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 
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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 (HR, BP, orthostatic changes, weight) 
• ECG 
• AEs and concomitant medications 
• CSF safety labs (cell counts, protein, glucose) 
• Plasma laboratory tests (clinical chemistry, hematology) 
• Urinalysis 
• Clinical assessments 
• Volumetric and safety neuroimaging assessments 
10.1.2 
Pharmacokinetic Endpoints 
A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and at 
1 Post-Treatment Period visit for PK analyses. 
Plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and at each 
Post-Treatment Period visit for PK analyses. 
Plasma Cmax, AUC, elimination half-life and trough and post-distribution drug levels will be 
assessed, where appropriate. 
10.1.3 
Exploratory Endpoints 
• Biochemical 
o CSF levels of mutant Htt* and total Htt 


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o CSF levels of neurofilament light chain*, proenkephalin, clusterin, FH, C3, IL-6, 
TNFα, IL-1β, MCP-1, YKL-40, VILIP1, apolipoprotein, chromogranin B, 
neurogranin, SNAP25, S100B and tau 
o Plasma or serum levels of IL-6, TNFα and 24S-hydroxycholesterol 
• Neuroimaging volumes, including but not limited to: 
o Structural MRI 
 Caudate 
 Whole brain 
 Ventricular* 
o MRS spectroscopy for frontal lobe myoinositol and N-Acetylaspartic acid (NAA) 
o Resting state functional MRI 
o Neurite orientation dispersion and density imaging (NODDI) 
• Electrophysiological 
o qEEG 
• Clinical 
o Functioning/ability to perform activities of daily living 
 UHDRS Total Functional Capacity Scale (TFC) 
 UHDRS Independence Scale 
 HD Work Function Scale 
o Cognitive and motor tests: 
 HD Cognitive Battery* 
• Self-Paced Tapping 
• Emotion Recognition 
• CANTAB One Touch Stockings 
• Symbol Digit Modalities Test 
• Hopkins Verbal Learning Test Revised 
• Trail Making Test Part B 


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 UHDRS Total Motor Scale 
 Stroop Word Reading Test 
 Map Search Test 
 Speeded Tapping 
o Neuropsychiatric evaluation 
 Problems Behavior Assessment for Huntington’s disease-short form (PBA-s) 
* Key exploratory biochemical, neuroimaging, electrophysiological and clinical assessments 
10.2 
Sample Size Considerations 
While there is no statistical rationale for the sample size, it has been selected based on prior 
experience with generation 2.0 ASOs given by IT injection to ensure that the safety, tolerability, 
pharmacokinetics and exploratory pharmacodynamics will be adequately assessed while 
minimizing unnecessary patient exposure. 
10.3 
Populations 
Safety Population:  All patients who are randomized and receive at least 1 dose of Study Drug. 
Per Protocol Population:  All patients who are randomized and receive all doses of the 
protocol-specified Study Drug (ISIS 443139 or placebo). 
PK Population:  All patients who are randomized to ISIS 443139 and receive at least 1 dose of 
ISIS 443139 and have sufficient sampling to permit pharmacokinetic evaluation. 
10.4 
Definition of Baseline 
For vital signs (BP, heart rate, respiration rate and temperature), baseline will be defined as the 
average of the 3 values collected prior to first dose (Screening, Study Day -1 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. 
10.5 
Interim Analysis 
An unblinded interim analysis may be performed and the results summarized by treatment group 
at the end of each cohort upon completion of dosing for that cohort or at any time if needed to 
address a safety concern.  The results of an analysis of this type will not be shared with patients 
or Investigators. 
A DSMB will be assembled to review safety, tolerability, pharmacokinetic and target 
engagement/pharmacodynamic (as needed) data collected on ISIS 443139 during this study.  
Unblinded statisticians or designees who will not be involved in the study conduct will generate 
and distribute the data to DSMB prior to each DSMB meeting.  Based on its ongoing assessment 
of the safety and tolerability of ISIS 443139, the DSMB will provide recommendations to the 
Sponsor for modifying, stopping or continuing the study as planned.  Details on the safety 


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assessments, frequency of review, meeting schedules and controlled access to unblinded data are 
outlined in the DSMB charter and/or the statistical analysis plan (SAP). 
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, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% Type I error rate unless otherwise stated. 
Since there are limited placebo-treated patients within each dose cohort, the placebo-treated 
patients will be pooled for analysis. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Patient disposition will be summarized by treatment group.  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 Study Drug received will be summarized by treatment group. 
All treatment-emergent adverse events (TEAEs) and SAEs will be summarized for each 
treatment group 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, etc., will be summarized by study visit 
for each treatment group.  These safety variables will also be presented as change and percent 
change from baseline over time after Study Drug administration, as appropriate. 
Vital sign and ECG measures will be tabulated by treatment group.  In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
Columbia – Suicide Severity Rating Scale will be summarized by study visit for each treatment 
group.  Physical examination, standard neurological assessment (including fundi), and clinical 
and neuroimaging results will be summarized, if appropriate, and listed. 
10.6.3 
Pharmacokinetic Analysis 
The pharmacokinetic analysis will be conducted on the PK Population. 


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A CSF sample will be collected pre-dose on each injection day (Days 1, 29, 57, 85) and at 
1 Post-Treatment Period visit for PK analyses.  The CSF concentrations will be summarized 
using descriptive statistics and the ISIS 443139 half-life in CSF will be calculated, if possible. 
Plasma samples will be collected on study Days 1, 2, 29, 57, 85 and 86 and at each 
Post-Treatment Period visit for PK analyses.  Plasma PK parameters will be summarized using 
descriptive statistics. 
Non-compartmental PK analysis of ISIS 443139 in plasma will be carried out on each individual 
patient data set.  Cmax and the time taken to reach Cmax (Tmax) will be obtained directly from the 
concentration-time data.  The plasma half-life (t1/2λz) associated with the apparent terminal 
elimination phase will be calculated, if appropriate using available data, from the equation, 
t1/2λz = 0.693/λz, where λz is the rate constant associated with the apparent terminal elimination 
phase.  Partial areas under the plasma concentration-time curve from zero time (pre-dose) to 
selected times (t) after the administration (AUCt) will be calculated using the linear trapezoidal 
rule. 
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 Statistical 
Analysis Plan. 
10.6.4 
Exploratory Analysis 
The exploratory analyses will be conducted on the Per Protocol and Safety Populations. 
Exploratory evaluations (Section 10.1.3) will be summarized using descriptive statistics by study 
visit and treatment group.  Change and percent change from baseline over time will be 
summarized as appropriate.  Comparison between ISIS 443139 group and the pooled placebo 
group will be performed in an exploratory manner.  Details will be described in the Statistical 
Analysis Plan. 
Additional exploratory 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 exploratory endpoints may be performed as where deemed appropriate. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
HD 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).  A prospective patient’s consent will be sought only if 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. 


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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 any Study Drug (ISIS 443139 or placebo) are 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 patient s 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. 
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.  


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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. 
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. 
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: 


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• 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.  
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. 


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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. 
 


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13. 
REFERENCES 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
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. 
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. Clinical Therapeutics 2012; 34: 1487-1504. 
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. 
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. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Henry SP, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation 
in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
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. 
Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Letters 1987; 215: 327-330. 
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. 


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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. 
Kantarci K, Reynolds G, Petersen RC, et al. Proton MR spectroscopy in mild cognitive impairment and Alzheimer 
disease: comparison of 1.5 and 3T. Am J Neuroradiol 2003; 24: 843–849. 
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. 
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. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J of Biol Chem 1999; 274: 1715-1722. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2′-modified oligonucleotides containing 2′-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
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, 
Third Edition, 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. 
Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal cognitive assessment (MoCA): a brief screening tool 
for mild cognitive impairment. J American Geriatrics Society 2005; 53: 695-699. 
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, 
editors. 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. 
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. American Journal of 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 Journal of Rare Diseases 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. 


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Shoulson I and Fahn S. Huntington disease: clinical care and evaluation. Neurology 1979; 29: 1-3. 
Shoulson I, Kurlan R, Rubin AJ, et al. Assessment of functional capacity in neurodegenerative movement disorders: 
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Butterworth 1989. Chapter 20. 
Shoulson I and Young AB. Milestones in Huntington disease. Mov Disord 2011; 26: 1127-1133. 
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Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of transcriptional dysregulation 
is correlated with behavioral benefits in the YAC128 mouse model of Huntington’s disease. J Huntington’s Disease 
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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 and 
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Videnovic A, Bernard B, Fan W, et al. The Montreal cognitive assessment as a screening tool for cognitive 
dysfunction in Huntington's disease. Mov Disord 2010; 25(3): 401-404. 
Walecki J, Barcikowska M, Cwikla JB, Gabryelewicz T. N-acetylaspartate, choline, myoinositol, glutamine and 
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Wexler NS, Young AB, Tanzi RE, et al. Homozygote for huntinton’s disease. Nature 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. 
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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. 
 
 


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14. 
APPENDICES 
 
 


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Appendix A 
Schedule of Procedures 
 
 
 


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Appendix A Schedule of Procedures 
Study Period 
Screen 
Treatment Evaluation Period 
(13 Weeks) 
Post-Treatment 
Period 
(15 Weeks) 
Study Week 
-6 to -1 
1 
2 
5 
6 
9 
10 
13 
14 
17/ 
ET2 
21 
29/ 
ET2 
Study Day 
-43 to -2 
-1 
1 
2 
3 
8 
28 
29 
30 31 36 56 
57 
58 59 64 84 
85 
86 87 92 
113 
141 
197 
Visit Window (days)* 
- 
* 
0 
* 
* 
± 2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
±2 
±7 
±7 
Visit Type1 
cl 
cl 
cl 
cl 
ph 
cl 
cl 
cl 
cl ph cl 
cl 
cl 
cl ph ph cl 
cl 
cl ph ph 
cl 
cl 
cl 
Overnight Stay3 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Capacity to Consent Assessment 
and Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and ISCED 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MoCA  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, T) 
X 
X 
Xa 
 
 
 
X 
Xa 
 
 
 
X 
Xa 
 
 
 
X 
Xa 
 
 
 
X 
X 
X 
Orthostasis  
X 
 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
X 
X 
Physical& Neurological Exam4 
X 
X 
Xc 
Xd 
 
X 
X 
Xc 
Xd 
 
X 
X 
Xc 
Xd 
 
 
X 
Xc 
Xd 
 
 
X 
X 
X 
Body Weight and Height5 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Functional, Cognitive, Motor and 
Neuropsychiatric assessments6 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
C-SSRS7 
X 
X 
Xb 
X 
 
X 
X 
Xb 
X 
 
X 
X 
Xb 
X 
 
 
X 
Xb 
X 
 
 
X 
X 
X 
qEEG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Structural MRI8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
T2 flair, T2 star, T2 FSE/TSE 
MRI8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
rsfMRI and NODDI8, 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MRI of the CSF space8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
1H-MRS8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
ECG (12-Lead)10 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


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Appendix A Schedule of Procedures Continued 
Study Period 
Screen 
Treatment Evaluation Period  
(13 Weeks) 
Post-Treatment 
Period 
(15 Weeks) 
Study Week 
-6 to -1 
1 
2 
5 
6 
9 
10 
13 
14 
17/ 
ET2 
21 
29/ 
ET2 
Study Day 
-43 to -2 
-1 
1 
2 
3 
8 
28 
29 
30 31 36 56 
57 
58 59 64 84 
85 
86 87 92 
113 
141 
197 
Visit Window (days)* 
- 
* 
0 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
* 
±2 
* 
* 
±2 
±2 
±7 
±7 
Visit Type1 
cl 
cl 
cl 
cl 
ph 
cl 
cl 
cl 
cl ph cl 
cl 
cl 
cl ph ph cl 
cl 
cl ph ph 
cl 
cl 
cl 
Chemistry Panel 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Genetic Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, Hepatitis B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug/Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Serum Biomarker Sample 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Thyroid Panel 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
PT, INR, aPTT 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Local PT, INR, aPTT and 
platelets14 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Xg 
Xg 
X h 
Plasma Sampling for PK 
 
 
Xe 
Xd 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xf 
Xd 
 
 
X 
X 
X 
Archived Serum Sample13 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
CSF Sample for 
PK/Safety/Biomarkers 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
X g 
Xg 
X h 
Archived CSF Sample 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
Xb 
 
 
 
Xg 
Xg 
Xh 
Study Drug Administration 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Appendix A Schedule of Procedures Continued 
 
Note:  If not specifically labeled, “X” means anytime; ET = early termination 
* 
Visit windows are calculated relative to Study Day 1.  Note that within each block of visits associated with dose 
administration, the visits must occur on 4 consecutive days.  There are 4 “visit blocks” in this study:   
(Study Days -1, 1, 2 and 3), (Study Days 28, 29, 30 and 31), (Study Days 56, 57, 58 and 59) and 
(Study Days 84, 85, 86 and 87). 
 
1 
cl = clinic visit; ph = phone visit 
2 
If the patient terminates early from the Treatment Period but is willing to participate in the Post-Treatment Period, 
(a) conduct the full block of visits associated with the last dose received (see asterisk above), (b) conduct the 
visit scheduled for 7 days after the last dose received, (c) proceed to the Week 17 visit approximately 4 weeks 
after last dose and conduct all visits in the Post-Treatment Period.  If the patient terminates early from the 
Treatment Period and is not willing to participate in the Post-Treatment Period, (a) conduct the full block of visits 
associated with the last dose received (see asterisk above), (b) conduct the visit scheduled for 7 days after the 
last dose received and (c) conduct the Week 29 visit as an Early Termination Visit.  If the patient terminates early 
from the Post-Treatment Period, conduct the Week 29 visit as an Early Termination Visit 
3 
On Study Day 1, the patient must stay in the clinic overnight and undergo safety monitoring follow-up as 
scheduled on Study Day 2.  On Study Days 29, 57 and 85, the patient may either stay in the clinic overnight or 
be discharged (after a minimum observation period of 6 hours after Study Drug administration), provided the 
patient returns to the clinic on the following day (Day 30, 58 or 86) for all required assessments 
4 
Full physical and neurological exam (including fundi) to be given at Screening and abbreviated physical (but full 
neurological) exam to be given during Treatment and Post-treatment Periods as indicated to assess changes 
from Screening 
5 
Height is measured at Screening only 
6 
Functional, Cognitive, Motor and Neuropsychiatric Tests are speeded tapping, UHDRS total functional capacity 
scale, UHDRS independence scale, UHDRS total motor scale, HD work function scale, HD Cognitive Battery 
(self-paced tapping, emotion recognition, CANTAB one-touch stockings, symbol-digit modalities test, Hopkins 
verbal learning test – revised and trail making tests), Problems Behavior Assessment for Huntington’s disease-
short form, Stroop Word Reading test and Map Search test 
7 
The C-SSRS must be administered on the study days shown.  It may also be administered at any time that the 
Investigator feels is necessary 
8 
For imaging during the Screening period, the scans should be conducted sufficiently early in the Screening 
Period to allow for repeat scanning if necessary.  For imaging at post-Screening visits, efforts should be made to 
conduct the imaging within the visit window.  If re-scanning at a post-Screening visit is necessary because the 
original scan is not usable, the re-scanning should be conducted within 1-week of the original scan if at all 
possible 
9 
rsfMRI and NODDI scans are conducted only in patients who have consented for these assessments 
10 Measured in triplicate at the Study Day -1 visit only 
11 Women who are not surgically sterile as confirmation of menopause 
12 Women who are not surgically sterile.  Serum test at Screen visit; dipstick at post-screen visits 
13 Stored at -80º C for follow-up exploration of laboratory findings and/or adverse events (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 ISIS 443139 
14 Local laboratory analysis of PT, INR, aPTT and platelets must be conducted and results reviewed prior to 
performing the lumbar puncture on the next day (Days -1, 28, 56, 84) or the same day (Day 113 or 141 or 197).  
If a lumbar puncture will not be performed, local analysis of PT, INR, aPTT and platelets is not necessary 
 
 


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Appendix A Schedule of Procedures Continued 
 
Time (in reference to time of Study Drug administration): 
a 
Pre-dose, 3 and 6 hours post IT injection 
b 
Pre-dose 
c 
Pre-dose and 3 hours post IT injection; also conduct at 6 hours post IT injection on any dosing day that the 
patient does not stay in the clinic overnight (overnight stays are optional on Study Days 29, 57 and 85) 
d 
24 hours after prior dose of Study Drug 
e 
Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours post IT injection 
f 
Pre-dose, 0.5, 1, 2, 3, 4 and 5 hours post IT injection 
g 
All patients in Cohort A will have CSF collected on Study Day 113 (Week 17) and not on Study Day 141 
(Week 21).  For all other cohorts, CSF sampling will be conducted in approximately 50% of patients on Study 
Day 113 (Week 17) and in the remaining 50% of patients on Study Day 141 (Week 21), as assigned by the 
Sponsor according to a predetermined, randomized assignment.  For each scheduled lumbar puncture, local 
laboratory analysis of coagulation factors (PT, INR and aPTT) and platelets must be conducted and results 
reviewed prior to performing the lumbar puncture.  Collection for local labs may occur on the day of the lumbar 
puncture provided results can be obtained and reviewed prior to performing the lumbar puncture 
h 
CSF sampling and local analysis of PT, INR, aPTT and platelets will be conducted at Study Day 197 (Week 29) 
in only those patients who attend the visit as an early termination visit, did not undergo CSF sampling on either 
Study Day 113 (Week 17) or Study Day 141 (Week 21) and will undergo CSF sampling on Study Day 197.  If 
CSF sampling was conducted on Study Day 113 (Week 17) or Study Day 141 (Week 21), do not collect CSF or 
perform local analysis of PT, INR, aPTT and platelets at Study Day 197 (Week 29) 
 
 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
77 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
78 
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 ISIS 443139 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 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 
White blood cells 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Color 
Appearance 
 
Thyroid Panel 
TSH 
Free T4 
Free T3 
 
Coagulation 
aPTT 
PT 
INR 
Screening Tests 
Hepatitis B surface 
antigen 
Hepatitis C antibody 
HIV antibody 
FSH (women only) 
Serum βhCG 
Drug/Alcohol screen2 
 
Genetics 
CAG repeat length 
apoE isoform genotype 
BCHE-K 
 
PK1 
Plasma ISIS 443139 
levels 
CSF ISIS 443139 levels 
 
Pregnancy 
Urine hCG 
CSF Safety Panel 
(Minimum Requirements) 
Red blood cells 
White blood cells 
Glucose 
Protein 
 
Exploratory CSF 
Biomarker Panel 
mu Htt 
total Htt 
Proenkephalin 
Clusterin 
FH 
C3 
IL-6 
TNFα 
IL-1β 
MCP-1 
YKL-40 
VILIP1 
ApoE 
Chromogranin B 
Neurogranin 
SNAP25 
S100B 
Tau 
Neurofilament light chain 
 
Exploratory 
Serum/Plasma Biomarker 
Panel 
IL-6 
TNFα 
24S-hydroxycholesterol 
1 
Any of the collected PK plasma and CSF samples from the study patients may also be used by Ionis for 
investigation of possible biomarkers of disease or the pharmacodynamic effects of ISIS 443139 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 ISIS 443139 with plasma and CSF 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. 
2 
Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, opiates 
 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
79 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
80 
Appendix C PK Sampling Schedule 
Study Period 
Treatment Evaluation Period 
(13 Weeks) 
Post-Treatment 
Period or Early 
Termination Visit 
(15 Weeks) 
Study Week 
1 
5 
9 
13 
17 
21 
29 
Study Day 
1 
2 
29 
57 
85 
86 
113 
141 
197 
CSF Sampling 
Pre-dose 
 
Pre-dose 
Pre-dose 
Pre-dose 
 
Anytime1 
Plasma Sampling 
Pre-dose, 0.5, 1, 2, 3, 
4, 5, 6, 8,12 hours 
post IT injection 
24 hours post Day 1 
IT injection 
Pre-dose 
Pre-dose 
Pre-dose, 0.5, 
1, 2, 3, 4, 5 
hours post IT 
injection 
24 hours post 
Day 85 
IT injection 
Any-
time 
Any-
time 
Any-
time 
1 
All patients in Cohort A will have CSF sampling on Study Day 113 (Week 17) and not on Study Day 141 (Week 21).  For all other cohorts, CSF sampling will 
be conducted in approximately 50% of patients in the cohort on Study Day 113 (Week 17) and in the remaining 50% of patients in the cohort on 
Study Day 141 (Week 21), as assigned by the Sponsor.  CSF sampling will be conducted on Study Day 197 (Week 29) in only those patients who attend the 
visit as an early termination visit and did not undergo CSF sampling on either Study Day 113 (Week 17) or Study Day 141 (Week 21).  If CSF sampling was 
conducted on Study Day 113 (Week 17) or Study Day 141 (Week 21), do not collect CSF on Study Day 197 (Week 29). 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
81 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
82 
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. 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
83 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
5 April 2017 
 
84 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 


ISIS 443139-CS1 
CONFIDENTIAL 
Protocol 
Ionis Pharmaceuticals  
 
Amendment Changes 
 
 
1 
 
PROTOCOL AMENDMENTS 
 
Protocol Number: 
ISIS 443139-CS1 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple 
Ascending Doses of Intrathecally Administered ISIS 443139 in Patients with 
Early Manifest Huntington’s Disease 
 
A list of changes to the protocol are below:  
Amendment 
Description of Change 
Dates 
Original 
Protocol 
There were 2 versions of the protocol for this study.  In the version for UK and 
Canada, fluoroscopy was permitted as an optional tool for assisting with 
correct spinal needle placement during lumbar puncture.  In the version for 
Germany, fluoroscopy was not included as an optional tool because its 
inclusion would have required additional regulatory approvals (due to the 
radiation exposure) and the German investigators indicated that they would 
not opt to use fluoroscopy even if it were permitted.   
06 Mar 2015 
(UK/Canada) 
 
19 Mar 2015 (Germany) 
Amendment 1 
Both versions: 
•Revised the DLT definition to exclude SAEs attributable to the LP procedure, 
other study procedure, or HD and those not of sufficient significance to be 
considered dose-limiting at the request of a reviewing regulatory agency; 
•Added referral of an event an Investigator considered to be a suspected DLT 
to the unblinded DSMB for determination of whether it constituted a DLT 
because the DSMB was in an ideal position to review accumulating study data 
across study centers and to judge whether an event was dose-limiting; and 
•Added Appendix D, a grading scale for AEs relating to laboratory 
abnormalities based on the CTCAE Version 4.03, to facilitate consistent 
grading across study centers. 
 
