Conditions: Hypertriglyceridemia Cardiovascular Diseases
Keywords: AKCEA-APOCIII-LRx IONIS-APOCIII-LRx Dyslipidemia Metabolic Disease Hyperlipidemia Cardiac Disease Lipid Metabolism Disorders Triglycerides High Vascular Diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 114
Healthy volunteers: no

Brief summary:
This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) levels in participants with hypertriglyceridemia and established CVD or at a high risk for CVD.

Detailed description:

Arms:
arm 1: Participants in each cohort (A, B, C and D) were randomized to receive placebo at a dose-matched volume of study drug (ISIS 678354). arm 2: Cohort A participants received 10 milligrams (mg) ISIS 678354, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses. arm 3: Cohort C participants received 15 mg ISIS 678354, SC injection, once every 2 weeks (Q2W) for up to 51 weeks and a maximum of 26 doses. arm 4: Cohort D participants received 10 mg ISIS 678354, SC injection, once weekly (QW) for up to 52 weeks and a maximum of 52 doses. arm 5: Cohort B participants received 50 mg ISIS 678354, SC injection, once Q4W for up to 49 weeks and a maximum of 13 doses.

Interventions: intervention 1: ISIS 678354 intervention 2: Placebo
Intervention descriptions: intervention 1: ISIS 678354 solution for SC injection. intervention 2: Sterile Normal Saline (0.9% NaCl).

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 
Study of ISIS 678354 Administered Subcutaneously to Patients With 
Hypertriglyceridemia and Established Cardiovascular Disease (CVD) or at a 
High Risk for CVD 
 
NCT03385239 
 
17-December-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Official Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 678354 Administered Subcutaneously to 
Patients with Hypertriglyceridemia and Established Cardiovascular 
Disease (CVD) or at High Risk for CVD 
NCT Number: 
NCT03385239 
Document Date: 
Protocol Amendment 3: 12 June 2019 


 
 
 
Sponsor: 
Akcea Therapeutics 
22 Boston Wharf Road, 9th Floor 
Boston, MA  02210 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
 
 
 
AKCEA THERAPEUTICS 
 
ISIS 678354-CS2 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 678354 Administered Subcutaneously to 
Patients with Hypertriglyceridemia and Established Cardiovascular 
Disease (CVD) or at High Risk for CVD  
 
Amendment 3 – 12 June 2019 
 
 






ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 678354-CS2 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 
Study of ISIS 678354 Administered Subcutaneously to Patients with 
Hypertriglyceridemia and Established Cardiovascular Disease (CVD) or at 
High Risk for CVD 
Amendment: 
Amendment 3 
Date: 
12 June 2019 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A 
Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 678354 
Administered Subcutaneously to Patients with Hypertriglyceridemia and Established 
Cardiovascular Disease (CVD) or at High Risk for CVD,” dated 12 June 2019, 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. and Akcea Therapeutics, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL SUMMARY OF CHANGES .............................................................................. 10 
PROTOCOL SYNOPSIS ........................................................................................................... 11 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 18 
STUDY GLOSSARY .................................................................................................................. 19 
1. 
STUDY OBJECTIVES ................................................................................................... 23 
1.1 
Primary Objective ..........................................................................................................23 
1.2 
Secondary Objectives ....................................................................................................23 
1.3 
Exploratory Objective ....................................................................................................23 
2. 
BACKGROUND AND RATIONALE .......................................................................... 23 
2.1 
Overview of Disease ......................................................................................................23 
2.1 
Therapeutic Rationale ....................................................................................................24 
2.3 
ISIS 678354 ...................................................................................................................28 
 
 
 