Germany version only: 
In response to a request from BfArM, the amendment added a requirement 
that an independent expert assist with determination of a patient’s capacity to 
consent if the Principal Investigator was uncertain of the patient’s capacity.   
07 May 2015 
(UK/Canada) 
 
03 Jun 2015 (Germany) 
Amendment 2 
Both versions: 
•Added results from a supplementary toxicology study in monkeys that 
provided an extended safety margin for doses used in the study and increased 
the maximum dose that could be tested from 70 to 120 mg; 
•Added local assessment of coagulation and platelets on the day of or day 
prior to scheduled lumbar punctures to standardize testing because pre-
lumbar puncture practices differed across study sites; and  
added routine safety laboratory testing to Study Days 56 and 113 as good 
clinical practice. 
25 May 2016 
(UK/Canada) 
 
26 May 2016 (Germany) 
Amendment 3 
Both versions: 
•Changed the size of Cohort D from 16 to 12 participants.  The Sponsor had 
decided to enroll a fifth cohort of patients (an optional cohort described in all 
prior versions of the protocol) and wanted to ensure that the fifth cohort 
contained enough patients to characterize the effects at that dose level.  
Cohort D was reduced from 16 to 12 patients to allow for sufficient enrollment 
05 Apr 2017 
(UK/Canada) 
 
04 Apr 2017 (Germany) 


ISIS 443139-CS1 
CONFIDENTIAL 
Protocol 
Ionis Pharmaceuticals  
 
Amendment Changes 
 
 
2 
 
into the fifth cohort while remaining within the protocol-specified maximum of 
48 patients. 
 
•Also, the Sponsor took the opportunity to align the dose levels indicated in the 
protocol with the doses that had been used during the study.  Prior protocols 
specified dose levels of 10 mg, 30 mg, 50 mg, and 70 mg (or placebo) in 
Cohorts A, B, C and D, respectively, with the options of updating the levels 
based on accumulating PK/PD data and adding a fifth cohort if needed.  The 
maximum permitted dose was 120 mg and, beginning with Cohort C, the dose 
level for a cohort was not permitted to exceed 2 times the dose tested in the 
prior cohort.  At each dose escalation meeting, the Sponsor and the study’s 
unblinded, independent DSMB reviewed all available safety, PK, and PD data 
to determine the appropriate dose for the next cohort, within the existing 
limitations on maximum dose and escalation.  The study was executed in 
accordance with this design, and the dose levels utilized were 10 mg, 30 mg, 
60 mg, 90 mg and 120 mg (or placebo) in Cohorts A, B, C, D, and E, 
respectively. 
 


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November ll ,2015
ISIS 443I39-CSO1
ISIS-
PHABMACEUTICALS
Statistical Analysis Plan
rsrs 443139-CS1
A Randomizedo Double-blind, Placebo-controlled Study to
Evaluate the Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of Muttipte Ascending Doses of Intrathecally
Administered ISIS 443139 in Patients with Early Manifest
Huntington's Disease
Date:1111112015
Version: 1 .0
Co¡tnoeunet
Confidential/Trade Secref information subject to 18-USC-1905 and to which all claims of privilege and
confidentiality are asserted in both statutory and common law. Further dissemination may be made
only with fhe express written permission of /srs Pharmaceuticals, lnc.


Isis Pharmaceutical s, Inc'
CONFIDENTIA.L
November ll,2015
ISIS 44313g-CSOI
Statistical AnalY sis Plan
Compound Name:
Protocol:
Study Title:
Issue Date
Statistical Analysis Plan Signature Page
Isis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
443139
csl
A Randomized, Double-blind, Placebo-controlled Study to Evaluate
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of
Multiple Ascending Doses of Intrathecally Administered ISIS 443139
in Patients with Early Manifest Huntington's Disease
7 May 2015 (Amendment 1)
3 June 2015 (Amendment I * Germany)
Signature:
Signature:
Biostatistician
 
 
 
 
 
  
 
 
 
Senior Biostatistician, Biometrics
 
 
 
 
 
 
 
  
 
 
 
 
Oats: /l¿Çv tt ,)-olÇ
Date:
'Ìrrfl
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Isis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
November lI ,20t5
ISIS 443139-CSO1
Signature:
Signature:
Signature:
te
 
Associate Direator, Biometrics
Isis Pharmaceuticals, Inc.
2855 Gazelle Court
cA 92010
Date:
 
 
Director, Pharmacokinetics & Clinical Pharmacology
Isis Pharmaceuticals, Inc.
2855 Gazelle Court
Nø tl ,,zntí
It' ' {
Date:
l/¡.1óVz¿Ú
 
Director, Clinical Development
Isis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
111
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Isis Pharmaceuticals, Inc.
Statistical Analvsis Plan
CONFIDENTIAL
November ll ,2015
ISIS 443I 39-CSOI
Table of Contents
Abbreviatìons ............. 
""""""""""'1
1.0 Introductíon....,.......... 
""""'3
1.1 
Study Overview 
""""""""""3
1.2 Objectives.
1.2.1 PrimaryObjectives...,
1.2.2 SecondaryObjectives....
1.2.3 ExploratoryObjectives.
1.3 Endpoints
1.3.1 Safety and Tolerability Endpoints
......4
,....,.4
.......4
1.3.2 Pharmacokinetic Endpoints............'.'.'..
2.0
2.1
at
2.3
2.4
1.3.3 ExploratoryEndPoints
Procedures 
""""'7
General Overview of Procedures............. 
""""""""'7
Randomization & Treatment Allocation. 
""""""""'7
Conduct.... 
"""""7
Data Monitoring...........
Safety Data Monitoring.
8
8
Data Management......
Case Report Form Data...
Laboratory Data
Pharmacokinetics Data
2.4.1
2.5
2.5.1
2.5.2
2.5.3
3.1
3.1.1
3.1.2
3.1.3
3.1.4
3.1.5
3.2
3.2.1
3.2.2
3.2.3
3.2.4
3.2.5
3.2.6
3.2.7
3.2.8
3.3
3.3.1
3.3.2
3.3.3
3.4
I
8
8I
General Overview of Analyses
Statistical Methods.....
Subj ect Populations Analyzed
Sample Size Consideration..
Incomplete or Missing Data............
Safety Analyses...
Exposure......
Adverse Events..........
Columbia Suicide Severity Rating Scale (C-SSRS)
Planned Interim Analysis
Laboratory Measurements...................
11
1l
1l
12
14
t6
16
l6
l6
Vital Signs Measurements and Weight
Neurological Examinations .........'.......,
l2-Lead Electrocardiograms (ECG)
Prior and Concomitant Medications
Pharmacokinetic Analysis ..............
CSF Concentration Data and Pharmacokinetics'..
l7
t7
Plasma Concentration Data.......... 
"""""" 18
Plasma Pharmacokinetics
18
Exploratory Pharmacokinetic-Pharmacodynamic AnaIysis.............. 
""""20
Exploratory Analyses. 
""""20
3.5
ll


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November Il ,2015
ISIS 443I39-CSO1
3.5.1
3.s.2
3.5.3
3,5.4
3.5.5
3.5.6
3.5.7
3.5.8
3.5.9
3.5.10
3.5.r I
3.5.12
3.5.13
3.5.14
qEEG
Biochemical
20
20
2l
21
22
22
22
24
25
25
25
25
26
27
Neuroimaging Findings
UHDRS Total Functional Capacity Scale (TFC)
UHDRS Independence Scale.........
4.0
5.0
Reference. 
,...,.,.27
Appendíces 
,.,.,.27
HD Work Function (HDWF) Scale
HD Cognitive Battery
UHDRS Total Motor Scale (TMS).
Stroop Word Reading Test ..........
Map Search Test,
Speeded Tapping
Problems Behavior Assessment for Huntington's Disease-Short Form (PBA-s)
Correlations between ISIS 443 1 39 Exposure and Exploratory Endpoints
Subset and Sensitivity Analyses
111


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November ll ,2015
rsrs 443139-CS01
AnnnEVIÄTIONS
Abbreviation
AE
ALT
aPTT
AST
AUCt
BP
BUN
C,nu*
CRF
CSF
C-SSRS
DBS
DSMB
ECG
eCRF
EDC
FDA
FH
GCP
HD
HDV/F
Htt
HR
HVLT.R
ICH
rL-18
TL-6
INR
ISIS 443139
IT
LCR
MCH
MCHC
MCP-I
MCV
Definition
Adverse event
Alanine aminotransferase (SGPT)
Activated partial thromboplastin time
Aspartate aminotransferase (SGOT)
Area under the plasma concentration-time curve from time zeto Io time t
Blood pressure
Blood urea nitrogen
Maximum concentration
Case report form
Cerebrospinal fluid
Columbia suicide severity rating scale
Disease burden score
Data and Safety Monitoring Board
Electrocardiogram
Electronic Case Report Form
Electronic Data Capture
Food and Drug Administration
Factor H
Good Clinical Practice
Huntington's disease
Huntington' s disease work function
Huntingtin protein
Heart rate
Hopkins verbal leaming test - revised
International Conference on Harmonization
Interleukin-1 beta
Interleukin-6
Internation al normalized rati o
Antisense inhibitor of Htt
Intrathecal(ly)
Local cutaneous reactions
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Monocyte chemoattractant protein- I
Mean corpuscular volume
I


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November II ,2015
ISIS 443139.CS01
MedDRA
MoCA
MRI
NODDI
on Study
Medical Dictionary for Regulatory Activities
Montreal cognitive assessment
Magnetic resonance imaging
Neurite orientation dispersion and density imaging
The patient is 'on Study' from signing of the informed consent until
his/her last study visit
One touch stockings
Measure of the acidity or basicity of a solution
Pharmacokinetic(s)
Problems behavior assessment for Huntington's disease - short form
Prothrombin time
Quantitative EEG
QT time corrected using the Friderica's method
QT time using theBazett's method
Relative ventricular rate
S100 calcium binding protein B
Serious adverse event
Statistical Analysis Plan
Synaptosomal-associated protein 25
Defined as the first day Study Drug is administered to the patient
ISIS 443139 orplacebo
Symbol digit modalities test
Treatment-emergent adverse event
Total functional capacity
Time to maximal concentration
Total motor scale
Trail-making test part A
Trail-making test part B
Tumor necrosis factor alpha
Turbo spin echo
Unified Huntington's disease rating scale
Visinin-like protein I
Ventricular rate
V/hite blood cell
V/orld health or ganization
Chitinase-3Jike protein 1
OTS
pH
PK
PBA-s
PT
qEEG
QTcF
QTcB
RR
SlOOB
SAE
SAP
SNAP25
Study Day 1
Study Drug
SDMT
TEAE
TFC
T.u*
TMS
TMT-A
TMT-B
TNFa
TSE
UHDRS
VILIP1
VR
WBC
wHo
YKL-40
2


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
L.0 lxrnonucrlof{
This document provides a description of the study organizalion, study procedures, and the
plan for the statistical analysis of the study data. Section I discusses study design, objectives,
and endpoints; Section 2 provides the study procedures; Section 3 provides the detailed plan
for the statistical analyses.
As with any statistical analysis plan (SAP), the proposed methods and approaches to the data
analysis should be viewed as flexible. The statistical analysis to some degree is iterative since
the planning is based, at least in part, on statistical and other assumptions, which require
verification.
1.1 Study Overview
This is a Phase ll2a, mulfi-center, double-blind, randomized, placebo-controlled, dose-
escalation study conducted in patients with early manifest Huntington's disease (HD). The
study consists of four cohorts (n : 4-16 per cohort, randomized in a ratio of 3 active: I
placebo). The doses planned for the study are shown below. Based on emerging safety data
from this study, one or more cohorts may be expanded by enrolling additional patients.
Additionally, pharmacokinetic and pharmacodynamic measures will be collected at each
dose level and compared to the results that are predicted by models constructed from
preclinical data. The doses utilized in remaining cohorts may be adjusted, or an additional
cohort may be added, if necessary to achieve pharmacologically relevant levels. The
maximum dose tested in a cohort will not exceed 70 mg.
Dose Cohorts:
November 1l ,2015
rsIS 443139-CS0l
Cohort A:
Cohort B:
Cohort C:
Cohort D:
N:4, 10 mg ISIS 443139 orplacebo (3:1)
N : 8, 30 mg ISIS 443139 or placebo (6:2)
N : 8, 50 mg ISIS 443139 or placebo (6:2)
N : 16, 70 mg ISIS 443139 or placebo (12:4)
Randomization in Cohort D will be stratified by early Stage I total functional capacity (TFC
> 12) or late Stage I (TFC : 11) disease, where Stage 1 represents the highest level of
capacity of the 5 stages of manifest disease.
Patients will receive 4 intrathecal (IT) bolus doses of Study Drug at 4 week intervals during
the l3-week Treatment Period (Days l, 29, 57 , 85)'
Approximately 36 patients are planned to be enrolled in this study. The number of patients
enrolled may be higher if some patients need to be replaced and/or if the sizes of the cohorts
aJ


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
are expanded to obtain further experience with particular dose levels. A maximum of 48
patients may be enrolled.
The overall study duration will be approximately 7-8 months. The study will consist of a
Screening Period of up to 6 weeks, a l3-week Treatment Period and a l5-week Post-
Treatment Period. The end of study is defined as last patient, last study visit. Please refer to
the Schedule of Procedures in Appendix A.
1.2 Objectives
1.2.1 Primary Objectives
To evaluate the safety and tolerability of ascending dose-levels of multiple IT bolus
administrations of an antisense inhibitor of Htt (ISIS 443139) to patients with HD.
1.2.2 Secondary Objectives
To characterize the cerebrospinal fluid (CSF) pharmacokinetics (PK) of ascending dose-
levels of multiple IT administrations of ISIS 443139.
1.2.3 Exploratory Objectives
To explore effects of multiple doses of ISIS 443139 on potential target engagement and
clisease progression biomarkers and clinical endpoints relevant to HD. Plasma
pharmacokinetic properties of ISIS 443139 will also be assessed. Disease progression
markers are included primarily as a safety measure to document any marked worsening. A
lesser objective is to gain experience with these measures in an ISIS 443139 clinical study as
preparation for subsequent, longer-term clinical studies. It is not expected that the majority of
biomarkers and clinical measures will be impacted significantly by the l3-week of dosing
planned for this study. For the current study, select disease progression markers are
considered to be key exploratory target engagement, biochemical, neuroimaging and
cognitive assessments based on their potential to evidence changes in disease progression in
early HD. These key exploratory endpoints are mutant Htt in CSF, neurofilament light chain
in CSF, ventricular volume as assessed by structural magnetic resonance imaging (MRI) and
the composite cognitive score resulting from assessment of the components of the HD
Cognitive Battery, respectively.
1.3 Endpoints
1.3.1 Safety and Tolerabitity Endpoints
o Columbia - Suicide Severity Rating Scale (C-SSRS)
o Physical examination and standard neurological assessment (including fundi)
o Pregnancy testing
November II ,2015
ISIS 443I39-CSOI
4


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November ll ,2015
ISIS 443139-CSOl
o Vital signs (HR, BP, orthostatic changes, weight)
o ECG
o AEs and concomitant medications
o CSF safety labs (cell counts, protein, glucose)
o Plasma laboratory tests (clinical chemistry, hematology)
o Urinalysis
o Clinical assessments
o Volumetric and safety neuroimaging assessments
1.3.2 Pharmacokinetic Endpoints
A CSF sample will be collected at pre-dose on each injection day (Days I, 29, 57 ,85) and at
one Post-Treatment Period visit for PK analyses.
Plasma samples will be collected on study Days 1, 2, 29, 57 , 85 and 86 and at each Post-
Treatment Period visit for PK analyses.
Plasma C,nu", AUC, elimination halflife and trough and post-distribution drug levels will be
assessed, where appropriate.
1.3.3 ExploratoryEndpoints
o Biochemical
o CSF levels of mutant Htt* and total Htt
o CSF levels of neurofilament light chain*, proenkephalin, clusterin, FH, C3,IL-6,
TNFa, IL-l8, MCP-I, YKL-40, VILIPI, apolipoprotein, chromogranin B,
neurogranin, SNAP25, Sl00B and tau
o Plasma levels of IL-6, TNFo and 24S-hydroxycholesterol
Neuroimaging volumes, including but not limited to:
o Structural MRI
. 
Caudate
. Whole brain
. Ventricular*
a
5


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November II ,2015
ISIS 443139-CSO1
o
o Magnetic resonance spectroscopy for frontal lobe myoinositol and N-
Acetylaspartic acid
o Resting state functional MRI
o NODDI
Electrophysiological
o qEEG
Clinical
o Functioninglabllity to perform activities of daily living
. UHDRS Total Functional Capacity Scale (TFC)
. UHDRS Independence Scale
. HD Work Function Scale
o Cognitive and motor tests:
. HD Cognitive Battery*
o Self-Paced Tapping
o Emotion Recognition
o CANTAB One Touch Stockings
o Symbol Digit Modalities Test
o Hopkins Verbal Learning Test Revised
o Trail Making Test Part B
. UHDRS Total Motor Scale
. 
Stroop Word Reading Test
r Map Search Test
. 
Speeded Tapping
o Neuropsychiatric evaluation
' 
Problems Behavior Assessment for Huntington's disease-short form (PBA-s)
6