 
2.3.3 
Preclinical Experience ............................................................................................29 
2.3.4 
Clinical Experience ................................................................................................31 
2.4 
Rationale for Dose and Schedule of Administration .....................................................31 
3. 
EXPERIMENTAL PLAN .............................................................................................. 32 
3.1 
Study Design ..................................................................................................................32 
3.2 
Number of Study Centers ..............................................................................................33 
3.3 
Number of Patients ........................................................................................................33 
3.4 
Overall Study Duration and Follow-up .........................................................................33 
3.4.1 
Screening ................................................................................................................33 
3.4.2 
Treatment ................................................................................................................34 
3.4.3 
Post-Treatment .......................................................................................................34 
3.5 
End-of-Study ..................................................................................................................34 
3.6 
Data and Safety Monitoring Board ................................................................................34 
4. 
PATIENT ENROLLMENT ........................................................................................... 35 
4.1 
Screening .......................................................................................................................35 
4.2 
Randomization ...............................................................................................................35 
4.3 
Replacement of Patients .................................................................................................35 
4.4 
Unblinding of Treatment Assignment ...........................................................................35 
5. 
PATIENT ELIGIBILITY .............................................................................................. 36 
5.1 
Inclusion Criteria ...........................................................................................................36 
5.2 
Exclusion Criteria ..........................................................................................................37 
6. 
STUDY PROCEDURES ................................................................................................ 39 
6.1 
Study Schedule ..............................................................................................................39 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
6 
6.1.1 
Screening ................................................................................................................39 
6.1.2 
Treatment Period ....................................................................................................39 
6.1.3 
Post-Treatment Period ............................................................................................40 
6.2 
Additional Study Assessments .......................................................................................40 
6.2.1 
Laboratory Assessments .........................................................................................40 
6.2.2 
Physical Exams and Vital Signs .............................................................................41 
6.2.3 
Electrocardiography ...............................................................................................41 
6.2.4 
PK Sampling ...........................................................................................................42 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................42 
6.3.1 
Contraception Requirements ..................................................................................42 
6.3.2 
Other Requirements ................................................................................................43 
7. 
STUDY DRUG ................................................................................................................ 43 
7.1 
Study Drug Description .................................................................................................43 
7.1.1 
ISIS 678354 ............................................................................................................43 
7.1.2 
Placebo 43 
7.2 
Packaging and Labeling .................................................................................................43 
7.3 
Study Drug Accountability ............................................................................................44 
8. 
TREATMENT OF PATIENTS ..................................................................................... 44 
8.1 
Study Drug Administration ............................................................................................44 
8.2 
Other Protocol-Required Drugs .....................................................................................45 
8.3 
Other Protocol-Required Treatment Procedures ............................................................45 
8.4 
Treatment Precautions ...................................................................................................45 
8.5 
Safety Monitoring Rules ................................................................................................45 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................46 
8.5.2 
Safety Monitoring for Renal Function ...................................................................47 
8.5.3 
Safety Monitoring for Platelet Count Results ........................................................48 
8.5.4 
Safety Monitoring for Bleeding Events ..................................................................49 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................50 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose ...........50 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia ...................................50 
8.5.8 
Safety Monitoring for Hyperglycemia in Patients with T2DM .............................51 
8.6 
Stopping Rules ...............................................................................................................52 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................52 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................53 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................53 
8.6.4 
Stopping Rule for Bleeding ....................................................................................54 
8.7 
Adjustment of Dose .......................................................................................................55 
8.8 
Discontinuation of Study Drug ......................................................................................55 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................56 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
7 
8.9 
Withdrawal of Patients from the Study ..........................................................................56 
8.10 
Concomitant Therapy and Procedures ...........................................................................57 
8.10.1 
Concomitant Therapy .............................................................................................57 
8.10.2 
Concomitant Procedures .........................................................................................58 
8.11 
Treatment Compliance ...................................................................................................58 
8.12 
Safety Monitoring Compliance ......................................................................................58 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 59 
9.1 
Sponsor Review of Safety Information .........................................................................59 
9.2 
Regulatory Requirements ..............................................................................................59 
9.3 
Definitions .....................................................................................................................59 
9.3.1 
Adverse Event ........................................................................................................59 
9.3.2 
Adverse Reaction and Unexpected Adverse Reaction ...........................................59 
9.3.3 
Serious Adverse Event (SAE) ................................................................................59 
9.3.3.1 
Adverse Events of Special Interest ..................................................................60 
9.4 
Monitoring and Recording Adverse Events ...................................................................60 
9.4.1 
Serious Adverse Events/Adverse Events of Special Interest .................................60 
9.4.2 
Non-Serious Adverse Events ..................................................................................61 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................61 
9.4.3.1 
Relationship to the Study Drug ........................................................................61 
9.4.3.2 
Severity ............................................................................................................61 
9.4.3.3 
Action Taken with Study Drug ........................................................................62 
9.4.3.4 
Treatment Given for Adverse Event ................................................................62 
9.4.3.5 
Outcome of the Adverse Event ........................................................................62 
9.5 
Procedures for Handling Special Situations ..................................................................63 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................63 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............63 
9.5.3 
Dosing Errors .........................................................................................................64 
9.5.4 
Contraception and Pregnancy .................................................................................64 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 65 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................65 
10.1.1 
Primary Endpoint(s) ...............................................................................................65 
10.1.2 
Secondary Endpoints ..............................................................................................65 
10.1.3 
Safety Endpoints .....................................................................................................65 
10.1.4 
Dose Selection ........................................................................................................66 
 
66 
10.3 
Analysis Populations ......................................................................................................67 
10.4 
Definition of Baseline ....................................................................................................67 
10.5 
Interim Analysis .............................................................................................................67 
10.6 
Planned Methods of Analysis ........................................................................................67 
10.6.1 
Demographic and Baseline Characteristics ............................................................67 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
8 
10.6.2 
Safety Analysis .......................................................................................................68 
10.6.2.1 
Adverse Events ................................................................................................68 
10.6.2.2 
Clinical Laboratory Data ..................................................................................68 
10.6.2.3 
Vital Signs and Examinations ..........................................................................68 
10.6.3 
Efficacy Analysis ...................................................................................................68 
10.6.3.1 
Analysis of Primary Efficacy Endpoint ...........................................................68 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints ......................................................69 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................69 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 70 
11.1 
Informed Consent ..........................................................................................................70 
11.2 
Ethical Conduct of the Study .........................................................................................70 
11.3 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) .....................70 
11.4 
Patient Confidentiality ...................................................................................................71 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 71 
12.1 
Protocol Amendments ....................................................................................................71 
12.2 
Study Termination .........................................................................................................71 
12.3 
Study Documentation and Storage ................................................................................71 
12.4 
Study Monitoring ...........................................................................................................72 
12.5 
Language ........................................................................................................................73 
12.6 
Compensation for Injury ................................................................................................73 
13. 
REFERENCES ................................................................................................................ 74 
14. 
APPENDICES ................................................................................................................. 77 
Appendix A   Schedule of Procedures .......................................................................................78 
Appendix B   List of Laboratory Analytes ................................................................................86 
Appendix C   PK Sampling Schedule ........................................................................................88 
Appendix D   Grading Scale for Adverse Events Relating to Laboratory Abnormalities .........91 
Appendix E   Additional Laboratory Tests for Patients with Platelet Count ˂ 100,000/mm3 ...95 
 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................43 
Table 2 
Study Drug Dosing Information ............................................................................45 
Table 3 
Actions in Patients with Low Platelet Count .........................................................54 
 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
9 
TABLE OF FIGURES 
Page 
Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms ...............25 
Figure 2 
ApoC-III is a Multifunctional Protein....................................................................27 
Figure 3 
Design of ISIS 678354, a GalNAc3 Conjugated Chimeric 2′-MOE 
Phosphorothioate Oligonucleotide .........................................................................29 
 