Isis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
November Il ,2015
ISIS 443139-CSOl
*
Key exploratory biochemical, neuroimaging, electrophysiological and clinical
assessments
2.0 PnOCnDURES
2.1 General Overview of Procedures
Isis (or designee) will review all study data including source documents, case report forms
(CRFs), and laboratory reports. Study site will enter subject source data into the case report
form. The CSF Safety lab data (CSF V/BC, CSF RBC, CSF protein, CSF glucose) will be
completed at each site's local lab and will be entered on a CRF (CSF Results CRF). Mutant
Htt will be transferred electronically from 
, total Htt will be transferred electronically
from
. Other laboratory data will be transferred electronically from 
 
. C-SSRS, UHDRS TFC, Independence Scale, UHDRS Total Motor
Scale, HD V/ork Function Scale, PBA-s will be collected using 
t device and data
provided by 
. Neuroimaging data including structural MRI, MRS spectroscopy will
be reported by 
 
. Resting state functional MRI and NODDI data will be generated
by 
 
. Self-Paced Tapping, Emotion Recognition, CANTAB One
Touch Stockings, and Speeded Tapping will be collected using the 
 device and data
provided by 
. ECGs will be centrally read by 
. EEGs will be collected
by 
 
 
. Those data will be transferred electronically to Isis
Pharmaceuticals, Inc.
Isis Pharmaceuticals, Inc. is responsible for the format of electronic data transfers, transfer
schedule and review of the data. Those data will be stored as SAS data sets.
2.2 Randomization & Treatment Allocation
A patient will be randomized after all Screening assessments have been completed and the
Investigator has verified that the patient is eligible per the study criteria. No patient may
begin the treatment prior to randomization and assignment of an unique patient identification
number.
Eligible patients will be randomized centrally by an automated system to receive
ISIS443139 or placebo. V/ithin each cohort, randomization will be 3:1 for ISIS 443139:
placebo respectively as outlined in Section 1.1. Patients in Cohort D will be stratified by early
Stage 1 (TFC >12) or late Stage I (TFC : 11) disease. Patients in Cohorts B, C, and D will also
be randomly assigned to have the CSF sampling visit at Week 17 or Week 2I ina 1:1 ratio
within cohort and treatment assignment. 
 will prepare the randomization list.
2.3 Conduct
The study will be conducted in accordance with current Good Clinical Practice (GCP) and
International Conference on Harmonization (ICH) guidelines, the World Medical Association
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Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of
Federal Regulations, and all other local regulatory requirements.
2.4 Data Monitoring
2.4.1 Safety Data Monitoring
Isis Pharmaceuticals, Inc. (or designee) is responsible for processing all reported adverse
events (AEs). All serious adverse events (SAEs), reported to Isis Pharmaceuticals, Inc. (or
designee), are reviewed according to standard operating procedures. The medical monitor
will review all AEs and SAEs on an ongoing basis throughout the study. For dose escalation,
the progression of the study from initiation of dosing in one cohort to the next will be
determined by the Sponsor and the DSMB. Isis Pharmaceuticals, Inc. (or designee) will
prepare and submit safety reports to the health authorities worldwide in accordance with
local requirements. If it becomes necessary to communicate new safety information, Isis
Pharmaceuticals, Inc. (or designee) will also prepare a safety notification letter and transmit
it to all applicable study sites.
2.5 Data Management
An electronic case report form (eCRF) utilizing an Electronic Data Capture application will
be used for this study.
2.5.1 Case Report Form Data
 (or designee) is responsible for creating the Electronic Data Capture (EDC)
data entry screens, database and edit checks using definitions developed by Isis
Pharmaceuticals, Inc. Isis Pharmaceuticals, Inc. is responsible for the review, data
management querying and locking of the database.
Data are single-entered into the EDC system by the investigator site staff. Programmed edit
checks (computer logic that checks the validity of the data entered and also prompts for
missing datathat is expected to be entered) are run and automatic queries are generated. Isis
Pharmaceuticals, Inc. reviews all data for accuracy and validity and generates additional
queries in the EDC system when necessary. The data is corrected or an explanation
conceming the query is provided in the EDC system. After all data is entered, reviewed and
queried the database is closed. The data is then reviewed by Isis Pharmaceuticals, Inc. and
additional queries may be generated. After all queries are resolved the database is locked.
2.5.2 Laboratory Data
Isis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data
transfers and the transfer schedule. Isis Pharmaceuticals, Inc. is responsible for the review of
the clinical laboratory data. This data is not stored in the EDC system. Investigator sites have
access to safety laboratory dataviaprinted lab reports sent directly from the laboratory.
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2.5.3 Pharmacokinetics Data
Isis Pharmaceuticals, Inc. is responsible for the management and review of the PK data. This
process involves reviewing the patient and visit identifiers with the clinical data collected in
the EDC system. The PK dataare not stored in the EDC system.
3.0 AN¡.r,vrrcAL PLAN
3.1 General Overview of Analyses
3.1.1 Statistical Methods
All CRF data, data transfers from external vendors (e.g., laboratory, cognitive testing, ECG,
qEEG), and any outcomes derived from the data will be provided in the subject data listings.
Subject data listings will be presented for all subjects enrolled into the study' Descriptive
summary statistics including n, mean, median, standard deviation, standard elror,
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, p-values will be reported. All statistical tests will
be conducted using 2-sided tests with 5o/o Type I error rate unless otherwise stated. Analyses
may be stratified by the stratification factor and/ot site if supported by data.
Since there are limited placebo-treated subjects within each dose cohort, the placebo-treated
subjects will be pooled for all analyses.
For vital signs [blood pressure (BP), heart rate, respiration rate, orthostatic change and
temperature], baseline will be defined as the avetage of the values collected prior to first dose
(Screening, Study Day -1, Study Day 1, and any measurements between Screening and Day
1).
Baseline ECG will be defined as the average of the triplicate taken on Day -1, if only one or
two assessments are available, the single assessment or average of the two assessments will
be used.
For all other measures and parameters, baseline will be defined as the last non-missing
measure prior to the first dose.
The treatment period will be defined as the period of time from the first dose administration
through Day 92 visit or, if the patient does not participate in Day 92 visit, from the first dose
administration through 9 days after the last dose administration.
The post-treatment assessment period will be defined as the period of time from the day aftet
the treatment period to the end of study.
November ll ,2015
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Demographic and baseline characteristics (e.g., age, sex, ethnicity, race, weight, height, BMI,
Montreal Cognitive Assessment (MoCA), ISCED level, CAG repeat length, ApoE isoform
genotype, BCHE-K variant, and disease burden score (DBS)) and subject disposition will be
summarized using descriptive statistics by treatment group. DBS is calculated by ICAG
repeat length - 35.5]*age in years. All subjects enrolled will be included in a summary of
subject disposition. Protocol deviations will be listed.
Multiple results within the same visit (or timepoint for measurements collected at multiple
timepoints) will be averaged for by visit analyses. Unscheduled results will not be included
in the by-visit analyses except for determining baseline, but will be presented in data listings.
PK parameters will be summarizedby treatment group using n, mean, standard deviation,
coefficient of variation (CV), geometric mean, median, minimum, and maximum'
3.1.2 Subject Populations Analyzed
The following analysis populations will be used for the analyses of data as described within
each analysis set:
Safety Population: All patients who are randomized and receive at least one dose of Study
Drug. This population will be used for safety and tolerability analyses.
Per Protocol Population: All patients who are randomizedandreceive all doses of the
protocol-specified Study Drug (ISIS 443139 or placebo) This population will be used for
pharmacodynamic s, exp loratory and biomarker analyses'
PK Population: All patients who are randomized to ISIS 443139 and receive at least one dose
of ISIS 443139 and have sufficient sampling to permit pharmacokinetic evaluation. This
population will be used for PK analyses.
In addition to the above analysis sets, it is recognized that some data displays will be
provided for "All Screened", "screening Failures" and "All Randomized" subjects but no
data analysis will be executed in these populations except for the disposition table that
includes all screened subjects.
3.1.3 Sample Size Consideration
While there is no statistical rationale for the sample size, it has been selected based on the
prior experience with generation 2.0 ASOs given by IT injection to ensure that the safety,
tolerability, pharmacokinetics and exploratory pharmacod¡mamics will be adequately
assessed while minimizing unnecessary patient exposure.
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3.1.4 Planned Interim Analysis
Unblinded interim analyses may be performed and the results summarized by treatment
group at the end of each cohort upon completion of dosing for that cohort or at any time if
needed to address a safety concern. The Investigator, study staff,, patients, monitors, Sponsor
Medical Monitor, members of the Sponsor's clinical operations team and data management
team will remain blinded throughout the study. The analysis will be executed with
controlled dissemination to ensure the integrity of ongoingdata collection.
A DSMB will be assembled to review safety, tolerability, pharmacokinetic and target
engagement/pharmacodynamic (as needed) data collected on ISIS 443139 during this study.
Unblinded statisticians or designees who will not be involved in the study conduct will generate
and distribute the data to DSMB prior to each DSMB meeting. Based on its ongoing assessment
of the safety and tolerability of ISIS 443139, the DSMB will provide recontmendations to the
Sponsor for modifuing, stopping or continuing the study as planned. Details on the safety
assessments, frequency of review, meeting schedules and controlled access to unblinded data are
outlined in the DSMB charter.
3.1.5 Incomplete or Missing Data
Missing values will not be imputed unless otherwise specified.
3.2 Safety Analyses
3.2.1 Exposure
Treatment duration and amount of Study Drug received will be summarized by treatment
group.
3.2.2 Adverse Events
An adverse event will be regarded as treatment emergent adverse event (TEAE) if it is
present prior to receiving the first dose of study drug and subsequently worsened, or is not
present prior to receiving the first dose ofstudy drug but subsequently appeared.
The most conservative approach will be used to determine if the event occurs after the first
dose of treatment. For example, if the onset date or resolution date of an AE is prior to the
first study treatment date, it will be considered to have occurred prior to the study period. If
the onset date of an AE is a partial date with only month or year available or completely
missing, then the event is assumed to be within the study period unless the year is prior to the
year of the first study treatment date, or if in the same year, the month is prior to the month of
the first study treatment date or a full or partial resolution date is available that definitively
demonstrates that the event ended prior to first dose of study drug.
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The incidence of AEs will be summarized by Medical Dictionary for Regulatory Activities
(MedDRArM) preferred term and system organ class for:
o All treatment emergent adverse events
o Related treatment emergent adverse events. Related is defined as 'oRelated" ,
"Possible" , or missing relationship to study drug
o All treatment emergent adverse events by severity. At each level of subject
summarization, a subject is classified according to the highest severity if the subject
reported one or more events. Adverse events with missing severity will be
categonzed as "Missing" for this summary
o Related treatment emergent adverse events by severity
o Serious treatment emergent adverse events
o Serious and related treatment emergent adverse events
Narratives of "on-study" deaths, serious and significant AEs, including early withdrawals
due to AEs, will be provided.
SAEs and non-serious AEs that lead to study discontinuation or investigational drug
discontinuation will be listed separately. Non-TEAEs will be flagged in the data listing.
3.2.3 Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS collects binary responses to 11 categories: five subtypes of suicidal ideation,
five subtypes of suicidal behavior, and self-injurious behavior without suicidal intent.
Specifically, the following outcomes are C-SSRS categories and have binary (Yes/l'{o)
responses. (The categories have been re-ordered from the actual scale to facilitate the
definitions of the composite endpoints and to enable clarity in the presentation of the results.)
Suicidal Ideation:
Category 1 - V/ish to Be Dead
Category 2 - Non-specific Active Suicidal Thoughts
Category 3 - Active Suicidal Ideation with Any Methods (Not Plan) without Intent to
Act
Category 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Category 5 - Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior:
Category 6 -Preparatory Acts or Behavior
Category 7 - Aborted Attempt
Category 8 - Intemrpted Attempt
Category 9 - Actual Attempt (non-fatal)
Category 10 - Completed Suicide
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Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
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Other
Category 11 - Non-suicidal Self-injurious Behavior
In addition, a numerical score, the Suicidal Ideation Score, will be defined as the highest
suicide ideation category (1-5) at which the patient responded "Yes" for the given visit. If
the patient did not respond "Yes" to any of these categories, the score will be set to zero.
For each of the 11 categories above, the number and percent of patients with a 'oYes"
response at any time post-baseline (regardless of baseline response) will be summarized by
treatment group.
In addition, emergent suicidal ideation or behavior will be summarized. The binary
categories above and the Suicidal Ideation Score will be used to identify the 8 composite
endpoints defined below. Note that "recent history'' for these composite endpoints is defined
as the 12 months prior to Screening and the Screening period. At the Screening visit, C-
SSRS data is collected for the prior 12 months. Therefore, analyses that utilize data from
"recent history''will include the historical l2-month data collected at Screening as well as all
on-study C-SSRS data collected prior to first dose.
o Suicidal Ideation: A "Yes" answer at any time post-first-dose to any one of the five
suicidal ideation questions (Categories 1-5), regardless of the pre-dose responses
o Suicidal Behavior: A "Yes" answer at any time post-first-dose to any one of the five
suicidal behavior questions (Categories 6-10), regardless of the pre-dose responses
o Suicidal Ideation or Behavior: A "Yes" answer at any time post-f,rrst-dose to any
one of the ten suicidal ideation or behavior questions (Categories 1-10), regardless of
the pre-dose responses
o Treatment-Emergent Suicidal Ideation compared to recent history: A maximum
post-first-dose suicidal ideation score that is increased from the maximum suicidal
ideation score in recent history.
o Treatment-Emergent Serious Suicidal Ideation compared to recent history: A
maximum post-first-dose suicidal ideation score of 4 or 5 when the maximum suicidal
ideation score during recent history was less than 4 (i.e., scores of 0-3). Only patients
with a recent history score of 0-3 will be considered evaluable for this outcome.
o Emergence of Serious Suicidal Ideation compared to recent history: A maximum
post-first-dose suicidal ideation score of 4 or 5 when the maximum suicidal ideation
score during recent history was 0. Only patients with a recent history score of 0 will
be considered evaluable for this outcome.
o Improvement in Suicidal ldeation compared to baseline: A decrease in the suicidal
ideation score at the patient's Study Day 86 C-SSRS assessment compared to the
baseline score, defined as the minimum score obtained during the Screening Period
(i.e., assessments collected from the Screening Visit through pre-dose on Study Day
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1). The analysis will be repeated for Study Days I 13, I4l and 197 . Only patients with
a baseline score >0 will be considered evaluable for these outcomes.
o Emergence of Suicidal Behavior compared to all prior history: The occurrence of
suicidal behavior (a "Yes" response to one or more of Categories 6-10) post-first-
dose from not having suicidal behavior prior to first dose (includes the "lifetime"
score collected at the Screening Visit as well as all C-SSRS assessments collected
from the Screening Visit through pre-dose on Study Day 1).
Each of the composite endpoints will be summarized by treatment group. For each treatment-
emergent outcome listed, only those patients with the specified screening condition will be
considered evaluable. In addition, patients who discontinue from the study with no post-first-
dose C-SSRS assessment will be considered unevaluable for analyses of suicidality. Percents
will be based on the number of evaluable patients for each outcome.
In addition, a shift table will be created to demonstrate the change in suicidal ideation score
from recent history to treatment period and/or post-treatment period. The maximum suicidal
ideation score in each period will be used to create the shift table. If a patient's recent history
suicidal ideation score is missing but has a post-first-dose score, then the recent history
assessment will be labeled as "unknown". Likewise, if a patient's recent history suicidal
ideation score is available but has no post-first-dose score, then the scores during the
treatment and post-treatment period will be labeled as "unknown".
3,2,4 Laboratory Measurements
The following is the list of lab analytes that will be measured throughout the study:
Chemistry: Sodium, Potassium, Chloride, Total protein, Albumin, Calcium, Magnesium,
Phosphorus, Bicarbonate, Glucose, BI-IN, Creatinine, Total serum bilirubin, Uric acid,
Alkaline phosphatase, ALT (SGOT), AST (SGPT), GGT and CPK.
Hematology: Red blood cells, Hemoglobin, Hematocrit, Platelets, MCV, MCH, MCHC,
White blood cells, and WBC differential (percentage and absolute count) (Basophils,
Eosinophils, Lymphocytes, Monocytes and Neutrophils)
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Coagulation: aPTT, PT, INR
Thyroid Panel: TSH, Free T4, and Free T3
PK' Plasma ISIS 443139 levels, and CSF ISIS 443139 levels
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Pregnancy: Urine hCG
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November ll ,2015
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CSF Safety Panel (Minimum Requirements): Red blood cells, White blood cells, Glucose
and Protein
o Urinalysis: Specific gravity, pH, Protein, PIC ratio, Glucose, Ketones, Urobilinogen,
Leukocyte esterase, Nitrite, Bilirubin, Blood, Red blood cells, 'White blood cells,
Epithelial cells, Bacteria, Casts, Crystals, Color and Appearance.
In addition, the following analytes are measured at screening only: plasma hCG, FSH,
hepatitis B surface antigen, hepatitis C antibody, HIV antibody, amphetamines, barbiturates,
b enzodiazepines, cannabinoids, cocaine, ethanol, opiates.
The following genetic testing is performed: CAG repeat length, ApoE isoform genotype,
BCHE-K.
Missing WBC differential absolute counts and percentages will be derived:
If V/BC differential absolute counts are missing, and percentages are available, then absolute
counts will be calculated by multiplying the percentage by total WBC count. Conversely, if
absolute count is available, and percentage is missing, then percentage will be calculated by
dividing absolute count by the total WBC count. If neutrophils counts and percentages are
missing, and segmented neutrophil and band neutrophil results are available, then neutrophils
will be calculated by adding segmented neutrophils and band neutrophils'
Laboratory tests to ensure subject safety including chemistry panel, hematology panel,
coagulation, and CSF safety labs (cell counts, protein, and glucose), will be summarizedby
study visit for each treatment group. These safety variables will also be presented as change
and percent change from baseline over time after Study Drug administration, as appropriate.
In addition, the shifts (relative to the normal range) from baseline to the minimum and
maximum post-baseline values will be presented. If a subject is missing a baseline value but
had a post-baseline value, then the baseline assessment is labeled as "unknown". Likewise,
if a subject had a baseline value but had no post-baseline values, then the minimum and
maximum are labeled as "unknown". For each parameter, the incidence of shift to low will
be summarized using the minimum post-baseline values; the incidence of shift to high will be
summarized using the maximum post-baseline values.
Only central laboratory data will be used for the summary tables and figures. Local
laboratory data will be provided in the listings only, with the exception of local results for
CSF safety tests which will be listed and summarizedin tables.
All lab data will also be displayed in subject listings.
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November Il ,2015
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3.2,5 Vital Signs Measurements and Weight
Vital signs will include body temperature,heartrate, respiration rate, orthostatic changes, and
systolic and diastolic blood pressure.
Orthostatic changes include 3 variables: change from seated systolic blood pressure to
average of all available standing systolic blood pressures, change from seated diastolic blood
pressure to average of all available standing diastolic blood pressure, and change from seated
heart rate to average ofall available standing heart rate.
Summary tables will be created to present the descriptive statistics (n, mean, standard elror,
standard deviation, median, Ql, Q3, minimum, and maximum) for vital sign values and
weight as well as the change and percent change from baseline at each study visits by
treatment group.
3.2.6 Neurological Examinations
Neurological examinations will be provided in patient listings.
3.2.7 l}-LeadElectrocardiograms (ECG)
ECG data will be collected through a central reader.
The ECG data will include ventricular rate (VR), PR interval, QRS duration, QT, QTC
(recorded from ECG machine), QToF (QT corrected using the Fridericia's formula), and
QTcB (QT corrected using the Bazett' s formula) as described below:
QTcF : QT / (RR) 1/3, where RR:604/R
QTcB : QT / (RR) t", where RR:60/VR
At Day -1, three replicates of ECG parameters will be recorded, and the mean from all
replicates will be used as the subject's reportable value atDay -1. For all other time points, a
single set of parameters will be recorded. QTcF and QTcB will be calculated based on the
subject's reportable ECG data at eachtime point using the formula described above.
Summary tables will be created to present the descriptive statistics (n, mean, standard error,
standard deviation, median, Ql, Q3, minimum, and maximum) as well as the change and
percent change from baseline at each study visits by treatment group.
3.2.8 Prior and Concomitant Medications
Prior and concomitant medications will be coded using WHO Drug dictionary and
summarized by ATC class, generic name and by treatment group.
A concomitant medication is defined as medications that were taken on or after the first study
drug administration (Study Day 1). This includes medications that were started prior to the
initiation of study drug if their use continued on or after the date of the first dosing. In order
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Statistical Analvsis Plan
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November II ,2015
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to define concomitant medications with missing start or stop dates, the following additional
criteria will be used:
if both the start and stop dates of a particular medication were missing, that
medication is considered concomitant;
if the start date of a medication was missing and the stop date of that medication fell
on or after the date of dosing, that medication is considered concomitant;
if the start date of a medication was prior to the date of first dosing and the stop date
of that medication was missing,thatmedication is considered concomitant; or
if the start/stop date of a medication is partial then where it is not possible to rule out
that it was not taken concomitantly it will be considered concomitant.
Non concomitant medications will be flagged in the data listing'
3.3 Pharmacokinetic Analysis
CSF and Plasma samples will be collected at protocol designated times for ISIS 443t39
pharmacokinetic assessments from the dose cohorts. Only concentration data from patients
randomized to receive study drug (ISIS 443139) will be included in this analysis.
3.3.1 CSF Concentration Data and Pharmacokinetics
A CSF sample will be collected pre-dose on each injection day (Days 1,29,57, 85) andat
one Post-Treatment Period visit for PK analyses. CSF concentrations of ISIS 443139, along
with the scheduled (nominal) and actual samples times (i.e., time from IT dosing) will be
listed (when applicable) for each patient, treatment group (cohort), nominal dose, and day.
Differences between scheduled and actual sampling days will also be listed for all patients, as
well as percent differences between actual administered dose and nominal dose.
CSF concentrations below the lower limit of quantification (LLOQ) will be indicated by
"BLQ". For the purpose of calculating typical descriptive statistics (n, mean, SD, o/oCV,
geometric mean, geometric o/oCV, median, minimum, and maximum) for CSF
concentrations, all BLQ values will be set to zero. Mean CSF concentrations that are BLQ
will be presented as BLQ, and the SD and %CV will be reported as not applicable. Summary
statistics of the ISIS 443139 CSF concentrations will be tabulated by treatment group
(cohort), nominal dose and day. At the discretion of the pharmacokineticist andlor
biostatistician, samples may be excluded from descriptive statistics if there are large
deviations between scheduled and actual sampling days, or large deviations between actual
dose and nominal dose.
The ISIS 443139 half-life in CSF will be calculated, if possible, and summarized by
treatment group (cohort), nominal dose, and nominal day.
ISIS 443139 CSF concentration versus time (actual) profiles from Day 1 to last collection
(nominal Study Day 113 or 141 in Cohorts A-D), for each patient, as well as the mean (+SE)
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CSF concentration versus time (scheduled) profiles for each treatment cohort, will be
presented graphically on linear scale. Samples may be excluded from the mean plots if there
are large deviations between scheduled and actual sampling times, or large deviations
between actual dose and nominal dose.
3.3.2 Plasma Concentration Data
Plasma concentrations of ISIS 443139, along with the scheduled (nominal) and actual
samples times (i.e., time from IT dosing) will be listed (when applicable) for each patient,
treatment group (cohort), nominal dose, and day. Percent differences between scheduled and
actual sampling times will also be listed for all patients as well as percent differences
between actual administered dose and nominal dose.
Plasma concentrations below the lower limit of quantification (LLOQ) will be indicated by
"BLQ". For the pu{pose of calculating typical descriptive statistics (n, mean, SD, o/oCV,
geometric mean, geometric o/oCY, median, minimum, and maximum) for plasma
concentrations, all BLQ values will be set to zero. Mean plasma concentrations that are BLQ
will be presented as BLQ, and the SD and %CV will be reported as not applicable. Summary
statistics of the ISIS 443139 plasma concentrations will be tabulated by treatment group
(cohort), nominal dose, duy, and scheduled time point. At the discretion of the
pharmacokineticist and./or biostatistician, samples may be excluded from descriptive statistics
if thcre are large deviations between scheduled and actual sampling times, or large deviations
between actual dose and nominal dose.
ISIS 443139 plasma concentration versus time (actual) profiles from Day I to Day 29 and
Day 85 to Day 197 (Cohorts A-D), for each patient, as well as the mean (+SE) plasma
concentration versus time (scheduled) profiles for each treatment cohort, will be presented
graphically on linear and semilogarithmic scales. Additionally, ISIS 443139 plasma
concentration versus time (actual) profiles from 0 to 24 hours on Days 1 and 85 for all
patients, as well as the mean (+SE) plasma concentration versus time (scheduled) profiles (0
to 24 hours on Days I and 85) for each applicable treatment cohort will be presented
graphically on linear and semilogarithmic scales. Samples may be excluded from the mean
plots if there are large deviations between scheduled and actual sampling times, or large
deviations between actual dose and nominal dose.
3.3.3 PlasmaPharmacokinetics
Non-compartmental pharmacokinetic analysis of ISIS 396443 will be carried out on each
individual patient data set using Phoenix V/inNonlin version 6.3 or higher (
 