 




ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
11 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-controlled, Dose-ranging Phase 2 Study of 
ISIS 678354 Administered Subcutaneously to Patients with Hypertriglyceridemia and 
Established Cardiovascular Disease (CVD) or at High Risk for CVD 
Study Phase 
2 
Indication 
Patients with hypertriglyceridemia and established CVD or at high risk for CVD. 
Investigational Drug 
ISIS 678354 is a second generation 2ʹ-MOE modified, GalNAc3–conjugated antisense 
oligonucleotide inhibitor of apolipoprotein C-III (apoC-III). 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of 
different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride 
(TG) levels in patients with hypertriglyceridemia and established CVD or at high risk for 
CVD. 
Secondary Objective(s) 
To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein C-III (apoC-III), 
total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), very low 
density lipoprotein cholesterol (VLDL-C), apolipoprotein B100 (apoB), and apolipoprotein 
A-1 (apoA-I). 
To evaluate pharmacokinetics (PK) of ISIS 678354 across different doses and dose 
regimens in patients with hypertriglyceridemia and established CVD or at high risk for CVD. 
Exploratory Objective(s) 
To evaluate the efficacy of ISIS 678354 on serum levels of lipoprotein (a) Lp(a) and 
angiopoietin-like 3 (ANGPTL3).   
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
After an up to 4-week screening period, including an up to 2-week qualification period 
following an at least a 2-week diet stabilization period, approximately 100 eligible patients 
will be randomized in a 4:1 ratio to receive ISIS 678354 or placebo.  Patients on stable diet 
known to the investigator and followed at the site may go from Screening to qualification 
period without a 2-week diet stabilization phase.  Study Drug (ISIS 678354 or placebo) will 
be administered by subcutaneous (SC) injection every week, every 2 weeks, or every 4 
weeks, depending on cohort assignment, for up to 52 weekly doses, up to 26 every 2-week 
doses, or up to 13 every 4-week doses.  Minimum treatment duration is 6 months.  
Maximum treatment duration is 12 months. 
The treatment portion of the study will be complete when the last patient reaches 6 months 
of exposure.  All patients still on treatment will then enter a 13-week post-treatment follow-
up period. Refer to Section 3.4.2 for additional detail regarding End of Treatment period 
and scheduling of End of Treatment Visits. 
The primary efficacy and safety analysis time point is at Week 25 for patients who received 
every 4-week dosing (Cohorts A-B) and at Week 27 for patients who received every 2-
week or weekly dosing (Cohorts C and D, respectively).  For patients continuing treatment 
beyond the primary analysis time point additional supportive efficacy and safety analyses 
will be repeated at the completion of Study Drug treatment. 
An independent Data and Safety Monitoring Board (DSMB) will be established to review 
safety, tolerability and efficacy data collected on ISIS 678354 during this study, both 
individual events and aggregate data. 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
12 
PROTOCOL SYNOPSIS Continued 
Number of Subjects 
Approximately 100 
Study Population  
Inclusion Criteria 
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. 
Males or females aged ≥ 18 and ≤ 80 years old at the time of informed consent 
3. 
a.    Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, 
or peripheral artery disease; refer to Section 3.1), or 
b.    High risk for CVD defined as: 
o 
Type 2 Diabetes Mellitus requiring treatment, and  
o 
Age ≥ 50 years, and  
o 
at least one additional CV risk factor: 
 
men ≥ 55 years of age and women ≥ 65 years of age, or 
 
current cigarette smoker, or stopped smoking within 3 months prior 
screening, or 
 
hypertension requiring antihypertensive treatment  
4. 
Fasting serum TG ≥ 200 mg/dL (≥ 2.3 mmol/L) and ≤ 500 mg/dL (≥ 5.7 mmol/L) at 
Screening.  If the fasting TG value at Screening is < 200 mg/dL (< 2.3 mmol/L) but 
≥ 150 mg/dL (≥ 1.7 mmol/L) one additional test may be performed in order to qualify 
5. 
Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.  If fasting TG is 
< 200 mg/dL but ≥ 150 mg/dL one additional test may be performed in order to qualify 
6. 
Must be on standard-of-care preventative therapy for their known CVD risk factors (e.g., 
hyperlipidemia, hypertension, diabetes) 
7. 
Patients on the following medications must be on a stable regimen for at least 4 weeks 
prior to Screening and expected to remain on a stable regimen through the end of the 
post-treatment follow-up period: 
a. 
Lipid lowering drugs (statins, ezetimibe, PCSK9 inhibitors, niacin, fibrates, fish oil or 
other products containing omega-3 fatty acids including OTC preparations) 
b. 
Antiplatelet drugs 
c. 
Testosterone, estrogens, progesterone, growth hormone or progestins 
8. 
Females:  must be non-pregnant and non-lactating and either:  
a. 
Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy); 
b. 
Post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 
55 years of age or, in females ≤ 55 years, 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 678354 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 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
13 
 
 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
 
9.     Males must be surgically sterile 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 ISIS 678354 
 
Exclusion Criteria 
1. 
Within 3 months of Screening:  acute coronary syndrome, major cardiac surgery, or 
stroke/transient ischemic attack  
2. 
Within 3 months of Screening:  coronary, carotid, or peripheral arterial 
revascularization, major non-cardiac surgery, or lipoprotein apheresis  
3. 
Heart failure NYHA class III and IV 
4. 
Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
5. 
History of acute kidney injury within 12 months of Screening 
6. 
Uncontrolled hyper or hypothyroidism  
7. 
Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
8. 
Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or 
chronic hepatitis B 
9. 
Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
10. Patients at high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse  
12. Hypersensitivity to the active substance or to any of the excipients 
13. Clinically-significant abnormalities in screening laboratory values that would render a 
patient unsuitable for inclusion, including the following: 
a. 
Positive test (including trace) for blood on urinalysis.  In the event of a positive 
test, eligibility may be confirmed with urine microscopy showing ≤ 5 red blood 
cells per high power field 
b. 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.   
c. 
Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney 
Disease-Epidemiological Collaboration (CKD-EPI) Equation  
d. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN 
e. 
Bilirubin > 1.2 x ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > 1.5 x ULN 
g. 
Platelet count ˂ LLN 
h. 
LDL-C > 130 mg/dL (> 3.4 mmol/L)  
14. Type 1 diabetes mellitus 
15. Type 2 diabetes mellitus with any of the following: 
a. 
Newly diagnosed within 12 weeks of Screening 
PROTOCOL SYNOPSIS Continued 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
14 
Study Population 
Continued 
 
b. 
HbA1c ≥ 9.0% at Screening 
c. 
Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of 
new medication within 12 weeks of Screening [with the exception of ± 10 units of 
insulin]) 
d. 
Anticipated need to change dose or type of medication during the treatment 
period of the Study (with the exception of ± 10 units for insulin) 
e. 
Current use of GLP-1 agonists, if patient has history of pancreatitis 
16. Use of warfarin or other vitamin K antagonists, direct thrombin inhibitors or factor Xa 
inhibitors 
17. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
18. Treatment with any non-Akcea/non-Ionis oligonucleotide (including small interfering 
ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis oligonucleotide or 
siRNA within 9 months of Screening.  Patients that have previously received only 1 
dose of an Ionis oligonucleotide as part of a clinical study may be included as long as 
≥ 4 months has elapsed since dosing 
19. BMI > 40 kg/m2  
20. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
21. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
22. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the Study 
Treatment Groups 
Patients will be randomized to 4 parallel cohorts (Cohorts A, B, C and D).   
Cohort A (n = 25):  Patients will be randomized 4:1 to receive 10 mg ISIS 678354 or 
placebo SC once every 4 weeks for up to 13 doses. 
Cohort B (n = 25):  Patients will be randomized 4:1 to receive 50 mg ISIS 678354 or 
placebo SC once every 4 weeks for up to 13 doses. 
Cohort C (n = 25):  Patients will be randomized 4:1 to receive 15 mg ISIS 678354 or 
placebo SC every 2 weeks for up to 26 doses. 
Cohort D (n = 25):  Patients will be randomized 4:1 to receive 10 mg ISIS 678354 or 
placebo SC every week for up to 52 doses. 
Cohort 
Treatment 
# Doses 
Total ISIS 678354 
A 
10 mg ISIS 678354 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 130 mg 
B 
50 mg ISIS 678354 or placebo  
(Every 4 weeks) 
≤ 13 
≤ 650 mg 
C 
15 mg ISIS 678354 or placebo 
(Every 2 weeks) 
≤ 26 
≤ 390 mg 
D 
10 mg ISIS 678354 or placebo 
(Every week) 
≤ 52 
≤ 520 mg 
 
 
PROTOCOL SYNOPSIS Continued 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol 
12 June 2019 
 
15 
Study Drug Dosage and 
Administration 
The Sponsor will provide ISIS 678354 in a concentration of 100 mg/mL and matching 
volume placebo: 
Cohort A:  10 mg every 4 weeks ISIS 678354 or placebo (0.10 mL) 
Cohort B:  50 mg every 4 weeks ISIS 678354 or placebo (0.50 mL) 
Cohort C:  15 mg every 2 weeks ISIS 678354 or placebo (0.15 mL) 
Cohort D:  10 mg every week ISIS 678354 or placebo (0.10 mL) 
All doses will be given by SC injection.  Self-administration will be allowed after appropriate 
training of patient and/or caregiver. 
Rationale for Dose and 
Schedule Selection 
The Phase 1 program evaluated ISIS 678354 doses of 15 mg and 30 mg given weekly and 
60 mg given every 4 weeks that were found to be generally well-tolerated and to induce 
clinically-relevant reductions in TG.  Four dosing regimens are planned for the present 
study, which are proposed to provide total monthly drug exposures equivalent to 10, 30, 40, 
and 50 mg administered as 10 mg every 4 weeks, 15 mg every 2 weeks, 10 mg every week, 
and 50 mg every 4 weeks, respectively. These doses are predicted to provide reductions 
from Baseline in serum TG ranging from approximately 30% to 64% at the end of the dosing 
interval at steady-state based on a preliminary PK/PD model developed using the available 
Phase 1 data. 
The present study will evaluate the safety and efficacy of ISIS 678354 in a 5-fold range of 
drug exposure utilizing 3 different dosing frequencies:  every 4 weeks, every 2 weeks, and 
weekly. Patients with hypertriglyceridemia will require chronic treatment and thus every       
2 weeks or every 4 weeks dosing regimens, if safe and well-tolerated, may provide 
advantages over weekly dosing in terms of convenience and compliance for patients.  The 
proposed range of doses are expected to provide sufficient data to characterize the dose- 
and exposure-response relationship. 
Adjustment of Dose 
and/or Treatment 
Schedule 
Dose adjustments, including dose interruptions, and/or decreasing the dose frequency may 
be allowed for safety or tolerability after consultation with the Sponsor Medical Monitor. 
Study Visit Schedule 
and Procedures 
Detailed information regarding the study procedures is outlined in Section 6. 
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
4 treatment cohorts.  On completion of the 6 months, patients will continue treatment within 
the same randomized cohort until the last patient reaches 6 months of exposure (for 
continuing safety assessments), with a maximal exposure period of 12 months. Refer to 
Section 3.4.2 for additional detail regarding End of Treatment period and scheduling of End 
of Treatment Visits. 
The study for an individual patient will generally consist of the following periods:  
• 
An up to 4-week screening period, including a up to 2-week qualification period 
following an at least 2-week diet stabilization period where appropriate 
• 
An up to 52-week treatment period during which Study Drug will be administered 
per assigned cohort by SC injection 
• 
A 13-week post-treatment follow-up period 
Patients in Cohorts A and B will receive up to 13 SC doses of ISIS 678354 or placebo every 
4 weeks.  Patients in Cohort C will receive up to 26 SC doses of ISIS 678354 or placebo 
every 2 weeks and patients in Cohort D will receive up to 52 SC doses of ISIS 678354 or 
placebo weekly.  Patients will return regularly for outpatient visits throughout the treatment 
and post-treatment follow-up periods according to the Schedule of Procedures 
(Appendix A).  
 