 
). Plasma pharmacokinetic parameters in each patient
(when applicable) will be determined. For calculation of PKparameters, all BLQ values will
be set to zero. The following plasma PK parameters will be calculated (when applicable) and
based on actual sampling times:
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November 1l , 2015
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C,nu*: the maximum observed drug concentration in plasma.
T-u": the time at which C.u* occurs.
AUCo-z¿n: areas under the plasma concentration-time curve from zero time þre-dose)
to 24 hours after the intrathecal administration will be calculated using the linear
trapezoidal rule after the dose administrations on Day 1 and Day 85.
AUCo-zs¿ (AUCs-x): areas under the plasma concentration-time curve from zero time
(pre-dose) to 28 days after the intrathecal administration will be calculated using the
linear trapezoidal rule for Days I and 85.
AUCo-inr: AUC from zero to infinity, calculated as the sum of the AUCo-zs¿plus the
final quantifiable concentration divided by 7"2, for only subjects in Cohorts A to D
where fr7,¡"cãtrbe accurately and appropriately determined and only on Day 1.
o MRTo-24¡i fitoârt residence time (MRT) from time zero to 24 hours after intrathecal
dose administration will be calculated from the equation, MRTo-z¿1.' : AUMCo-z¿r'
l\lJCo-zqn, where AUMC6-2a¡ is the area under the moment plasma concentration-time
curve from time zero to 24 hours after dosing. This parameter will be calculated for
Days I and 85. This parameter will be calculated and reported mainly as an index
measure to reflect the expected initial rapid disposition of ISIS 443139 from plasma
to tissues shortly after dosing.
The following PK parameters may be calculated using actual sampling times where
appropriate data exists at the discretion of the pharmacokinetic scientist:
ty,x,: the plasma disposition halflife associated with the apparent terminal
elimination phase may be calculated from the equation, ttlzL': 0.69311tz., on Day 85
profiles for Cohorts A to D.
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Additional pafüal AUC values may be calculated depending upon the samples
collected during the study.
CLIF: Plasma clearance will be calculated from CL : Actual Dose/AUC0-inf, for
subjects in Cohorts A to D where AUCo-- can be accurately and appropriately
determined, and from the equation CL: Actual Dose/AUC6-x for subjects in Cohorts
A to D after the Day 85 dose.
Plasma pharmacokinetic parameters (if applicable) will be summarized using descriptive
statistics (n, mean, SD, o/oCV, geometric mean, geometric yoCV, median, minimum, and
maximum) treatment cohort, nominal dose, and day.
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Other PK parameters, as appropriate,frdy be determined or calculated at the discretion of the
PK scientist.
3.4 Exploratory Pharmacokinetic-Pharmacodynamic Analysis
Potential relationships between selected pharmacodynamic (e.g., mutant Htt protein or total
Htt protein) and plasma post-distribution exposure (i.e., trough and post-treatment) measures
may also be explored, where deemed appropriate.
3.5 Exploratory Analyses
For the continuous exploratory variables, descriptive statistics (n, mean, standard elror,
standard deviation, median, Ql, Q3, minimum, and maximum) of the results, as well as the
change and percent change from baseline to each study visit, will be presented by treatment
group in summary tables; for the categorical variables, counts and percentages will be
provided. Where appropriate, inferential analyses will be conducted as described below.
The following exploratory endpoints will be summarizedby treatment group as the above
method according to their data charucteristics.
These analyses will be performed on the Per Protocol Set. If deemed appropriate, these
analyses may be repeated for the Safety Population or appropriate subset(s), as needed.
3.5.1 Biochemical
The results and change and percent change from baseline for CSF biomarkers and plasma
biomarkers at each visit will be summarized using descriptive statistics and compared
between each dose group and placebo using the ANOVA or V/ilcoxon Rank Sum test, as
appropriate. The normality will be assessed using the Kolmogorov-Smirnov test on the
residuals.
Changes in mutant Htt in CSF and neurofilament light chain in CSF are key exploratory
endpoints for the study.
Considerable between-patient variability is expected in the baseline levels of CSF and plasma
biomarkers, and there may be patients with baseline levels that are comparable to a normal
(i.e., not diseased) state. In this event, additional analyses will be conducted to account for
differences in baseline (such as including baseline levels as covariates) and/or analyses will
be repeated on the subset of the analysis population with baseline levels that ate abnormal.
3,5.2 NeuroimagingFindings
V/hole brain volume, intraventricular volume and caudate volume assessed using MRI as
well as changes and percent changes from baseline at each visit will be summarized using
descriptive statistics and compared between each dose group and placebo using the ANOVA
or V/ilcoxon Rank Sum test, as appropriate. The normality will be assessed using the
20


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November II ,20T5
ISIS 443139-CSO1
Kolmogorov-Smimov test on the residuals. Change in ventricular volume is a key
exploratory endpoint for the study.
The following parameters collected during MRS of a frontal white matter voxel will be
summarized at each visit. Changes and percent changes from baseline at each visit will also
be summarized. These parameters will be analyzed in a similar way to the brain volumes.
o tNAA (N-Acetyl-aspartate [NAA] and N-Acetyl-aspartyl-glutamate [NAAG])
concentration
. myo-inositol (mI) concentration
o tNAA / mI
o tNAA %SD
o mI %SD
o tNAA concentration corrected for the fraction of white matter in voxel
o mI concentration corrected for the fraction of white matter in voxel
o tNAA, corrected / mI, corrected
Parameters characterizing connectivity between different brain regions will be determined
using rsfMRI and NODDI. These analyses will be conducted outside the scope of this SAP
by subject matter experts, and an independent report will be generated to describe the results.
3.5.3 qEEG
The primary endpoints obtained using quantitative EEG methods are the anterior-posterior
gradients of relative alpha and delta power, global alpha power, global delta power,
thetalalphaborder power and mean frequency at resting state with eyes closed. The values at
each visit as well as changes and percent changes from baseline at each visit will be
summarized using descriptive statistics and analyzed in a similar way to the brain volumes.
Data for anterior-posterior gradients of relative alpha and delta power, global alpha power,
global delta power,thetalalpha border power and mean frequency at resting state with eyes
open will be provided in the data listing.
3.5.4 UHDRS Total Functional Capacity Scale (TFC)
The TFC represents the Investigator's assessment of the patient's capacity to perform a wide
range of activities of daily living including occupation, finances, domestic chores, activities
of daily living and care level. It is based on a brief interview with the patient and the study
partner. Scores range from 0 to 13, and higher scores represent better functioning.
The TFC scores as well as changes and percent changes from baseline will be summarizedby
visit and analyzed in a similar way to the brain volumes.
21


Isis Pharmaceuticals, Inc.
CONFIDENTIAL
November ll ,2015
ISIS 443139-CSO1
Statistical Analvsis Plan
3.5.5 UHDRS Independence Scale
The patient's independence scale is the Investigator's assessment of the patient's degree of
independence. The scale consists of 19 discrete levels ranging from 10 to 100 (bV 5) where
no special care needed corresponds to a scale of 100 and tube fed and total bed care
corresponds to a scale of 10. The Independence Scale as well as changes and percent changes
from baseline will be summarizedby visit and analyzed in a similar way to the brain volumes
data.
3.5.6 HD \ilork Function (HDWF) Scale
The HDWF scale is a measure of work role limitations and effort, which are areas that may
be affected by the cognitive, behavioral and motor changes associated with HD (Brossman et
al.2012). It was developed for prodromal HD, the stage prior to overt motor impairment and
HD diagnosis in which structural and functional brain changes lead to subtle changes in
cognition and motor function. Patients and their trial partners each complete a questionnaire
consisting of 20 questions, where the response to each is based on a 7-point Likert scale
ranging from 'onot at all like me" to o'very much like me". The HDWF scores for both patient-
completed questionnaire and the trial-partner-completed questionnaire are the sums of the
individual question ratings, range from 20 to 140, and higher scores represent higher work
function ability.
For both the patient-completed HDWF and the trial-partner-completed HDWF, the scores as
well as changes and percent changes from baseline will be summarizedby visit and analyzed
in a similar way to the brain volume data.
3.5.7 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 six 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 ofthe six individual tests. The z-score for each
test will be calculated as follows:
lx-x)
t-¿-- 
s
Where i is the overall baseline mean and s is the baseline standard deviation.
This composite cognitive score is a key exploratory endpoint for the study. The individual
tests that comprise the battery are described below. The composite score, individual scores as
well as changes and percent changes from baseline will be summarizedby visit and analyzed
in a similar way to the brain volume data.
-Self-Paced Tapping
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Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
Self-paced tapping measures cognitive and motor timing. The patient listens to a repeating
tone at 3Hz and taps in time with the tone, alternating between left and right thumbs. The
patient continues to tap after the tone stops, attempting to maintain the same rate of tapping.
Four trials are conducted.
Scoring of each effort is based on the precision of taps, which is directly estimated, and
timing precision, which is calculated as the reciprocal of the standard deviation of the
intertap interval. Higher values indicate better performance, i.e., more consistent tapping
rates. The paced tapping dependent measure (consistency of the intertap intervals) is
computed using partial data if the participant does not complete the four trials within six
minutes. The data will be summarized by visit and analyzed in a similar way to the brain
volume data.
-Emotion Recognition
For this test, patients view faces depicting a neutral expression or an emotion (anger, disgust,
fear, sadness, surprise, happiness). After a practice trial for each category, the patient views
70 test trials and categorizes each face by emotion. The number of correct responses for
negative emotions (anger, disgust, fear, sadness), out of 24 possible, is tallied (Johnson et al.
2007). The correct response number will be summarized by visit and analyzed in a similar
way to the brain volume data.
-CANTAB One Touch Stockings (OTS)
The OTS test measures executive function, spatial planning and working memory. On a
computer or tablet screen, the patient is shown two stacks of colored balls, which can be
perceived balls stacked in hanging socks or stockings. The patient must move the balls
between the stockings to achieve a particular color pattem. Rearranging the balls to make the
target pattern may take one, two, three or four moves. Then, the patient is shown two stacks
of colored balls and must determine, without moving the balls, the minimum number of
moves necessary to achieve the target pattern.
The outcome is the mean latency to correct response. Higher values indicated worse
performance (longer time to a correct response). The mean latency will be summarized by
visit and analyzedin a similar way to the brain volume data.
-Symbol Digit Modalities Test (SDMT)
The SDMT is used to assess attention, visuoperceptual processing, working memory and
psychomotor speed. It has been shown to have strong reliability and validity (Smith 1982;
Hinton-Bayre et al. 1999). The patient must pair abstract symbols with specific numbers
according to a translation key. The test measures the number of items correctly paired
(maximum of 110) in 90 seconds. The scores will be summarized by visit and analyzed in a
similar way to the brain volume data.
-Hopkins Verbal Learning Test - Revised (HVLT-R)
November Il ,2015
ISIS 44313g-CSO1
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Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
The HVLT-R is used to assess verbal memory through tests of recall and recognition. The
HVLT-R consists of a word list, containing12 words from three taxonomic categories, which
is read aloud to the patient at the rate of approximately one word every two seconds. The
Immediate Recall test includes three learning trials. Delayed Recall is assessed 20 to 25
minutes after completion of the Immediate Recall test. Immediately after administration of
the Delayed Recall tnal, a forced-choice recognition test is administered. The recognition test
includes the 12 target words, plus t2 distractors (six semantically-related and six
semantically-unrelated words). Patients must recall a series of 12 words over three immediate
trials (learning), free recall after a 25-minute delay and a recognition trial. The outcome
measure will be calculated as the sum of words correctly recalled over four trials (three
immediate and one delayed) with the maximum value of 48. The data will be summarized by
visit and analyzed in a similar way to the brain volume data.
-Trail-Making Test
The Trail-Making Test Part B (TMT-B) is a test of executive functioning. Patients are
presented with a picture of 25 circles, each labeled with a number (1 - 13) or a letter (A - L).
The patient must draws lines to connect the circles in an ascending pattern that altemates
between the numbers and letters (i.e.,L-A-2-B-3-C ...). The patient is instructed to connect
the circles as quickly as possible, and the time to complete the task is recorded.
The Trail-Making Test Part A (TMT-A) is also administered, but the results of the TMT-A
are not considered to be part of the battery. For the TMT-A, patients are presented with 25
circles, each labeled with a number (I-25) and are asked to connect the numbers.
Administration of TMT-A prior to TMT-B provides practice to aid in administering TMT-B.
Times to complete TMT-A and TMT-8, as well as changes and percent changes from
baseline will be summarized by visit andanalyzed in a similar way to the brain volume data.
3.5.8 UHDRS Total Motor Scale (TMS)
The TMS is the sum of the individual motor ratings obtained during administration of the
motor assessment portion of the UHDRS, including ocular pursuit (horizontal and vertical),
saccade initiation (horizontal and vertical), saccade velocity (horizontal and vertical),
dysarthria, tongue protrusion, finger taps(right and left), pronate/supinate-hands (right and
left), luria (fist-hand palm test), rigidity-arms(right and left), bradykinesia-body, maximal
dystonia(trunk, rue, lue, rle and lle), maximal chorea (face, bol, trunk, rue, lue, rle and lle),
gait, tandem walking, retropulsion pull test, and diagnosis confidence level. Scores range
from 0 to I24, and higher scores represent more severe impairment.
The TMS scores will be summarized by visit and analyzed in a similar way to the brain
volume data.
November ll ,2015
ISIS 443139-CSO1
24


Isis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
November ll ,2015
ISIS 44313g-CSOl
3.5.9 Stroop Word Reading Test
The Stroop Word Reading Test is a measure of processing and psychomotor speed. Patients
are presented with a page of color names printed in black ink and are asked to read aloud as
many words as possible within a given amount of time. Scoring is based on the number of
correct responses in a fixed amount of time, typically within 45 seconds. Higher scores
indicate better cognitive performance. The scores will be summarized by visit and analyzed
in a similar way to the brain volume data.
3.5.10 Map Search Test
The Map Search Test is a test of sustained visual attention. Patients are presented with a
visually cluttered map and asked to circle as many target symbols on the map as possible
within a fixed period of time. Scoring is based on the number of correctly identified s¡rmbols.
The scores will be summarized by visit and analyzed in a similar way to the brain volume
data.
3.5.11 Speeded Tapping
The speeded tapping test is a measure of psychomotor speed and has been used as a
longitudinal marJ<er of disease severity in manifest and pre-manifest HD. For the test, the
patient taps the index finger of his/her non-dominant hand as quickly as possible for a 10
second period. The task is repeated with a brief rest period held between trials. The outcome
measure is the mean of the intertap intervals across taps from all trials, with higher values
indicating worse performance (i.e., slower tapping).
The data as well as change and percent change at each visit will be summarized using
descriptive statistics and analyzed in a similar way to the brain volume data.
3.5.12 Problems Behavior Assessment for Huntington's Disease-Short Form (PBA-s)
The PBA-s assesses common behavioral and psychiatric manifestations of HD, including
affect, irritability, loss of motivation, perseverative phenomena and psychotic symptoms.
The test administrator interviews the patient and trial partner and rates the patient's behavior
over the prior four weeks according to the guidelines for the test. The syraptoms include
depressed mood, suicidal ideation, anxiety, irritability, angry or aggressive behavior, lack of
initiative (apathy), perseverative, obsessive-compulsive behaviors, delusions, hallucinations
and disoriented behavior. Each symptom is rated for severity, frequency and worst. Severity
and frequency scores will be multiplied to produce a PBA score for each s¡imptom.
In addition, the following composite scores will also be calculated:
o Sum of the PBA scores for depressed mood, anxiety, and suicidal ideation
o Sum of the PBA scores for irritability and angry or aggressive behaviors
o Sum of the PBA scores for delusions and hallucinations and disoriented behavior
o Sum of the PBA scores for perseveration and obsessive-compulsive behaviors
25


Isis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
The square roots of the individual PBA scores and the composites scores will be reported and
summarized by visit and analyzed in a similar way to the brain volume data.
3.5.13 Correlations between ISIS 443139 Exposure and Exploratory Endpoints
The following correlations are planned. The correlations will be evaluated using the Pearson
correlation coefficients and corresponding p-values. Other correlations may be conducted
based on findings in the by-visit analyses of exploratory endpoints.
o CSF mutant Htt at Day 85 and change in CSF mutant Htt (baseline to Day 85) versus
concentration of ISIS 443139 in CSF at Day 85
. 
CSF total Htt at Day 85 and change in CSF total Htt (baseline to Day 85) versus
concentration of ISIS 443139 in CSF at Day 85
o CSF NFL at Day 85 and change in CSF NFL (baseline to Day 85) versus
concentration of ISIS 443139 in CSF at Day 85
o CSF tau aI Day 85 and change in CSF tau (baseline to Day 85) versus concentration
of ISIS 443139 in CSF at Day 85
o CSF VILP1 at Day 85 and change in CSF VILPI (baseline to Day 85) versus
concentration of ISIS 443139 in CSF at Day 85
o Ventricular volume atDay 113 and Day I97 and change from baseline in ventricular
volume at each of these Days versus concentration of ISIS 443139 in CSF at Day 85
o Whole brain volume at Day 113 and Day I97 and change from baseline in whole
brain volume at each of these Days versus concentration of ISIS 443139 in CSF at
Day 85
o Metabolite concentrations (tNAA, mI, tNAA/mI) at Day 113 and Day 197 and change
from baseline in metabolite concentrations at each of these Days versus concentration
of ISIS 443139 in CSF at Day 85
o HD Cognitive Battery composite score at Day 84,Day I4I and Day I97 and change
from baseline in HD Cognitive Battery composite score at each of these Days versus
concentration of ISIS 443139 in CSF at Day 85
o qEEG changes in anterior-posterior gradients of relative alpha and delta power atDay
113, Day l4l andDay I97 and change from baseline in anterior-posterior gradients
of relative alpha and delta power at each of these Days versus concentration of ISIS
443139 in CSF at Day 85
o qEEG changes in global alpha power, global delta power, thetalalpha border power
and mean frequency atDay 113, Day l4l and Day 197 and change from baseline in
global alpha power, global delta power, thetalalpha border power and mean frequency
ateach of these Days versus concentration of ISIS 443139 in CSF at Day 85
o Changes in UHDRS-TMS atDay 84,Day I4I andDay I97 and change from baseline
in UHDRS-TMS at each of these Days versus concentration of ISIS 443139 in CSF at
Day 85
November ll ,2015
ISIS 443139-CSOI
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Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
November Il ,2015
ISIS 443139-CSOI
3.5.14 Subset and Sensitivity Analyses
Patients enrolled into this study are early in the disease; therefore, for a given endpoint
parameter, there may be patients with baseline levels that are essentially normal (i.e., not
altered as would be.expected in a diseased state). In these patients, there would be no ability
to measure an improvement in that parameter, which confounds interpretation of an analysis
that includes all patients. The confounding effect could be in either direction, i.e., it could
lead to a false positive or a false negative. Where appropriate based on the observed baseline
data, sensitivity and/or subset analyses will be conducted either to account for differences in
baseline within the analysis or to utilize a subset of the analysis population with baseline
levels reflective ofa diseased state.
In addition, sensitivity analyses may be conducted if imbalances are detected in baseline
characteristics or when particular baseline characteristics, such as DBS or TFC, are
reasonably anticipated to impact the course of disease.
4.0 RnnnnnNCE
5.0 AppnuDrcns
27


Isis Pharmaceuticals, Inc
Statistical Analysis Plan
Appendix A Schedule of Procedures
CONFIDENTIAL
June 18'h , 2015
ISIS 443139-CSOl
Post-Treatment
Period
(15 Weeks)
29t
ETz
197
!7
cl
X
X
X
X
X
X
X
X
X
X
21
'|.41
!7
cl
X
X
X
X
X
X
X
171
ET2
113
t2
cl
X
X
X
X
X
X
X
Treatment Evaluation Period
(13 Weeks)
14
92
+t
ph
13
87
*
ph
86
*
cl
X"
X
85
!2
cl
X-
X"
Xb
XC
xb
84
*
cl
X
X
X
X
X
10
64
!2
ph
9
59
*
ph
58
*
cl
Xd
X
57
+t
cl
X-
X"
X"
Xb
56
*
cl
X
X
X
X
6
36
!2
cl
X
X
5
31
ph
30
*
cl
Xd
X
29
!2
cl
X_
X,
X"
Xb
28
cl
X
X
X
X
2
I
!2
cl
X
X
1
3
*
ph
2
cl
Xd
X
1
0
cl
X-
X"
xb
X.
X"
-1
cl
X
X
X
X
X
X
Screen
-6 to -l
43to -2
cl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Period
Study Week
Study Day
Visit Window (days) *
Visit Type 
1
Jvernight Stay 3
3apacity to Consent
nstrument and lnformed
Sonsent
nclusion/Exclusion
\4edical History and ISCED
VIoCA
r/italSigns (BP, HR, RR, T)
Jrthostasis
rhysical& Neurological Exama
3ody Weight and Height 
5
=unctional, Cognitive, Motor
rnd Neuropsychiatric
¡ssessments o
3-SSRS 7
qEEG
Structural MRI
Í2flair, T2 star, T2 FSE/ïSE
VIRI
\4Rl of the CSF space
'H-MRS
28


Isis Pharmaceuticals, Inc.
CONFIDENTIAL
June 18th ,2015
ISIS 443I39-CSOl
Statistical
Plan
Appendix A Schedule of Procedures Continued
Post-Treatment
Period
(15 Weeks)
29t
ETz
197
!7
cl
X
X
X
X
X
X
X
X
X
X
xh
Xh
X
X
21
141
!7
cl
X
X
X
X
X
X
X
X
X
Xe
¡e
X
X
17t
ET2
113
+t
cl
X
X
X
X
X
Xs
Xs
X
X
Treatment Evaluation Period
(13 Weeks)
14
92
!2
ph
X
X
13
87
ph
X
X
86
cl
Xd
X
X
85
+t
cl
X
X"
Xb
X
X
X
84
cl
X
X
X
X
X
X
X
X
X
X
l0
64
+2
ph
X
X
9
59
*
ph
X
X
58
*
cl
X
X
57
!2
cl
Xþ
Xb
xb
X
X
X
56
*
cl
X
X
X
X
X
6
36
!2
cl
X
X
5
31
ph
X
X
30
*
cl
X
X
29
+t
cl
X"
Xb
Xb
X
X
X
28
cl
X
X
X
X
X
X
X
X
X
X
2
I
!2
cl
X
X
1
3
ph
X
X
2
*
cl
X
Xd
X
X
1
0
cl
X"
Xb
X"
X
X
X
,1
cl
X
X
X
X
X
X
X
X
X
X
X
Screen
-6 to -1
43to -2
cl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Period
Study Week
Study Day
Visit Window (days) *
Visit Type I
-CG (12-Lead) I
3hemistry Panel
lematology
Jrinalysis
3enetic Tests
llV,HepatitisB&C
)rug/Alcohol Screen
:SH 9
)regnancy Test 
1o
3erum Biomarker Sample
-ipid and Thyroid Panels
rT, lNR, aPTT
)lasma Sampling for PK
\rchived Serum Sample 
11
3SF Sample for
)l(Safety/Biomarkers
\rchived CSF Sample
Study Drug Administration
\dverse Events
loncomitant Medications
29


Isis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
June 18th , 2015
ISIS 443139-CSOl
Appendix A Schedule of Procedures Contínued
Note: lf not specifically labeled, "X" means anytime; ET = early termination
* 
Visit windows are calculated relative to Study Day 1. Note that within each block of visits associated with
dose administration, the visits must occur on 4 consecutive days. There are four "visit blocks" in this study:
(Study Days -1 , 1,2 and 3), (Study Days 28, 29, 30 and 31), (Study Days 56, 57, 58 and 59) and (Study
Days 84, 85, 86 and 87).
1 cl = clinic visit; ph = phone visit
2 
lf the patient terminates early from the Treatment Period but is willing to participate in the Post-Treatment
Period, (a) conduct the full block of visits associated with the last dose received (see asterisk above), (b)
conduct the visit scheduled for 7 days after the last dose received, (c) proceed to the Week 17 visit
approximately 4 weeks after last dose and conduct all visits in the Post-Treatment Period. lf the patient
terminates early from the Treatment Period and is not willing to participate in the Post-Treatment Period, (a)
conduct the full block of visits associated with the last dose received (see asterisk above), (b) conduct the
visit scheduled for 7 days after the last dose received and (c) conduct the Week 29 visit as an Early
Termination Visit. lf the patient terminates early from the Post-Treatment Period, conduct the Week 29 visit
as an Early Termination Visit.
3 On Study Day 1, the patient must stay in the clinic overnight and undergo safety monitoring follow-up as
scheduled on Study Day 2. On Study Days 29,57 and 85, the patient may either stay in the clinic overnight
or be discharged (after a minimum observation period of 6 hours after Study Drug administration), provided
the patient returns to the clinic on the following day (Day 30, 58 or 86) for all required assessments.
4 
Full physical and neurological exam (including fundi) to be given at Screening and abbreviated physical (but
full neurological) exam to be given during Treatment and Post-treatment Periods as indicated to assess
changes from Screening.
5 Height is measured at Screening only.
6 
Functional, Cognitive, Motor and Neuropsychiatric Tests are speeded tapping, UHDRS total functional
capacity scale, UHDRS independence scale, UHDRS total motor scale, HD work function scale, HD
Cognitive Battery (self-paced tapping, emotion recognition, CANTAB one-touch stockings, symbol-digit
modalities test, Hopkins verbal learning test - revised and trail making tests), Problems Behavior
Assessment for Huntington's disease-short form, Stroop Word Reading test and Map Search test.
7 The C-SSRS must be administered on the study days shown. lt may also be administered at any time that
the lnvestigator feels is necessary.
I 
Measured in triplicate at the Study Day -1 visit only.
9 Women who are not surgically sterile as confirmation of menopause.
10 Women who are not surgically sterile. Serum test at Screen visit; dipstick at post-screen visits.
11 Stored at -80o C for follow-up exploration of laboratory findings andior adverse events (e.9., measurement of
cytokine and/or chemokine levels, measurement of additional markers of kidney function, measurement of
antibodies) in this or subsequent clinical studies of lSlS 443139.
Time (in reference to time of Study Drug administration):
a 
Predose, 3 and 6 hours post lT injection
b 
Predose
c 
Predose and 3 hours post lT injection; also conduct at 6 hours post lT injection on any dosing day that the
patient does not stay in the clinic overnight (overnight stays are optional on Study Days 29, 57 and 85)
d 24 hours after prior dose of Study Drug
e 
Predose, 0.5, 1, 2,3, 4,5, 6, 8 and 12 hours post lT injection
f 
Predose, 0.5, 1 , 2,3, 4 and 5 hours post lT injection
g All patients in Cohort A will have CSF collected on Study Day 113 (Week 17) and re!on Study Day 141
(Week 21). For all other cohorts, CSF sampling will be conducted in approximately 50% of patients on
Study Day 1 13 (Week 17) and in the remaining 50% of patients on Study Day 141 (Week 21), as assigned
by the Sponsor according to a predetermined, randomized assignment.
h CSF sampling will be conducted at Study Day 197 (Week 29) in only those patients who attend the visit as
an early termination visit and did not undergo CSF sampling on either Study Day 1 13 (Week 17) or Study
Day 141 (Week 21). fi CSF sampling was conducted on Study Day 1 13 (Week 17) or Study Day 141 (Week
21), do not collect CSF at Study Day 197 (Week 29)
30


Ionis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
March 15,2018
ISIS 443139-CS1
loNls.
PHARMACEUTICALS
Statistical Analysis Plan
fsrs 443139-CSl
A Randomized, Double-blind, Placebo-controlled Study to
Evaluate the Safety, Tolerability, Pharmacokinetics and
Pharmacodynamics of Multiple Ascending Doses of Intrathecatty
Administered rSIs 443139 in Patients with Early Manifest
Huntingtonos Disease
Date: 0311512018
Version: 2.0
Counoennet
Confidential/Trade Secret information subject to 1B-USC-l905 and to which all ctaims of privilege and
confidentiality are asserted in both statutory and common law. Further dissemination may be made
only with fhe express wriften permission of lonis Pharmaceuticals, lnc.