 
PROTOCOL SYNOPSIS Continued 


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Study Visit Schedule 
and Procedures 
Continued 
Blood and urine samples will be collected regularly throughout the study for safety, efficacy, 
and PK analysis.  Appendix B shows a list of analytes required for the study and Appendix C 
details the PK sample schedules. 
Safety and Tolerability 
Evaluations 
Safety and tolerability assessments include:  adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, ECGs (including serial ECGs in a subgroup 
of patients undergoing serial PK sampling) and use of concomitant medications.  Safety and 
tolerability results in patients receiving ISIS 678354 will be compared with those receiving 
placebo. 
Efficacy Evaluations 
The primary analysis time point is at 6 months (Week 25 for patients who received every 
4-week dosing (Cohorts A and B) and at Week 27 for patients who received every 2-week or 
weekly dosing (Cohorts C and D)). 
The primary endpoint is the percent change in serum TG from Baseline at the primary 
analysis time point for ISIS 678354 treatment groups compared to placebo. 
The secondary endpoints comprise the effect of ISIS 678354 as compared to placebo at the 
primary analysis time point on the following: 
• 
Percent change from Baseline in apoC-III, TC, LDL-C, HDL-C, non-HDL-C, 
VLDL-C, apoB, and apoA-I 
• 
Proportion of patients who achieve serum TG ≤ 150 mg/dL (≤ 1.7 mmol/L) 
Proportion of patients achieving TG ≤ 100 mg/dL (≤ 1.13 mmol/L) 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all patients for the measurement of ISIS 678354 plasma 
trough levels throughout treatment and during the post-treatment follow-up period.  In 
addition, in a subset of patients (approximately 10 patients per cohort), more frequent 
plasma samples will be taken following the first and Day 169 (for every week and every 
2-week dosing cohorts) or Day 141 (for every 4-week dosing cohort) dose to determine PK 
parameters.  Plasma sample collection time points are detailed in Appendices A and C. 
The plasma ISIS 678354 levels over time will be descriptively summarized by treatment with 
and without stratification by subject immunogenicity status.  Apparent terminal elimination 
half-life will be calculated in patients who received ISIS 678354 treatment using a 
non-compartmental method, if data permitted.  In addition, Cmax, Tmax, and AUC values will 
be calculated for the PK subgroup.  PK parameters will be descriptively summarized by 
treatment with and without stratification by subject immunogenicity status 
Statistical 
Considerations 
The primary efficacy analysis for the primary endpoint will be the pairwise comparison of 
percent change from Baseline to the primary analysis time point in fasting TG between ISIS 
678354 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the baseline TG level as a 
covariate. 
Dose selection for the further development will be based on the following efficacy and safety 
considerations; more than 1 dose may meet these criteria.  An effective dose, or dose 
regimen, will be one that achieves a clinically-meaningful reduction in serum TG levels.  
Safety will be evaluated on the basis of incidence of expected and unexpected treatment-
related SAEs, and other specific safety considerations including the incidence of platelet 
reductions. 
 
 
 




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STUDY DESIGN AND TREATMENT SCHEMA 
 
SCREENING PERIOD 
Weeks -4 to -1 
Qualification Period following 2-week 
diet stabilization period for patients not 
already on a stable diet 
TREATMENT PERIOD 
Weeks 1 to 52* 
Dosing per assigned cohort: 
Cohorts A and B:  Every 4 weeks SC 
administration of 10 or 50 mg ISIS 678354 or 
placebo 
Cohort C:  Every 2 weeks SC administration of 
15 mg ISIS 678354 or placebo 
Cohort D:  Every week SC administration of 10 mg 
ISIS 678354 or placebo 
Routine safety assessments:  PK and PD/efficacy 
assessments at specified time points 
*Treatment portion of the study will be complete 
when the last patient reaches 6 months of 
exposure. Refer to Section 3.4.2 for additional 
detail regarding End of Treatment period and 
scheduling of End of Treatment Visits. 
POST-TREATMENT 
EVALUATIONS 
3 clinical visits for safety, efficacy,  
PK and PD assessments during 13 
week after Treatment Period 
EARLY 
TERMINATION 
(ET) 
Follow Week 53 Schedule 
of Procedures at ET;  
Patient strongly 
encouraged to visit clinic 
for post-treatment 
assessments 
END-OF-STUDY 
PROCEDURES 
Early Termination or 3rd 
Follow-Up visit (13 Weeks 
after Treatment Period) 