Ionis Pharmaceuticals, Inc.
Statistical Analysis PIan
CONFIDENTIAL
March 15, 2018
ISIS 443139-CS1
Compound Name
Protocol:
Srudy Title:
Issue Date:
Statistical Analysis Plan Signature Page
Ionis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
443139
csl
A Randomized, Double-blind, Placebo-controlled Study to Evaluate
the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of
Multiple Ascending Doses of Intrathecally Administered ISIS 443139
in Patients with Early Manifest Huntington's Disease
5 April2017 (Amendment 3)
4 April 2017 (Amendment 3 - Germany)
5 April20l7 (Amendment 3.1 - Canada)
Date:
)4t
Signature:
Sigrrature:
Biostatistician
Director, Biometrics
f/GnA t5,>a8
Date:
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Ionis Pharmaceuticals, Inc.
Statistical Analysis Plan
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March 15,2018
ISIS 443I39.CS1
Date:
z / rsfu1/
Signature:
Signature:
Signature
Associate Direator, Biometrics
Ionis Pharmaceuticals, Inc.
2
Court
cA 92010
Executive Director, Clinical Development
Ionis Pharmaceuticals, lnc.
2855 Gazelle Court
Carlsbad, CA 92010
Darc: tg /l'/aA74 t8
Date: 15 tl'ar 2oltr
Director, Pharmacokinetics & Clinical Pharmacology
Ionis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
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Ionis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
March 15,2018
ISIS 443139-CSI
Table of Contents
Primary Rationale for Amendment............
Abb reviations .............
1.0 Introduction
1.1 Study Overview
1.2 
Objectives.
1.2.1 PrimaryObjectives
1
3
5
5
1.2.2 Secondary Objectives....
6
6
6
6
6
6
7
7
1.2.3 ExploratoryObjectives
1.3 
Endpoints
l 3.I 
Safety and Tolerability Endpoints
1.3.2 Pharmacokinetic Endpoints...................
1.3.3 ExploratoryEndpoints
2.0 Procedures 
..........9
2.1 
GeneralOverviewofProcedures.............
2.2 
Randomization & Treatment Allocation.
2.3 
Conduct....
2.4 DataMonitoring........
2.4.1 Safety Data Monitoring
2.5 
Data Management...... 
........10
2.5.1 Case Report Form Data... 
......................... 10
2.5.2 Laboratory Data ............ 
..'..' l0
2.5.3 Pharmacokinetics Data....... 
....'.......'........' I I
3.0 Analytical P1an.......... 
.........11
3.1 General Overview of Analyses 
.............11
3.1.1 StatisticalMethods
1l
3.1.2 Subject Populations Analyzed..... 
.............12
3.1.3 Sample Size Consideration..
t2
10
l0
9
9
9
18
l8
l8
l8
3.1.4 Planned Interim Analysis 
......................... 13
3.1.5 Incomplete or Missing Data
l3
3.2 
Safety Analyses...
3.2.1 Exposure......
13
13
3.2.5 Vital Signs Measurements and Weight
3.2.6 Neurological Examinations ...................
3.2.7 l2-LeadElectrocardiograms(ECG)
3.2.8 Prior and Concomitant Medications
3.3 
Pharmacokinetic Ana1ysis.............. 
......19
3.3.1 CSF Concentration Data and Pharmacokinetics...... 
.....'....'.'...'.'....... 19
3.3.2 Plasma Concentration Data.......... 
....'....'..20
3.3.3 PlasmaPharmacokinetics
20
3.4 Exploratory Pharmacokinetic-Pharmacodynamic Analysis. 
.....................22
3.2.2
3.2.3
3.2.4
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Statistical Analvsis Plan
3.5 Exploratory Analyses....
3.5.1 Biochemical
3.5.2 NeuroimagingFindings
22
22
22
23
23
23
23
24
26
26
26
26
27
27
28
28
3.5.3
3.5.4
3.5.5
qEEG..........
UHDRS Total Functional Capacity Scale (TFC).
UHDRS Independence Scale.........
3.5.6 HD Work Function (HDWF) Scale
3.5.8 UHDRS Total Motor Scale (TMS)
3.5.9 Stroop Word Reading Test
3.5.10 Map Search Test
3.5.7 HD Cognitive Battery......
3.5.11 SpeededTapping
4.0
5.0
3.5.12 Problems Behavior Assessment for Huntington's Disease-Short Form (PBA-s)
3.5.13 Correlations between ISIS 443139 Exposure and Exploratory Endpoints
3.5.14 Subset and Sensitivity Analyses
Reference
Appendices 
.......28
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Statistical Analysis Plan
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March 15,2018
ISIS 443I39-CS1
AnnnnVIATIONS
Abbreviation
AE
ALT
aPTT
AST
AUCt
BP
BUN
C,nu*
CRF
CSF
C-SSRS
DBS
DSMB
ECG
eCRF
EDC
FDA
FH
GCP
HD
HDWF
Htt
HR
HVLT-R
ICH
rl,-l8
IL-6
INR
ISIS 443I39
IT
LCR
MCH
MCHC
MCP-I
MCV
Definition
Adverse event
Alanine aminotransferase (SGPT)
Activated partial thromboplastin time
Aspartate aminotransferase (SGOT)
Area under the plasma concentration-time curve from time zero to time t
Blood pressure
Blood urea nitrogen
Maximum concentration
Case report form
Cerebrospinal fluid
Columbia suicide severity rating scale
Disease burden score
Data and Safety Monitoring Board
Electrocardiogram
Electronic Case Report Form
Electronic Data Capture
Food and Drug Administration
Factor H
Good Clinical Practice
Huntington's disease
Huntington's disease work function
Huntingtin protein
Heart rate
Hopkins verbal learning test - revised
Intemational Conference on Harmonization
Interleukin-l beta
Interleukin-6
International normalized ratio
Antisense inhibitor of Htt
Intrathecal(ly)
Local cutaneous reactions
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Monocyte chemoattractant protein- I
Mean corpuscular volume
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Statistical Analysis Plan
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March 15,2018
ISIS 443I39-CSI
MedDRA
MoCA
MRI
NODDI
on Study
Medical Dictionary for Regulatory Activities
Montreal cognitive assessment
Magnetic resonance imaging
Neurite orientation dispersion and density imaging
The patient is 'on Study' from signing of the informed consent until
his/her last study visit
One touch stockings
Measure of the acidity or basicity of a solution
Pharmacokinetic(s)
Problems behavior assessment for Huntington's disease - short form
Prothrombin time
Quantitative EEG
QT time corrected using the Friderica's method
QT time using theBazett' s method
Relative ventricular rate
S100 calcium binding protein B
Serious adverse event
Statistical Analysis Plan
Synaptosomal-associated protein 25
Defined as the first day Study Drug is administered to the patient
ISIS 443139 or placebo
Symbol digit modalities test
Treatment-emergent adverse event
Total functional capacity
Time to maximal concentration
Total motor scale
Trail-making test part A
Trail-making test part B
Tumor necrosis factor alpha
Turbo spin echo
Unified Huntington's disease rating scale
VisininJike protein I
Ventricular rate
White blood cell
World health organization
Chitinase-3-like protein I
OTS
pH
PK
PBA-s
PT
qEEG
QTcF
QTcB
RR
SlOOB
SAE
SAP
SNAP25
Study Day I
Study Drug
SDMT
TEAE
TFC
T-u*
TMS
TMT-A
TMT-B
TNFcr
TSE
UHDRS
VIIP1
VR
WBC
wHo
YKL.4O
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Ionis Pharmaceuticals, Inc.
Statistical Analysis Plan
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L.0 lNrnouucrroN
This document provides a description of the study organization, study procedures, and the
plan for the statistical analysis of the study data. Section I discusses study design, objectives,
and endpoints; Section 2 provides the study procedures; Section 3 provides the detailed plan
for the statistical analyses.
As with any statistical analysis plan (SAP), the proposed methods and approaches to the data
analysis should be viewed as flexible. The statistical analysis to some degree is iterative since
the planning is based, at least in part, on statistical and other assumptions, which require
verification.
1.1 Study Overview
This is a Phase ll2a, multi-center, double-blind, randomized, placebo-controlled, dose-
escalation study conducted in patients with early manifest Huntington's disease (HD). The
study consists of five cohorts (n : 4-12 per cohort, randomized in a ratio of 3 active: I
placebo). The doses planned for the study are shown below. Based on emerging safety data
from this study, one or more cohorts may be expanded by enrolling additional patients.
Additionally, pharmacokinetic and pharmacodynamic measures will be collected at each
dose level and compared to the results that are predicted by models constructed from
preclinical data. The doses utilized in remaining cohorts may be adjusted, or an additional
cohort may be added, if necessary to achieve pharmacologically relevant levels. The
maximum dose tested in a cohort will not exceed 120 mg.
Dose Cohorts:
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ISIS 443139-CS1
Cohort A:
Cohort B:
Cohort C:
Cohort D:
Cohort E:
N : 4, 10 mg ISIS 443139 or placebo (3:l)
N: 8, 30 mg ISIS 443139 or placebo (6:2)
N : 8, 60 mg ISIS 443139 or placebo (6:2)
N : 12, 90 mg ISIS 443139 or placebo (9:3)
N: 12, l20mgISIS 443139 orplacebo (9:3)
Randomization in Cohort D will be stratified by early Stage I total functional capacity (TFC
> 12) or late Stage I (TFC : 1l) disease, where Stage I represents the highest level of
capacity of the 5 stages of manifest disease.
Patients will receive 4 intrathecal (IT) bolus doses of Study Drug at 4-week intervals during
the 13-week Treatment Period (Days l, 29, 57, 85).
Approximately 44 patients are planned to be enrolled in this study. The number of patients
enrolled may be higher if some patients need to be replaced and/or if the sizes of the cohorts
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Ionis Pharmaceuticals, Inc
Statistical Analysis Plan
CONFIDENTIAL
are expanded to obtain further experience with particular dose levels. A maximum of 48
patients may be enrolled.
The overall study duration will be approximately 7-8 months. The study will consist of a
Screening Period of up to 6 weeks, a l3-week Treatment Period and a l5-week Post-
Treatment Period. The end of study is defined as last patient, last study visit. Please refer to
the Schedule of Procedures in Appendix A'
1.2 Objectives
1.2.1 Primary Objectives
To evaluate the safety and tolerability of ascending dose-levels of multiple IT bolus
administrations of an antisense inhibitor of Htt (ISIS 443139) to patients with HD.
1.2.2 Secondary Objectives
To characteize the cerebrospinal fluid (CSF) pharmacokinetics (PK) of ascending dose-
levels of multiple IT administrations of ISIS 443139.
1.2.3 Exploratory Objectives
To explore effects of multiple doses of ISIS 443139 on potential target engagement and
disease progression biomarkers and clinical endpoints relevant to HD. Plasma
pharmacokinetic properties of ISIS 443139 will also be assessed. Disease progtession
markers are included primarily as a safety measure to document any marked worsening. A
lesser objective is to gain experience with these measures in an ISIS 443139 clinical study as
preparation for subsequent, longer-term clinical studies. It is not expected that the majority of
biomarkers and clinical measures will be impacted significantly by the l3-week of dosing
planned for this study. For the current study, select disease progression markers are
considered to be key exploratory target engagement, biochemical, neuroimaging and
cognitive assessments based on their potential to evidence changes in disease progression in
early HD. These key exploratory endpoints are mutant Htt in CSF, neurofilament light chain
in CSF, ventricular volume as assessed by structural magnetic resonance imaging (MRI) and
the composite cognitive score resulting from assessment of the components of the HD
Cognitive Battery, resPectivelY.
1.3 Endpoints
1.3.1 Safety and Tolerabitity Endpoints
o Columbia - Suicide Severity Rating Scale (C-SSRS)
o Physical examination and standard neurological assessment (including fundi)
o Pregnancy testing
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o Vital signs (HR, BP, orthostatic changes, weight)
o ECG
o AEs and concomitant medications
o CSF safety labs (cell counts, protein, glucose)
o Plasma laboratory tests (clinical chemistry, hematology)
o Urinalysis
o Clinical assessments
o Volumetric and safety neuroimaging assessments
1.3.2 Pharmacokinetic Endpoints
A CSF sample will be collected at pre-dose on each injection day (Days 1,29,57, 85) and at
one Post-Treatment Period visit for PK analyses.
Plasma samples will be collected on study Days l, 2,29, 57,85 and 86 and at each Post-
Treatment Period visit for PK analyses.
Plasma C-"*, AUC, elimination half-life and trough and post-distribution drug levels will be
assessed, where appropriate.
1.3.3 Exploratory EndPoints
o Biochemical
o CSF levels of mutant Htt*
o CSF levels of neurofilament light chain*, YKL-40, , neurogranin, and tau
o Plasma levels of IL-6, TNFa and 24S-hydroxycholesterol
o Neuroimaglng volumes, including but not limited to:
o Structural MRI
. Caudate
' Whole brain
' Ventricular*
o Resting state functional MRI
o NODDI
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Statistical Analysis Plan
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March 15,2018
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a
Electrophysiological
o qEEG
Clinical
o Functioninglability to perform activities of daily living
' 
UHDRS Total Functional Capacity Scale (TFC)
. UHDRS Independence Scale
' HD Work Function Scale
o Cognitive and motor tests:
. HD Cognitive Battery*
o Self-Paced Tapping
o Emotion Recognition
o CANTAB One Touch Stockings
. Symbol Digit Modalities Test
o Hopkins Verbal Learning Test Revised
o Trail Making Test Part B
. UHDRS Total Motor Scale
. Stroop Word Reading Test
' 
Map Search Test
. Speeded Tapping
o Neuropsychiatric evaluation
. Problems Behavior Assessment for Huntington's disease-short form (PBA-s)
Key exploratorybiochemical, neuroimaging, electrophysiological and clinical
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Statistical Analysis Plan
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March 15,2018
ISIS 443139-CS1
2.0 PNOCrcDURES
2.1 General Overview of Procedures
Ionis (or designee) will review all study data including source documents, case report forms
(CRFs), and laboratory reports. Study site will enter subject source data into the case report
form. The CSF Safety lab data (CSF WBC, CSF RBC, CSF protein, CSF glucose) will be
completed at each site's local lab and will be entered on a CRF (CSF Results CRF). Mutant
Htt will be transferred electronically from
 Other laboratory data will be transferred
electronically from 
 
. C-SSRS, UHDRS TFC, Independence
Scale, UHDRS Total Motor Scale, HD Work Function Scale, PBA-s will be collected using
device and data provided by 
. Neuroimaging data including structural MRI,
MRS spectroscopy will be reported by 
 
. Resting state functional MRI and NODDI
data will be generated by 
. Self-Paced Tapping, Emotion
Recognition, CANTAB One Touch Stockings, and Speeded Tapping will be collected using
the 
device and data provided by 
 
. ECGs will be centrally read by
. EEGs will be collected by 
 
 
 
. Those data will be
transferred electronically to Ionis Pharmaceuticals, Inc.
Ionis Pharmaceuticals, Inc. is responsible for the format of electronic data transfers, transfer
schedule and review of the data. Those data will be stored as SAS data sets.
2.2 Randomization & Treatment Allocation
A patient will be randomized after all Screening assessments have been completed and the
Investigator has verified that the patient is eligible per the study criteria. No patient may
begin the treatment prior to randomization and assignment of a unique patient identification
number.
Eligible patients will be randomized centrally by an automated system to receive
ISIS 443139 or placebo. Within each cohort, randomization will be 3:l for ISIS 443139:
placebo respectively as outlined in Section l.l. Patients in Cohort D will be stratified by early
Stage I (TFC >12) or late Stage 1 (TFC : ll) disease. Patients in Cohorts B, C, D, and E will
also be randomly assigned to have the CSF sampling visit at Week 17 or Week 2I in a 1:1 ratio
within cohort and treatment assignment. 
 will prepare the randomization list.
2.3 Conduct
The study will be conducted in accordance with current Good Clinical Practice (GCP) and
International Conference on Harmonization (ICH) guidelines, the World Medical Association
Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of
Federal Regulations, and all other local regulatory requirements.
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2.4 Data Monitoring
2.4.1 Safety Data Monitoring
Ionis Pharmaceuticals, Inc. (or designee) is responsible for processing all reported adverse
events (AEs). A11 serious adverse events (SAEs), reported to Ionis Pharmaceuticals, Inc. (or
designee), are reviewed according to standard operating procedures. The medical monitor
will review all AEs and SAEs on an ongoing basis throughout the study. For dose escalation,
the progression of the study from initiation of dosing in one cohort to the next will be
determined by the Sponsor and the DSMB. Ionis Pharmaceuticals, Inc. (or designee) will
prepare and submit safety reports to the health authorities worldwide in accordance with
local requirements. If it becomes necessary to communicate new safety information, Ionis
Pharmaceuticals, Inc. (or designee) will also prepare a safety notification letter and hansmit
it to all applicable study sites.
2.5 Data Management
An electronic case report form (eCRF) utilizing an Electronic Data Capture application will
be used for this study.
2.5.1 Case Report Form Data
 (or designee) is responsible for creating the Electronic Data Capture (EDC)
data entry screens, database and edit checks using definitions developed by Ionis
Pharmaceuticals, Inc. Ionis Pharmaceuticals, Inc. is responsible for the review, data
management querying and locking of the database.
Data are single-entered into the EDC system by the investigator site staff. Programmed edit
checks (computer logic that checks the validity of the data entered and also prompts for
missing datathatis expected to be entered) are run and automatic queries are generated. Ionis
Pharmaceuticals, Inc. reviews all data for accuracy and validity and generates additional
queries in the EDC system when necessary. The data is corrected or an explanation
concerning the query is provided in the EDC system. After all data is entered, reviewed and
queried the database is closed. The data is then reviewed by Ionis Pharmaceuticals, Inc. and
additional queries may be generated. After all queries are resolved the database is locked.
2.5.2 Laboratory Data
Ionis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data
transfers and the transfer schedule. Ionis Pharmaceuticals, Inc. is responsible for the review
of the clinical laboratory data. This data is not stored in the EDC system. Investigator sites
have access to safety laboratory dataviaprinted lab reports sent directly from the laboratory.
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2.5.3 PharmacokineticsData
Ionis Pharmaceuticals, Inc. is responsible for the management and review of the PK data.
This process involves reviewing the patient and visit identifiers with the clinical data
collected in the EDC system. The PK data are not stored in the EDC system.
3.0 ANar,vrrcAl, PLAN
3.1 General Overview of AnalYses
3.1.1 StatisticalMethods
A11 CRF data, datatransfers from external vendors (e.g., laboratoty, cognitive testing, ECG,
qEEG), and any outcomes derived from the data will be provided in the subject data listings.
Subject data listings will be presented for all subjects enrolled into the study. Descriptive
sunmary statistics including 11, mean, median, standard deviation, standard elror,
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, p-values will be reported. All statistical tests will
be conducted using 2-sided tests with 5o/o Type I error rate unless otherwise stated. Analyses
may be stratified by the stratification factor and/or site if supported by data.
Since there are limited placebo-treated subjects within each dose cohort, the placebo-treated
subjects will be pooled for all analyses.
For vital signs [blood pressure (BP), heart rate, respiration rate, orthostatic change and
temperature], baseline will be defined as the average of the values collected prior to first dose
(Screening, Study Day -1, Study Day 1, and any measurements between Screening and Day
1).
Baseline ECG will be defined as the average of the triplicate taken on Day -1, if only one or
two assessments are available, the single assessment or average of the two assessments will
be used.
For all other measures and parameters, baseline will be defined as the last non-missing
measure prior to the first dose.
The treatment period will be defined as the period of time from the first dose administration
through Day g2visit or, if the patient does not participate in Day 92 visit, from the first dose
administration through 9 days after the last dose administration.
The post-treatment assessment period will be defined as the period of time from the day after
the treatment period to the end of study.
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Demographic and baseline characteristics (e.g., age, sox, ethnicity, race, weight, height, BMI,
Montreal Cognitive Assessment (MoCA), ISCED level, CAG repeat length, ApoE isoform
genotype, BCHE-K variant, and disease burden score (DBS)) and subject disposition will be
summarized using descriptive statistics by treatment group. DBS is calculated by ICAG
repeat length - 35.5lxage in years. A11 subjects enrolled will be included in a summary of
subject disposition. Protocol deviations will be listed.
Multiple results within the same visit (or timepoint for measurements collected at multiple
timepoints) will be averaged for by visit analyses. Unscheduled results will not be included
in the by-visit analyses except for determining baseline, but will be presented in data listings'
PK parameters will be summarizedby treatment group using n, mean, standard deviation,
coefficient of variation (CV), geometric mean, median, minimum, and maximum.
3|1..2 Subject Populations Analyzed
The following analysis populations will be used for the analyses of data as described within
each analysis set:
Safety Population: All patients who are randomized and receive at least one dose of Study
Drug. This population will be used for safety and tolerability analyses.
Per Protocol Population: A1l patients who are randomized and receive all doses of the
protocol-specified Study Drug (ISIS 443139 or placebo). This population will be used for
pharmacodynamics, exploratory and biomarker analyses.
pK Population: All patients who are randomized to ISIS 443139 and receive at least one dose
of ISIS 443139 and have sufficient sampling to permit pharmacokinetic evaluation. This
population will be used for PK analyses.
In addition to the above analysis sets, it is recognized that some data displays will be
provided for "All Screened", "screening Failures" and "A11 Randomized" subjects but no
data analysis will be executed in these populations except for the disposition table that
includes all screened subjects.
3.1.3 Sample Size Consideration
While there is no statistical rationale for the sample size, it has been selected based on the
prior experience with generation 2.0 ASOs given by IT injection to ensure that the safety,
tolerability, pharmacokinetics and exploratory pharmacodynamics will be adequately
assessed while minimizing unnecessary patient exposure.
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3.1.4 Planned Interim AnalYsis
Unblinded interim analyses may be performed and the results summarized by treatment
group at the end of each cohort upon completion of dosing for that cohort or at any time if
needed to address a safety concem. The Investigator, study staff, patients, monitors, Sponsor
Medical Monitor, members of the Sponsor's clinical operations team and data management
team will remain blinded throughout the study. The analysis will be executed with controlled
dissemination to ensuro the integrity of ongoing data collection.
A DSMB will be assembled to review safety, tolerability, pharmacokinetic and target
engagement/pharmacodynamic (as needed) data collected on ISIS 443139 during this study.
Unblinded statisticians or designees who will not be involved in the study conduct will generate
and distribute the data to DSMB prior to each DSMB meeting. Based on its ongoing assessment
of the safety and tolerability of ISIS 443139, the DSMB will provide recommendations to the
Sponsor for modiffing, stopping or continuing the study as planned. Details on the safety
assessments, frequency of review, meeting schedules and controlled access to unblinded data are
outlined in the DSMB charter.
3.1.5 Incomplete or Missing Data
Missing values will not be imputed unless otherwise specified.
3.2 Safety Analyses
3.2.1 Exposure
Treatment duration and amount of Study Drug received will be summarizedby treatment
group.
3.2.2 Adverse Events
An adverse event will be regarded as treatment emergent adverse event (TEAE) if it is
present prior to receiving the first dose of study drug and subsequently worsened, or is not
present prior to receiving the first dose of study drug but subsequently appeared.
The most conservative approach will be used to determine if the event occurs after the first
dose of treatment. For example, if the onset date or resolution date of an AE is prior to the
first study treatment date, it will be considered to have occurred prior to the study period. If
the onset date of an AE is a partial date with only month or year available or completely
missing, then the event is assumed to be within the study period unless the year is prior to the
year of the first study treatment date, or if in the same year, the month is prior to the month of
the first study treatment date or a full or partial resolution date is available that definitively
demonstrates that the event ended prior to first dose of study drug.
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Statistical Analvsis Plan
The incidence of AEs will be summarized by Medical Dictionary for Regulatory Activities
(MedDRArM) preferred term and system organ class for:
o All treatment emergent adverse events
o Related treatment emergent adverse events. Related is defined as "Related",
"Possible", or missing relationship to study drug
o All treatment emergent adverse events by severity. At each level of subject
summarization, a subject is classified according to the highest severity if the subject
reported one or more events. Adverse events with missing severity will be
categoizedas ooMissing" for this summary
o Related treatment emergent adverse events by severity
o Serious treatment emergent adverse events
o Serious and related treatment emergent adverse events
Narratives of "on-study'' deaths, serious and significant AEs, including early withdrawals
due to AEs, will be provided.
SAEs and non-serious AEs that lead to study discontinuation or investigational drug
discontinuation will be listed separately. Non-TEAEs will be flagged in the data listing'
3.2.3 Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS collects binary responses to I I categories: five subtypes of suicidal ideation,
five subtypes of suicidal behavior, and self-injurious behavior without suicidal intent.
Specificaily, the following outcomes are C-SSRS categories and have binary (YesA{o)
,..porrr"r. (The categories have been re-ordered from the actual scale to facilitate the
definitions of the composite endpoints and to enable clarity in the presentation of the results.)
Suicidal Ideation:
Category I - Wish to Be Dead
Category 2 - Non-specific Active Suicidal Thoughts
Category 3 - Active Suicidal Ideation with Any Methods (Not Plan) without lntent to
Act
Category 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Category 5 - Active Suicidal Ideation with Specific Plan and Intent
Suicidal Behavior:
Category 6 - Preparatory Acts or Behavior
Category 7 - Aborted AttemPt
Category 8 - IntemrPted AttemPt
Category 9 - Actual Attempt (non-fatal)
Category 10 - ComPleted Suicide
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Other
Category I I - Non-suicidal Self-injurious Behavior
In addition, a numerical score, the Suicidal Ideation Score, will be defined as the highest
suicide ideation category (1-5) at which the patient responded "Yes" for the given visit. If
the patient did not respond'oYes" to any of these categories, the score will be set to zero.
For each of the l1 categories above, the number and percent of patients with a o'Yes"
response at any time post-baseline (regardless of baseline response) will be summarized by
treatment group.
In addition, emergent suicidal ideation or behavior will be summarized. The binary
categories above and the Suicidal Ideation Score will be used to identify the 8 composite
endpoints defined below. Note that "recent history" for these composite endpoints is defined
as the 12 months prior to Screening and the Screening period. At the Screening visit, C-
SSRS data is collected for the pior 12 months. Therefore, analyses that utilize data from
oorecent history''will include the historical l2-month data collected at Screening as well as all
on-study C-SSRS data collected prior to first dose.
o Suicidal Ideation: A ooYes" answer at any time post-first-dose to any one of the five
suicidal ideation questions (Categories 1-5), regardless of the pre-dose rosponses
o Suicidal Behavior: A ooYes" answer at any time post-first-dose to any one of the five
suicidal behavior questions (Categories 6-10), regardless of the pre-dose responses
o Suicidal Ideation or Behavior: A "Yes" answer at any time post-first-dose to any
one of the ten suicidal ideation or behavior questions (Categories l-10), regardless of
the pre-dose responses
o Treatment-Emergent Suicidal ldeation compared to recent history: A maximum
post-first-dose suicidal ideation score that is increased from the maximum suicidal
ideation score in recent history.
o Treatment-Emergent Serious Suicidal ldeation compared to recent history: A
maximum post-first-dose suicidal ideation score of 4 or 5 when the maximum suicidal
ideation score during recent history was less than 4 (i.e., scores of 0-3). Only patients
with a recent history score of 0-3 will be considered evaluable for this outcome.
o Emergence of Serious Suicidal ldeation compared to recent history: A maximum
post-first-dose suicidal ideation score of 4 or 5 when the maximum suicidal ideation
score during recent history was 0. Only patients with a recent history score of 0 will
be considered evaluable for this outcome.
. Improvement in Suicidal Ideation compared to baseline: A decrease in the suicidal
ideation score at the patient's Study Day 86 C-SSRS assessment compared to the
baseline score, defined as the minimum score obtained during the Screening Period
(i.e., assessments collected from the Screening Visit through pre-dose on Study Day
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1). The analysis will be repeated for Study Days I 13 , l4I and 197 . Only patients with
a baseline score )0 will be considered evaluable for these outcomes.
o Emergence of Suicidal Behavior compared to all prior history: The occurrence of
suicidal behavior (a "Yes" response to one or more of Categories 6-10) post-first-
dose from not having suicidal behavior prior to first dose (includes the "lifetime"
score collected at the Screening Visit as well as all C-SSRS assessments collected
from the Screening Visit through pre-dose on Study Day 1).
Each of the composite endpoints will be summarized by treatment group. For each treatment-
emergent outcome listed, only those patients with the specified screening condition will be
considered evaluable. In addition, patients who discontinue from the study with no post-first-
dose C-SSRS assessment will be considered unevaluable for analyses of suicidality. Percents
will be based on the number of evaluable patients for each outcome.
In addition, a shift table will be created to demonstrate the change in suicidal ideation score
from recent history to treatment period and/or post-treatment period. The maximum suicidal
ideation score in each period will be used to create the shift table. If a patient's rocent history
suicidal ideation score is missing but has a post-first-dose score, then the recent history
assessment will be labeled as "unknown". Likewise, if a patient's recent history suicidal
ideation score is available but has no post-first-dose score, then the scores during the
treatment and post-treatment period will be labeled as "unknown".
3.2.4 Laboratory Measurements
The following is the list of lab analytes that will be measured throughout the study:
Chemistry: Sodium, Potassium, Chloride, Total protein, Albumin, Calcium, Magnesium,
Phosphorus, Bicarbonate, Glucose, BIIN, Creatinine, Total serum bilirubin, Uric acid,
Alkaline phosphatase, ALT (SGOT), AST (SGPT), GGT and CPK.
a
a
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o
a
Hematology: Red blood cells, Hemoglobin, Hematocrit, Platelets, MCV, MCH, MCHC,
White blood cells, and WBC differential (percentage and absolute count) (Basophils,
Eosinophils, Lymphocytes, Monocytes and Neutrophils)
Coagulation: aPTT, PT, INR
Thyroid Panel: TSH, Free T4, and Free T3
PK'Plasma ISIS 443139 levels, and CSF ISIS 443139 levels
Pregnancy: Urine hCG
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CSF Safety Panel (Minimum Requirements): Red blood cells, White blood cells, Glucose
and Protein
o Urinalysis: Specific gravity, pH, Protein, PIC ratio, Glucose, Ketones, Urobilinogen,
Leukocyte esterase, Nitrite, Bilirubin, Blood, Red blood cells, White blood cells,
Epithelial cells, Bacteria, Casts, Crystals, Color and Appearance.
In addition, the following analytes are measured at screening only: plasma hCG, FSH,
hepatitis B surface antigen, hepatitis C antibody, HIV antibody, amphetamines, barbiturates,
beruodiazepines, cannabinoids, cocaine, ethanol, opiates.
The following genetic testing is performed: CAG repeat length, ApoE isoform genotype,
BCHE-K.
Missing WBC differential absolute counts and percentages will be derived:
If WBC differential absolute counts are missing, and percentages are available, then absolute
counts will be calculated by multiplying the percentage by total WBC count. Conversely, if
absolute count is available, and percentage is missing, then percentage will be calculated by
dividing absolute count by the total WBC count. If neutrophils counts and percentages are
missing, and segmented neutrophil and band neutrophil results are avulable, then neutrophils
will be calculated by adding segmented neutrophils and band neutrophils.
Laboratory tests to ensure subject safety including chemistry panel, hematology panel,
coagulation, and CSF safety labs (cell counts, protein, and glucose), will be summarizedby
study visit for each treatment group. These safety variables will also be presented as change
and percent change from baseline over time after Study Drug administration, as appropriate.
In addition, the shifts (relative to the normal range) from baseline to the minimum and
maximum post-baseline values will be presented. If a subject is missing a baseline value but
had a post-baseline value, then the baseline assessment is labeled as "unknown". Likewise,
if a subject had a baseline value but had no post-baseline values, then the minimum and
maximum are labeled as "unknown". For each parameter, the incidence of shift to low will
be summarized using the minimum post-baseline values; the incidence of shift to high will be
summarized using the maximum post-baseline values.
Only central laboratory data will be used for the sunmary tables and figures. Local
laboratory data will be provided in the listings only, with the exception of local results for
CSF safety tests which will be listed and summarizedin tables.
Al1lab data will also be displayed in subject listings
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3.2.5 Vital Signs Measurements and Weight
Vital signs will include body temperature, heart rate, respiration rate, orthostatic changes, and
systolic and diastolic blood pressure.
Orthostatic changes include 3 variables: change from seated systolic blood pressure to
average of all available standing systolic blood pressures, change from seated diastolic blood
pressuro to average of all available standing diastolic blood pressure' and change from seated
heart rate to average ofall available standing heart rate.
Summary tables will be created to present the descriptive statistics (n, mean, standard elror,
standard deviation, median, Ql, Q3, minimum, and maximum) for vital sign values and
weight as well as the change and percent change from baseline at each study visits by
treatment group.
3.2.6 Neurological Examinations
Neurological examinations will be provided in patient listings.
3.2.7 l2-LetdElectrocardiograms (ECG)
ECG data will be collected through a central reader.
The ECG data will include ventricular rate (VR), PR interval, QRS duration, QT, QTC
(recorded from ECG machine), QTcF (QT corrected using the Fridericia's formula), and
QToB (QT corrected using theBazett's formula) as described below:
QToF : QT / (RR) 1/3, where RR: 60/VR
QTcB : QT / (RR) r/2, where RR:60A/R
At Day -1, three replicates of ECG parameters will be recorded, and the mean from all
replicates will be used as the subject's reportable value atDay -1. For all other time points, a
single set of parameters will be recorded. QToF and QTcB will be calculated based on the
subject's reportable ECG data at each time point using the formula described above.
Summary tables will be created to present the descriptive statistics (n, mean, standard effor'
standard deviation, median, Ql, Q3, minimum, and maximum) as well as the change and
percent change from baseline at each study visits by treatment group.
3.2.8 Prior and Concomitant Medications
prior and concomitant medications will be coded using WHO Drug dictionary and
summarized by ATC class, generic name and by treatment group'
A concomitant medication is defined as medications that were taken on or after the first study
drug administration (Study Day 1). This includes medications that were started prior to the
initiation of study drug if their use continued on or after the date of the first dosing. In order
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to define concomitant medications with missing start or stop dates, the following additional
criteria will be used:
if both the start and stop dates of a particular medication were missing, that
medication is considered concomitant;
if the start date of a medication was missing and the stop date of that medication fell
on or after the date of dosing, that medication is considered concomitant;
if the start date of a medication was prior to the date of first dosing and the stop date
of that medication was missing,thatmedication is considered concomitant; or
if the start/stop date of a medication is partial then where it is not possible to rule out
that it was not taken concomitantly it will be considered concomitant.
Non concomitant medications will be flagged in the data listing.
3.3 Pharmacokinetic AnalYsis
CSF and Plasma samples will be collected at protocol designated times for ISIS 443139
pharmacokinetic assessments from the dose cohorts. Only concentration data from patients
randomized to receive study drug (ISIS 443139) will be included in this analysis.
3.3.1 CSF Concentration Data and Pharmacokinetics
A CSF sample will be collected pre-dose on each injection day (Days I,29,57, 85) and at
one Post-Treatment Period visit for PK analyses. CSF concentrations of ISIS 443139, along
with the scheduled (nominal) and actual samples times (i.e., time from IT dosing) will be
listed (when applicable) for each patient, treatment group (cohort), nominal dose, and day.
Differences between scheduled and actual sampling days will also be listed for all patients, as
well as percent differences between actual administered dose and nominal dose.
CSF concentrations below the lower limit of quantification (LLOQ) will be indicated by
ooBLQ". For the purpose of calculating typical descriptive statistics (n, mean, SD, o/oCV,
geometric mean, geometric yoCV, median, minimum, and maximum) for CSF
concentrations, all BLQ values will be set to zero. Mean CSF concentrations that are BLQ
will be presented as BLQ, and the SD and %CV will be reported as not applicable. Summary
statistics of the ISIS 443139 CSF concentrations will be tabulated by treatment group
(cohort), nominal dose and day. At the discretion of the pharmacokineticist and/or
biostatistician, samples may be excluded from descriptive statistics if there are large
deviations between scheduled and actual sampling days, or large deviations between actual
dose and nominal dose.
The ISIS 443139 half-life in CSF will be calculated, if possible, and summarized by
treatment group (cohort), nominal dose, and nominal day.
ISIS 443139 CSF concentration versus time (actual) profiles from Day I to last collection
(nominal Study Day 113 or 141 in Cohorts A-D), for each patient, as well as the mean (+SE)
a
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CSF concentration versus time (scheduled) profiles for each treatment cohort, will be
presented gaphically on linear scale. Samples may be excluded from the mean plots if there
are Iarge deviations between scheduled and actual sampling times, or large deviations
between actual dose and nominal dose.
3.3.2 Plasma Concentration Data
Plasma concentrations of ISIS 443139, along with the scheduled (nominal) and actual
samples times (i.e., time from IT dosing) will be listed (when applicable) for each patient,
treatment group (cohort), nominal dose, and day. Percent differences between scheduled and
actual sampling times will also be listed for all patients as well as percent differences
between actual administered dose and nominal dose.
Plasma concentrations below the lower limit of quantification (LLOQ) will be indicated by
.'BLQ". For the purpose of calculating typical descriptive statistics (n, mean, SD, o/oCV,
geometric mean, geometric yoCY, median, minimum, and maximum) for plasma
concentrations, all BLQ values will be set to zero. Mean plasma concentrations that are BLQ
will be presented as BLQ, and the SD and %CY will be reported as not applicable. Summary
statistics of the ISIS 443139 plasma concentrations will be tabulated by treatment group
(cohort), nominal dose, duy, and scheduled time point. At the discretion of the
pharmacokineticist and/or biostatistician, samples may be excluded from descriptive statistics
if there are large deviations between scheduled and actual sampling times, or large deviations
between actual dose and nominal dose.
ISIS 443139 plasma concentration versus time (actual) profiles from Day I to Day 29 and
Day 85 to Day 197 (Cohorts A-D), for each patient, as well as the mean (tSE) plasma
concentration versus time (scheduled) profiles for each treatment cohort, will be presented
graphically on linear and semilogarithmic scales. Additionally, ISIS 443139 plasma
concentration versus time (actual) profiles from 0 Io 24 hours on Days I and 85 for all
patients, as well as the mean (+SE) plasma concentration versus time (scheduled) profiles (0
to 24 hours on Days I and 85) for each applicable treatment cohort will be presented
graphically on linear and semilogarithmic scales. Samples may be excluded from the mean
plots if there are large deviations between scheduled and actual sampling times, or large
deviations between actual dose and nominal dose.
3.3.3 Plasma Pharmacokinetics
Non-compartmental pharmacokinetic analysis of ISIS 443139 will be carried out on each
individual patient data set using Phoenix WinNonlin version 6.3 or higher 
 
 
 