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STUDY GLOSSARY  
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANCOVA 
analysis of covariance  
ANA 
antinuclear antibody 
ANGPTL3 
angiopoietin-like 3 
ApoA-1 
apolipoprotein A-1 
apoB 
apolipoprotein B 
apoC-III 
apolipoprotein C-III 
aPTT 
activated partial thromboplastin time 
ASGPR 
asialoglycoprotein receptor  
ASO 
antisense oligonucleotide 
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) 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
centigrade 
C5a 
complement factor C5a (activated complement split product) 
CAD 
coronary artery disease 
Cmax 
maximum concentration 
CBC 
complete blood count 
CKD-EPI 
Chronic Kidney Disease –Epidemiological Collaboration 
CMV 
cytomegalovirus 
CRF 
case report form 
CRP 
C-reactive protein 
 


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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
CVD 
cardiovascular disease 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
Cys-C 
cystatin 3 
dL 
deciliter 
DNA 
phosphorothioate-modified oligodeoxynucleotides 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ET 
early termination 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GalNAc3 
triantennary N-acetyl galactosamine 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
HAV 
hepatitis A virus 
HbA1c 
glycated hemoglobin  
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol  
HIV 
human immunodeficiency virus 
HOMA-IR 
homeostatic model assessment of insulin resistance 
hr, hrs 
hour(s) 
hsCRP 
C-reactive protein measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
 


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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 678354 
antisense inhibitor of apolipoprotein C-III 
IV 
intravenous(ly) 
IXRS 
interactive voice/internet response system 
KIM-1 
kidney injury molecule 1 
kg 
kilogram 
L 
liter 
LDL-C 
low density lipoprotein cholesterol 
LICA 
Lp(a) 
ligand conjugated antisense 
lipoprotein (a)  
m2 
square meter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm 
millimeter 
mRNA 
messenger ribonucleic acid 
NAG 
N-acetyl-β D-glucosaminidase 
NCS 
not clinically-significant 
NGAL 
neutrophil gelatinase-associated lipocalin 
Non-HDL-C 
non- high-density lipoprotein cholesterol 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PAD 
peripheral arterial disease 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
 


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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
PPS 
per protocol set 
PT 
prothrombin time 
RBC 
red blood cells 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA 
strand in RNA/DNA hybrids 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Drug 
ISIS 678354 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
TC 
total cholesterol 
TG 
triglyceride 
Tmax 
time to maximal concentration 
TSH 
thyroid stimulating hormone 
UACR 
urine albumin -creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein- creatinine ratio 
VLDL-C 
very low density lipoprotein cholesterol 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 


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1. 
STUDY OBJECTIVES 
1.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of 
different doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride (TG) 
levels in patients with hypertriglyceridemia and established cardiovascular disease (CVD) or at a 
high risk for CVD. 
1.2 
Secondary Objectives 
To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein C-III (apoC-III), total 
cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C), non-high density lipoprotein cholesterol (non-HDL-C), very low density 
lipoprotein cholesterol (VLDL-C), apolipoprotein B100 (apoB), and apolipoprotein A-1 
(apoA-I). 
To evaluate pharmacokinetics (PK) of ISIS 678354 across different doses and dose regimens in 
in patients with hypertriglyceridemia and established CVD or at a high risk for CVD. 
1.3 
Exploratory Objective  
To evaluate the efficacy of ISIS 678354 on serum levels of lipoprotein (a) (Lp(a)) and 
angiopoietin-like 3 (ANGPTL3).  
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Despite advances in diagnosis and treatment, CVD remains the most common underlying cause 
of death, being responsible for ~30% of all deaths in the United States, according to the Heart 
Disease and Stroke Statistics-2017 (Benjamin et al. 2017).  
Elevated low density lipoprotein cholesterol (LDL-C) has long been recognized and established 
as an independent risk factor for CVD, and therapies aimed to reduce LDL-C levels, such as 
statins which have been available for over 25 years, and PCSK9-inhibitors more recently, while 
showing a benefit in reduction of CV events (Cannon et al. 2006, Sabatine et al. 2017), have not 
changed the position of CVD as the leading cause of mortality in the western world.  Despite 
lowering LDL-C levels with these therapies, the residual CV risk remains high and the rate of 
major adverse cardiac events (MACE) ranges from 32% in a 6 year follow-up in the IMPROVE-
IT study with simvastatin/ezetimibe (Cannon et al. 2015) to 12% in a 3 year follow-up in the 
FOURIER study with PCSK9-inhibitor evolocomab (Sabatine et al. 2017).  These results 
indicate that to achieve further reduction in CV events other risk factors also need be addressed.  
An association between elevated TG levels (especially postprandial) and CV events has been 
suggested by several earlier observational studies (Hokanson et al.1996, Austin et al. 2000, 
Nordestgaard et al. 2007).  Subgroup analysis from PROVE-IT TIMI 22 study with atorvastatin 
showed that patients who continued to have TG level >150 mg/dL had an increased risk for 
future CV events despite achieving low LDL-C levels, while patients with normal TG levels 
achieved CV benefit from treatment with statins (Miller et al. 2008).  This finding has been 
recently confirmed by the large outcome trial and registry with bezafibrate (BIP) (> 15,000 


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patients with coronary heart disease followed for 22 years), demonstrating that elevated fasting 
TG levels were independently associated with increased mortality even after adjusting for other 
known risk factors (Klempfner et al 2016).  
Several non-statin drug therapies are currently available for the management of 
hypertriglyceridemia, including fibrates, niacin and omega-3 fatty acids.  Unfortunately, clinical 
trials that evaluated the use of these agents in addition to optimal statin therapy for CV event 
reduction failed to clearly show additional benefit (Ginsberg et al 2010, Guyton et al 2013, 
Roncaglioni et al 2013, Sampson et al 2012).  As a result of these negative trials and the potential 
harm of these agents the 2013 ACC AHA cholesterol guidelines currently do not recommend 
routinely adding TG lowering medications to statin therapy in patients with elevated TGs 
(Stone et al 2014).  
Taking into account the amount of data that links even mildly elevated TG levels to an increased 
risk for CV events, these negative results of current TG lowering drugs clearly indicate the 
unmet need for an effective TG-lowering agent in patients with, or at risk for, CVD.  
ApoC-III plays a pivotal role in regulating plasma TG levels (Sacks 2015), and elevated apoC-III 
levels have been shown to be an independent risk factor for CVD, especially when apoC-III is 
present on apolipoprotein B-containing lipoproteins (Sacks et al. 2000, Mendivil et al. 2011).  
Reduction of apoC-III levels by targeting apoC-III mRNA by ISIS 304801 antisense 
oligonucleotide (ASO) resulted in substantial lowering of TG levels in patients with 
hypertriglyceridemia (Gaudet et al. 2015). 
Therefore, the present study was designed to evaluate a new approach to lowering TG and   
apoC-III levels, specifically in high-risk patients, those with established CVD whose LDL-c 
levels are controlled by standard therapeutic strategies but whose elevated TG and apoC-III 
levels place them at continued risk of recurrent CV events, or in patients at high risk for CVD.  
The study will evaluate treatment efficacy using a range of doses and dose interval treatment 
cohorts, while further assessing the safety and tolerability of a ligand conjugated antisense 
(LICA)-based ASO in this indication.  
2.2 
Therapeutic Rationale 
Elevated triglyceride levels are thought to play an important role in development of 
atherosclerosis and subsequently CVD due to accumulation of TRL and their remnant cholesterol 
in the arterial wall.  ApoC-III is an integral part of this process. 
ApoC-III, a key regulator of plasma TG levels, is a 79 amino acid glycoprotein synthesized 
principally in the liver (Ooi et al. 2008, Figure 1).  Multiple apoC-III protein molecules reside on 
the surface of apoB-containing lipoproteins and high-density lipoprotein (HDL) and exchanges 
rapidly between these particles.  The majority of apoC-III is associated with triglyceride-rich 
lipoprotein (TRL) in hypertriglyceridemic patients.  In subjects with normolipidemia, the 
majority of the protein is associated with HDL (Chan et al. 2008). 


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Figure 1 
ApoC-III Regulates Lipoprotein Metabolism by Multiple Mechanisms 
From Ooi et al. 2008; ABCA1 = ATP-binding cassette A1, apo = apolipoprotein, CE = cholesterol ester, 
CETP = cholesterol ester transfer protein, FC = free cholesterol, HDL = high-density lipoprotein, 
HL = hepatic lipase, IDL = intermediate-density lipoprotein, LCAT = lecithin cholesterol acyltransferase, 
LDL = low-density lipoprotein, LDLr = LDL receptor, LPL = lipoprotein lipase, LSR = lipolysis-stimulated 
receptor, SR-B1 = scavenger receptor B-1, TG = triglyceride, VLDL = very low-density lipoprotein. 
The apoC-III gene is located in a cluster between the apolipoprotein A (apoA) apoA-I and apoA-
IV genes on chromosome 11q23 (Bruns et al. 1984).  ApoC-III expression is down-regulated, in 
part, by insulin via the insulin response element in the promoter of the apoC-III gene 
(Li et al. 1995).  More recent findings indicate that TRL carrying apoC-III impair insulin 
signaling in vascular endothelial cells and suggest that apoC-III could link dyslipidemia with 
endothelial dysfunction (Kawakami et al. 2006).  Regulation of transcription of the apoC-III 
gene is also mediated by peroxisome proliferator activated receptors (PPAR).  Activation of 
PPAR-α reduces apoC-III expression, accounting in part for the hypotriglyceridemic action of 
these compounds (Staels et al. 1995). 
ApoC-III is a potent inhibitor of LPL-catalyzed lipolysis of TRL, which antagonizes lipoprotein 
lipase (LPL) activation via apoC-III (Lemieux et al. 2003).  ApoC-III also inhibits hepatic lipase, 


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which plays an important role in the conversion of dense very low-density lipoprotein (VLDL) to 
intermediate-density lipoproteins (IDL) to low-density lipoprotein (LDL) (Mendivil et al. 2010), 
as well as in the remodeling of HDL (Brown et al. 2010).  ApoC-III has other recognized 
properties as a direct player in inflammation and atherogenesis, which may further contribute to 
its positive correlation with risk of coronary events.  ApoC-III stimulates the recruitment of 
blood monocytes to vascular endothelial cells by activating adhesion molecules on both cell 
types, and also promotes endothelial dysfunction (Kawakami et al. 2006).  Taken together, these 
results support the concept that apoC-III is a multifunctional protein that not only regulates the 
metabolism of TRL, but it is also influences endothelial function and cardiovascular risk 
(Figure 2). 
A growing body of human genetic data have demonstrated associations with functional 
mutations affecting apoC-III gene expression and CVD risk (Atzmon et al. 2006, 
Pollin et al. 2008, Petersen et al. 2010, Crosby et al. 2014, Jørgensen et al. 2014).  The 
Cholesterol and Recurrent Events (CARE) trial demonstrated that apoB particles containing 
apoC-III more strongly predicted coronary events than plasma TG levels (Sacks et al. 2000).  In 
a substudy of the CARE trial, the plasma concentration of LDL particles containing apoC-III was 
an independent risk factor for coronary events in patients with diabetes, supporting the role of 
apoC-III in promoting atherosclerosis (Lee et al. 2003).  Human genetic data have demonstrated 
positive phenotypic associations with loss (e.g., null or nonsense mutations) and negative effects 
with gain of function mutations.  Recently, a novel nonsense mutation in the apoC-III gene was 
identified in the heritability and phenotype intervention (HAPI) heart study in Old Order Amish 
that results in lower plasma apoC-III and TG levels and a cardioprotective profile characterized 
by lower LDL-C, increased high-density lipoprotein cholesterol (HDL-C) and reduced 
atherosclerosis (Pollin et al. 2008).  In another study involving a group of 214 Ashkenazi Jews of 
advanced age (had passed or nearly reached 100 years of age), genotype analysis revealed a 
polymorphism in the apoC-III gene (APOC3641CC genotype) with a clear pattern of age-
dependent frequency that was associated with significantly lower levels of apoC--III protein, a 
favorable lipoprotein profile, a lower incidence of hypertension, and greater insulin sensitivity, 
cardiovascular health, and longevity (Atzmon et al. 2006).  In contrast to the Amish and 
Ashkenazi apoC-III polymorphisms associated with lower plasma TG, apoC-III polymorphisms 
associated with higher plasma TG have been recently described as well (Petersen et al. 2010).  In 
a cohort of otherwise healthy, lean (mean body mass index [BMI] = 24.7 ± 3.6 kg/m2) Asian 
Indians, carriers of apoC-III variant alleles (C-482T, T-455C, or both) were noted to have 
significantly higher plasma apoC-III and TG levels, and decreased ability to clear post-prandial 
plasma TG from the circulation.  Furthermore, they were also noted to have an increased risk of 
nonalcoholic fatty liver disease (NAFLD) and insulin resistance compared to patients with 
homozygous wild-type alleles. 
In a recent study of 75,725 Danish participants, loss-of-function mutations in the apoCIII gene 
were associated with low levels of non-fasting triglycerides and a reduced risk of ischemic 
cardiovascular disease (Jørgensen et al. 2014).  An unrelated exome sequencing study found that 
rare loss-of-function mutations in apoC-III associated with triglycerides carry reduced risk of 
coronary heart disease in a population of European, African, and Hispanic ancestry in a database 
of 110,970 participants (Crosby et al. 2014). 