). Plasma pharmacokinetic parameters in each patient
(when applicable) will be determined. For calculation of PK parameters, all BLQ values will
be set to zero. The following plasma PK parameters will be calculated (when applicable) and
based on actual sampling times:
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o
a
Cmaxr the maximum observed drug concentration in plasma.
. 
Tmaxl the time at which Cmax occurs.
o AUCo-z4h: areas under the plasma concentration-time curve from zero time (pre-dose)
to 24 hours after the intrathecal administration will be calculated using the linear
trapezoidalrule after the dose administrations on Day 1 and Day 85.
o AUCo-zaa (AUCo-t): areas under the plasma concentration-time curve from zero time
(pre-dose) to 28 days after the intrathecal administration will be calculated using the
linear trapezoidal rule for Days I and 85.
o MRTo-24h: mean residence time (MRT) from time zero to 24 hours after intrathecal
dose administration will be calculated from the equation, MRTo-zar' : AUMCo-z+t'
IA1JCo-z*,where AUMCo-zar, is the area under the moment plasma concentration-time
curve from time zero to 24 hours after dosing. This parameter will be calculated for
Days 1 and 85. This parameter will be calculated and reported mainly as an index
measure to reflect the expected initial rapid disposition of ISIS 443139 from plasma
to tissues shortly after dosing.
The following PK parameters may be calculated using actual sampling times where
appropriate data exists at the discretion of the pharmacokinetic scientist:
tu"r,,; the plasma disposition half-life associated with the apparent terminal
elimination phase may be calculated from the equation, tu2^r: 0.6931)"2, on Day 85
profiles for Cohorts A to D.
AUCo-inr: AUC from zero to infinity, calculated as the sum of the AUCo-z8dplus the
final quantifiable concentration divided by )r.2, for only subjects in Cohorts A to D
where ty"x"canbe accurately and appropriately determined and only on Day l.
Additional pafiial AUC values may be calculated depending upon the samples
collected during the study.
CLIF: Plasma clearance will be calculated from CL : Actual Dose/AUC0-inr, for
subjects in Cohorts A to D where AUCo-- can be accurately and appropriately
determined, and from the equation CL: Actual Dose/AUCo-t for subjects in Cohorts
A to D after the Day 85 dose.
a
Plasma pharmacokinetic parameters (if applicable) will be summarized using descriptive
statistics (n, mean, SD, o%CV, geometric mean, geometric ohCV, median, minimum, and
maximum) treatment cohort, nominal dose, and day.
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Other PK parameters, as appropriate , frLy be determined or calculated at the discretion of the
PK scientist.
3.4 ExploratoryPharmacokinetic-PharmacodynamicAnalysis
Potential relationships between selected pharmacodynamic (e.g., mutant Htt protein) and
plasma post-distribution exposure (i.e., trough and post-treatment) measures may also be
explored, where deemed appropriate.
3.5 Exploratory Analyses
For the continuous exploratory variables, descriptive statistics (n, mean, standard effor,
standard deviation, median, Ql, Q3, minimum, and maximum) of the results, as well as the
change and percent change from baseline to each study visit, will be presented by treatment
group in summary tables; for the categorical variables, counts and percentages will be
provided. Where appropriate, inferential analyses will be conducted as described below.
The following exploratory endpoints will be summarized by treatment group as the above
method according to their data characteristics.
These analyses will be performed on the Per Protocol Set. If deemed appropriate, these
analyses may be repeated for the Safety Population or appropriate subset(s), as needed.
3.5.1 Biochemical
The results and change and percent change from baseline for CSF biomarkers and plasma
biomarkers at each visit will be summarized using descriptive statistics and compared
between each dose group and placebo using the ANOVA or Wilcoxon Rank Sum test, as
appropriate. The normality will be assessed using the Kolmogorov-Smirnov test on the
residuals.
Changes in mutant Htt in CSF and neurofilament light chain in CSF are key exploratory
endpoints for the study.
Considerable between-patient variability is expected in the baseline levels of CSF and plasma
biomarkers, and there may be patients with baseline levels that are comparable to a normal
(i.e., not diseased) state. In this event, additional analyses will be conducted to account for
differences in baseline (such as including baseline levels as covariates) and/or analyses will
be repeated on the subset of the analysis population with baseline levels that are abnormal.
3.5.2 NeuroimagingFindings
Whole brain volume, intraventricular volume and caudate volume assessed using MRI as
well as changes and percent changes from baseline at each visit will be summarized using
descriptive statistics and compared between each dose group and placebo using the ANOVA
or Wilcoxon Rank Sum test, as appropriate. The normality will be assessed using the
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Kolmogorov-Smirnov test on the residuals. Change in ventricular volume is a key
exploratory endpoint for the study.
Parameters characteizing connectivity between different brain regions will be determined
using rsfMRI and NODDI. These analyses will be conducted outside the scope of this SAP
by subject matter experts, and an independent report will be generated to describe the results.
3.5.3 qEEG
The primary endpoints obtained using quantitative EEG methods are the anterior-posterior
gradients of relative alpha and delta power, global alpha power, global delta power,
theta/alphaborder power and mean frequency at resting state with eyes closed. The values at
each visit as well as changes and percent changes from baseline at each visit will be
summarized using descriptive statistics and analyzed in a similar way to the brain volumes.
Data for anterior-posterior gradients of relative alpha and delta power, global alpha power,
global delta power,thetalalpha border power and mean frequency at resting state with eyes
open will be provided in the data listing.
3.5.4 UHDRS Total Functional Capacity Scale (TFC)
The TFC represents the Investigator's assessment of the patient's capacity to perform a wide
range of activities of daily living including occupation, finances, domestic chores, activities
of daily living and care level. It is based on a brief interview with the patient and the study
partner. Scores range from 0 to 13, and higher scores represent better functioning.
The TFC scores as well as changes and percent changes from baseline will be summarizedby
visit and analyzedin a similar way to the brain volumes.
3.5.5 UHDRS Independence Scale
The patient's independence scale is the Investigator's assessment of the patient's degree of
independence. The scale consists of 19 discrete levels ranging from 10 to 100 (bV 5) where
no special care needed corresponds to a scale of 100 and tube fed and total bed care
corresponds to a scale of 10. The Independence Scale as well as changes and percent changes
from baseline will be summarizedby visit and analyzedin a similar way to the brain volumes
data.
3.5.6 HD Work Function (HDWF) Scale
The HDWF scale is a measure of work role limitations and effort, which are areas that may
be affected by the cognitive, behavioral and motor changes associated with HD (Brossman et
al.2012). It was developed for prodromal HD, the stage prior to overt motor impairment and
HD diagnosis in which structural and functional brain changes lead to subtle changes in
cognition and motor function. Patients and their trial partners each complete a questionnaire
consisting of 20 questions, where the response to each is based on a 7-point Likert scale
ranglng from "not at all like me" to 'overy much like me". The HDWF scores for both patient-
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completed questionnaire and the trial-partner-completed questionnaire are the sums of the
individual question ratings, range from 20 to 140, and higher scores represent higher work
function ability.
For both the patient-completed HDWF and the trial-partner-completed HDWF, the scores as
well as changes and percent changes from baseline will be summarizedby visit and analyzed
in a similar way to the brain volume data.
3.5.7 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 six 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 six individual tests. The z-score for each
test will be calculated as follows:
(x-x)
s
Where i is the overall baseline mean and s is the baseline standard deviation.
This composite cognitive score is a key exploratory endpoint for the study. The individual
tests that comprise the battery are described below. The composite score, individual scores as
well as changes and percent changes from baseline will be summarizedby visit and analyzed
in a similar way to the brain volume data.
-Self-Paced Tapping
Self-paced tapping measures cognitive and motor timing. The patient listens to a repeating
tone at 3Hz and taps in time with the tone, alternating between left and right thumbs. The
patient continues to tap after the tone stops, attempting to maintain the same rate of tapping'
Four trials are conducted.
Scoring of each effort is based on the precision of taps, which is directly estimated, and
timing precision, which is calculated as the reciprocal of the standard deviation of the
intertap interval. Higher values indicate better performance, i.e., more consistent tapping
rates. The paced tapping dependent measure (consistency of the intertap intervals) is
computed using partial data if the participant does not complete the four trials within six
minutes. The data will be summarized by visit and analyzed in a similar way to the brain
volume data.
-Emotion Recognition
For this test, patients view faces depicting a neutral expression or an emotion (anger, disgust,
fear, sadness, surprise, happiness). After a practice trial for each category, the patient views
70 test trials and categorizes each face by emotion. The number of correct responses for
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negative emotions (anger, disgust, fear, sadness), out of 24 possible, is tallied (Johnson et al.
2007). The correct response number will be summarized by visit and analyzed in a similar
way to the brain volume data.
-CANTAB One Touch Stockings (OTS)
The OTS test measures executive function, spatial planning and working memory. On a
computer or tablet screen, the patient is shown two stacks of colored balls, which can be
perceived balls stacked in hanging socks or stockings. The patient must move the balls
between the stockings to achieve a particular color pattern. Rearranging the balls to make the
target pattern may take one, two, three or four moves. Then, the patient is shown two stacks
of colored balls and must determine, without moving the balls, the minimum number of
moves necessary to achieve the target pattern.
The outcome is the mean latency to correct response. Higher values indicated worse
performance (longer time to a correct response). The mean latency will be summarized by
visit and analyzed in a similar way to the brain volume data.
-Symbol Digit Modalities Test (SDMT)
The SDMT is used to assess attention, visuoperceptual processing, working memory and
psychomotor speed. It has been shown to have strong reliability and validity (Smith 1982;
Hinton-Bayre et al. Iggg). The patient must pair abstract symbols with specific numbers
according to a translation key. The test measures the number of items correctly paired
(maximum of I l0) in 90 seconds. The scores will be summarized by visit and analyzed in a
similar way to the brain volume data.
-Hopkins Verbal Learning Test - Revised (HVLT-R)
The HVLT-R is used to assess verbal memory through tests of recall and recognition' The
HVLT-R consists of a word list, containing12 words from three taxonomic categories, which
is read aloud to the patient at the rate of approximately one word every two seconds. The
Immediate Recall test includes three learning trials. Delayed Recall is assessed 20 to 25
minutes after completion of the Immediate Recall test. Immediately after administration of
the Delayed Recall tial, aforced-choice recognition test is administered. The recognition test
includes the 12 target words, plus 12 distractors (six semantically-related and six
semantically-unrelated words). Patients must recall a series of 12 words over three immediate
trials (leaming), free recall after a 25-minute delay and a recognition trial. The outcome
measure will be calculated as the sum of words correctly recalled over four trials (three
immediate and one delayed) with the maximum value of 48. The data will be summarized by
visit and analyzedin a similar way to the brain volume data.
-Trail-Making Test
The Trail-Making Test Part B (TMT-B) is a test of executive functioning. Patients are
presented with a picture of 25 circles, each labeled with a number (1 - 13) or a letter (A - L).
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The patient must draws lines to connect the circles in an ascending pattern that alternates
between the numbers and letters (i.e., L-A-2-B-3-C ...). The patient is instructed to connect
the circles as quickly as possible, and the time to complete the task is recorded.
The Trail-Making Test Part A (TMT-A) is also administered, but the results of the TMT-A
are not considered to be part of the battery. For the TMT-A, patients are presented with 25
circles, each labeled with a number (l-25) and are asked to connect the numbers.
Administration of TMT-A prior to TMT-B provides practice to aid in administering TMT-B'
Times to complete TMT-A and TMT-B, as well as changes and percent changes from
baseline will be summarized by visit and analyzed in a similar way to the brain volume data.
3.5.8 UHDRS Total Motor Scale (TMS)
The TMS is the sum of the individual motor ratings obtained during administration of the
motor assessment portion of the UHDRS, including ocular pursuit (horizontal and vertical),
saccade initiation (horizontal and vertical), saccade velocity (horizontal and vertical),
dysarthria, tongue protrusion, finger taps(right and left), pronate/supinate-hands (right and
left), luria (fist-hand palm test), rigidity-arms(right and left), bradykinesia-body, maximal
dystonia(trunk, rue, lue, rle and lle), maximal chorea (face, bol, trunk, rue, lue, rle and lle),
gait, tandem walking, and retropulsion pull test. Scores range from 0 to 124, and higher
scores represent more severe impairment.
The TMS scores will be summarized by visit and analyzed in a similar way to the brain
volume data.
3.5.9 Stroop Word Reading Test
The Stroop Word Reading Test is a measure of processing and psychomotor speed. Patients
are presented with a page of color names printed in black ink and are asked to read aloud as
many words as possible within a given amount of time. Scoring is based on the number of
correct responses in a fixed amount of time, typically within 45 seconds. Higher scoros
indicate better cognitive performance. The scores will be summarized by visit and analyzed
in a similar way to the brain volume data.
3.5.10 Map Search Test
The Map Search Test is a test of sustained visual attention. Patients are presented with a
visually cluttered map and asked to circle as many target symbols on the map as possible
within a fixed period of time. Scoring is based on the number of correctly identified symbols.
The scores will be summarized by visit and analyzed in a similar way to the brain volume
data.
3.5.11 Speeded TaPPing
The speeded tapping test is a measure of psychomotor speed and has been used as a
longitudinal marker of disease severity in manifest and pre-manifest HD. For the test, the
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patient taps the index finger of his/her non-dominant hand as quickly as possible for a l0
second period. The task is repeated with a brief rest period held between trials. The outcome
measure is the mean of the intertap intervals across taps from all trials, with higher values
indicating worse performance (i.e., slower tapping).
The data as well as change and percent change at each visit will be summarized using
descriptive statistics and analyzed in a similar way to the brain volume data.
3.5.12 Problems Behavior Assessment for lluntington's DiseasrShort Form (PBA-s)
The PBA-5 assesses common behavioral and psychiatric manifestations of HD, including
affect, irritability, loss of motivation, perseverative phenomena and psychotic symptoms.
The test administrator interviews the patient and trial partner and rates the patient's behavior
over the prior four weeks according to the guidelines for the test. The symptoms include
depressed mood, suicidal ideation, anxiety, irritability, angry or aggressive behavior, lack of
initiative (apathy), perseverative, obsessive-compulsive behaviors, delusions, hallucinations
and disoriented behavior. Each symptom is rated for severity, frequency and worst. Severity
and frequency scores will be multiplied to produce a PBA score for each symptom.
In addition, the following composite scores will also be calculated:
o Sum of the PBA scores for depressed mood, anxiety, and suicidal ideation
o Sum of the PBA scores for irritability and angry or aggressive behaviors
o Sum of the PBA scores for delusions and hallucinations and disoriented behavior
o Sum of the PBA scores for perseveration and obsessive-compulsive behaviors
The square roots of the individual PBA scores and the composites scores will be reported and
summarized by visit and analyzed in a similar way to the brain volume data.
3.5.13 Correlations between ISIS 443139 Exposure and Exploratory Endpoints
The following correlations are planned. The correlations will be evaluated using the Pearson
correlation coefficients and corresponding p-values. Other correlations may be conducted
based on findings in the by-visit analyses of exploratory endpoints'
o CSF mutant Httat latest from Day 85 or Day 113 and change in CSF mutant Htt
(baseline to latest from Day 85 or Day 113) versus concentration of ISIS 443139 in
CSF at latest from Day 85 or DaY 113
. CSF NFL at latest from Day 85 or Day 113 and change in CSF NFL (baseline to
latest from Day 85 or Day I 13) versus concentration of ISIS 443139 in CSF at latest
from Day 85 or Day 113
o CSF tau aI latest from Day 85 or Day 113 and change in CSF tau (baseline to latest
from Day 85 or Day 113) versus concentration of ISIS 443139 in CSF at latest from
Day 85 or Day 113
27


Ionis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
March 15,2018
ISIS 443139-CSI
a
a
a
a
Ventricular volume atDay 113 and Day 197 and change from baseline in ventricular
volume at each of these Days versus concentration of ISIS 443139 in CSF at latest
from Day 85 or Day 113
Whole brain volume at Day ll3 and Day 197 and change from baseline in whole
brainvolume at each of these Days versus concentration of ISIS 443139 in CSF at
latest from Day 85 or Day 113
HD Cognitive Battery composite score at Day 84,Day l4l and Day 197 and change
from baseline in HD Cognitive Battery composite score at each of these Days versus
concentration of ISIS 443139 in CSF at latest from Day 85 or Day 113
qEEG changes in anterior-posterior gradients of relative alpha and delta power atDay
113, Day l4l and Day 197 and change from baseline in anterior-posterior gradients
of relative alpha and delta power at each of these Days versus concentration of ISIS
443139 in CSF at latest from Day 85 or Day I l3
qEEG changes in global alpha power, global delta power, theta/alpha border power
and mean frequency atDay Il3,Day l4l and Day T97 and change from baseline in
global alpha power, global delta power, theta/alpha border power and mean frequency
at each of these Days versus concentration of ISIS 443139 in CSF at latest from Day
85 or Day 113
Changes in UHDRS-TMS atDay 84,Day 141 and Day 197 and change from baseline
in UHDRS-TMS at each of these Days versus concentration of ISIS 443139 in CSF at
latest from Day 85 or Day 113
O
3.5.14 Subset and Sensitivity Analyses
Patients enrolled into this study are early in the disease; therefore, for a given endpoint
parameter, there may be patients with baseline levels that are essentially normal (i.e., not
altered as would be expected in a diseased state). In these patients, there would be no ability
to measure an improvement in that parameter, which confounds interpretation of an analysis
that includes all patients. The confounding effect could be in either direction, i.e., it could
lead to a false positive or a false negative. Where appropriate based on the observed baseline
data, sensitivity and/or subset analyses will be conducted either to account for differences in
baseline within the analysis or to utilize a subset of the analysis population with baseline
levels reflective of a diseased state.
In addition, sensitivity analyses may be conducted if imbalances are detected in baseline
characteristics or when particular baseline characteristics, such as DBS or TFC, are
reasonably anticipated to impact the course of disease.
4.0 RnrrcnnNcE
5.0 AppnNDICES
28


Ionis Pharmaceuticals, lnc.
Statistical Analvsis Plan
Appendix A Schedule of Procedures
CONFIDENTIAL
March 15,2018
ISIS 443I39-CS1
Post-Treatment
Period
(15 Weeks)
29t
ETz
197
+7
cl
X
X
X
X
X
X
X
X
X
X
21
141
+7
cl
X
X
X
X
X
X
X
171
ET2
113
+t
cl
X
X
X
X
X
X
X
Treatment Evaluation Period
(13 Weeks)
14
92
!2
ph
13
87
*
ph
86
*
cl
Xd
X
85
+t
cl
X-
xa
Xb
xc
Xb
84
*
cl
X
X
X
X
X
10
64
t2
ph
9
59
*
ph
58
*
cl
Xd
X
57
t2
cl
X-
xa
xc
Xb
56
*
cl
X
X
X
X
6
36
x2
cl
X
X
5
31
*
ph
30
*
cl
Xd
X
29
+t
cl
X_
xa
xc
Xb
28
*
cl
X
X
X
X
2
+t
cl
X
X
1
3
ph
2
*
cl
xd
X
1
0
cl
X-
xa
xb
xc
Xb
,1
*
cl
X
X
X
X
X
X
Screen
-6 to -l
43to -2
cl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Period
StudyWeek
Study Day
Visit Window (days) *
Visit Type 
1
Cvernight Stay 3
Oapacity to Consent
lnstrument and lnformed
Consent
lnclusion/Exclusion
Medical History and ISCED
MoCA
VitalSigns (BP, HR, RR, T)
Orthostasis
)hysical& Neurological Exama
3ody Weight and Height 5
:unctional, Cognitive, Motor
and Neuropsychiatric
assessments 6
3-SSRS 7
qEEG
Structural MRI
12flair, T2 star, T2 FSE/TSE
MRI
MRI of the CSF space
IH-MRS
29


Ionis Pharmaceuticals, Inc.
Statistical Analvsis Plan
Appendix A Schedule of Procedures Continued
CONFIDENTIAL
March 15,2018
ISIS 443139-CSI
Post-Treatment
Period
(15 Weeks)
291
ET2
197
t7
cl
X
X
X
X
X
X
X
X
X
X
xh
Xh
X
X
21
141
+7
cl
X
X
X
X
X
X
X
X
X
xs
xs
X
X
17t
ET2
113
!2
cl
X
X
X
X
X
xs
xs
X
X
Treatment Evaluation Period
(13 Weeks)
14
92
!2
ph
X
X
13
87
*
ph
X
X
86
*
cl
xd
X
X
85
!2
cl
Xf
Xb
Xb
X
X
X
84
*
cl
X
X
X
X
X
X
X
X
X
X
10
64
t2
ph
X
X
I
59
*
ph
X
X
58
*
cl
X
X
57
+t
cl
xb
xb
Xb
X
X
X
56
*
cl
X
X
X
X
X
6
36
!2
cl
X
X
5
31
*
ph
X
X
30
*
cl
X
X
29
t2
cl
xb
xb
xb
X
X
X
28
*
cl
X
X
X
X
X
X
X
X
X
X
2
I
!2
cl
X
X
1
3
*
ph
X
X
2
*
cl
X
xd
X
X
1
0
cl
xe
Xb
Xb
X
X
X
-1
*
cl
X
X
X
X
X
X
X
X
X
X
X
Screen
-6 to -l
43to -2
cl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Period
StudyWeek
Study Day
Visit Window (days) .
Visit Type 
1
ECG (12-Lead) I
3hemistry Panel
lematology
Jrinalysis
Senetic Tests
HlV,HepatitisB&C
Drug/Alcohol Screen
FSH 9
Pregnancy Test 1o
Serum Biomarker Sample
Lipid and Thyroid Panels
]T, INR, aPTT
)lasma Sampling for PK
\rchived Serum Sample 
11
3SF Sample for
rt(Safety/Biomarkers
Archived CSF Sample
Study Drug Administration
Adverse Events
Concomitant Medications
30


Ionis Pharmaceuticals, Inc.
Statistical Analysis Plan
CONFIDENTIAL
March 15,2018
ISIS 443139-CS1
Appendix A Schedule of Procedures Continued
Note: lf not specifically labeled, "X" means anytime; ET = early termination
* 
Visit windows are calculated relative to Study Day 1. Note that within each block of visits associated with
dose administration, the visits must occur on 4 consecutive days. There are four "visit blocks" in this study:
(Study Days -1 , 1,2 and 3), (Study Days 28, 29, 30 and 31 ), (Study Days 56, 57, 58 and 59) and (Study
Days 84, 85, 86 and 87).
1 cl = clinic visit; ph = phone visit
2 lf the patient terminates early from the Treatment Period but is willing to participate in the Post-Treatment
period, (a) conduct the full biock of visits associated with the last dose received (see asterisk above), (b)
conduct'the visit scheduled for 7 days after the last dose received, (c) proceed to the Week 17 visit
approximately 4 weeks after last dose and conduct all visits in the Post-Treatment Period. lf the patient
terminates eirly trom the Treatment Period and is not willing to participate in the Post-Treatment Period, (a)
conduct the fuliblock of visits associated with the last dose received (see asterisk above), (b) conduct the
visit scheduled for 7 days after the last dose received and (c) conduct the Week 29 visit as an Early
Termination Visit. lf the patient terminates early from the Post-Treatment Period, conduct the Week 29 visit
as an Early Termination Visit.
3 On Study Day 1, the patient must stay in the clinic overnight and undergo safety monitoring follow-up as
scheduled on StuOy Day 2. On Study Days 29,57 and 85, the patient may either stay in the clinic overnight
or be discharged (ifter i minimum observation period of 6 hours after Study Drug administration), provided
the patient reiurns to the clinic on the following day (Day 30, 58 or 86) for all required assessments.
4 Full physical and neurological exam (including fundi) to be given at Screening and abbreviated physical (but
full neurological) exam to be given during Treatment and Post-treatment Periods as indicated to assess
changes from Screening.
5 Height is measured at Screening only.
6 Functional, Cognitive, Motor and Neuropsychiatric Tests are speeded tapping, UHDRS total functional
capacity scate, UHORS independence scale, UHDRS total motor scale, HD work function scale, HD
Cognitive Battery (self-paced tapping, emotion recognition, CANTAB one-touch stockings, symbol-digit
molalities test, Hopkins verbal learning test - revised and trail making tests), Problems Behavior
Assessment for Huntington's disease-short form, Stroop Word Reading test and Map Search test.
7 The C-SSRS must be administered on the study days shown. lt may also be administered at any time that
the lnvestigator feels is necessary.
8 Measured in triplicate at the Study Day -1 visit only.
9 Women who are not surgically sterile as confirmation of menopause'
1O Women who are not surgically sterile. Serum test at Screen visit; dipstick at post-screen visits.
11 Stored at -80o C for follow-up exploration of laboratory findings and/or adverse events (e.9., measurement of
cytokine and/or chemokine levels, measurement of additional markers of kidney function, measurement of
antibodies) in this or subsequent clinical studies of lSlS 443139.
Time (in reference to time of Study Drug administration):
a Predose, 3 and 6 hours post lT injection
b Predose
c 
Predose and 3 hours post lT injection; also conduct at 6 hours post lT injection on any dosing day that the
patient does not stay in the clinic overnight (overnight stays are optional on Study Days 29, 57 and 85)
d 24 hours after prior dose of Study Drug
e Predose, 0.5, 1, 2,3, 4,5, 6, 8 and 12 hours post lT injection
f 
Predose,0.5, 1 ,2,3,4 and 5 hours post lT injection
g Alt patients in Cohort A will have CSF collected on Study Day 113 (Week 17) and not on Study Day 141
- giek 21). For alt other cohorts, CSF sampling will be conducted in approximately 50% o! patients on
btuCy Oay 113 (Week 17) and in the remaining 50% of patients on Study Day 141 (Week 21), as assigned
by the Sponsor according to a predetermined, randomized assignment.
h CSF sampling will be conducted at Study Day 197 (Week 29) in only those patients who attend the visit as
an early termination visit and did not undergo CSF sampling on either Study Day '113 (Week 17) or Study
Oay 1it (Week 21). tf CSF samffig was conducted on Study Day 113 (Week 17) or Study Day 141 (Week
21), do not collect CSF at Study Day 197 (Week 29)
3l


ISIS 443139-CS1 
CONFIDENTIAL 
SAP 
Ionis Pharmaceuticals 
Version Changes 
1 
STATISTICAL ANALYSIS PLAN VERSIONS 
Protocol Number: 
ISIS 443139-CS1 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple 
Ascending Doses of Intrathecally Administered ISIS 443139 in Patients with 
Early Manifest Huntington’s Disease 
A list of changes to the statistical analysis plan are below: 
Version 
Description of Change 
Dates 
Original SAP 
No Changes 
11 Nov 2015 
Version 2 
•Updated study description to align with final protocol
•Updated select exploratory correlation analyses from utilizing exploratory 
endpoint values at Day 85 to utilizing exploratory endpoint values at the latter 
available of Day 85 and Day 113 because Day 113, though not available in all 
patients due to study design, is 28 days after the last dose of study drug and 
therefore serves as the best possible estimate of trough steady-state. 
Summary tables of raw and change data are planned for individual study days 
(e.g., Day 85 and Day 113) as well as for this defined endpoint (i.e., latter 
available of Day 85 and Day 113)
•Removed planned summaries of data that were ultimately entirely or largely 
missing due to unavailability of reliable laboratory assays, CSF volume 
limitations or data quality control failure
•Corrected formula for calculation of TMS
15 Mar 2018