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Figure 2 
ApoC-III is a Multifunctional Protein 
ApoC-III modulates TG metabolism, enhances vasoconstriction, and enhances monocyte adhesion to 
endothelial cells.  These apoC-III-mediated effects may independently contribute to the risk of CVD.  From 
Caron and Staels 2008; EC = endothelial cell, ICAM-1 = intracellular adhesion molecule-1, NO = nitric oxide, 
TG = triglyceride, TLR2 = toll-like receptor-2, VCAM-1 = vascular cell adhesion molecule-1,  
VLDL = very low-density lipoprotein. 
Potential mechanisms that explain how apoC-III inhibition results in triglyceride reduction in 
patients with hypertriglyceridemia include:  (1) by enhancing the activity of LPL, (2) through 
potentially enhanced activity of other lipases also involved in the metabolism and breakdown of 
triglycerides, such as hepatic lipase or endothelial lipase (Kinnunen and Ehnolm 1976), and (3) it 
is known that apoC-III interacts with apoE, an important factor in liver reuptake of lipid particles 
by blocking apoE-mediated uptake of lipid particles in the liver (Breyer et al. 1999), and 
therefore, reducing apoC-III might enhance apoE-mediated uptake of lipid particles.  ISIS 
678354-mediated reduction of apoC-III could be contributing to one or all of these mechanisms 
resulting in the observed potent and sustained reductions in TG. 
In summary, inhibition of apoC-III by ISIS 678354 is expected to lower TRLs, and reverse the 
pro-inflammatory and proatherogenic effects of apoC-III.  Through this novel mechanism of 
action ISIS 678354 is expected to effectively lower TG levels and has potential to reduce CV 
risk in patients with hypertriglyceridemia.  






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• in monkeys, compared to baseline values, increases in glutamate dehydrogenase (GLDH) 
and ALT (up to ~5- and 4-fold over control, respectively) were observed at ≥ 6 mg/kg/wk 
(420 mg/wk human equivalent dose (HED) assuming 70 kg human body weight and 
direct scaling to humans on the basis of body weight) after 39 weeks of treatment with no 
microscopic correlates.  
• pro-inflammatory changes in mice and monkeys after up to 26 and 39 weeks of 
treatment, respectively, included slight increases in liver weights (up to ~1.6- and up to 
~2.1-fold over control) mainly at ≥ 6 and ≥ 12 mg/kg/wk in mice and monkeys, 
respectively.  Increased spleen weights (up to ~1.9- and up to ~2.5-fold over control) 
were also observed mainly at ≥ 6 and ≥ 12 mg/kg/wk in mice and monkeys, respectively.  
In mice, increased MCP-1 (up to 7.7-fold over control) was accompanied by 
splenomegaly and multi-organ vacuolated/granular macrophage infiltrates in the 
20 mg/kg/wk dose group. 
• in monkeys, sporadic incidences of minimal to marked mononuclear cell infiltration at 
injection site skin were seen in all dose groups.  
The most noteworthy finding in the monkey study was a marked PLT reduction, which occurred 
in one male monkey at the mid-high dose level, 12 mg/kg/wk (840 mg/wk HED).  At Day 65, 
this animal presented with petechia and oral mucosal bleeding with a PLT count of 8x103/µL. 
This animal was treated with methylprednisolone on Days 65 and 72, and the PLT count quickly 
recovered to 145x103/µL on Day 70.  This animal continued treatment with ISIS 678354, 
without a dosing holiday, until scheduled necropsy on Day 93 (interim) with the last clinical 
pathology evaluation on Day 93 again showing a marked reduction in PLT count (6x103/µL).  
Marked PLT reductions were not observed in the 30 mg/kg/wk dose group (2100 mg/wk HED) 
for up to 13 weeks or in any of the remaining dose groups for up to 39 weeks.  
 
In vivo safety pharmacology and in vitro genetic toxicity studies indicate that ISIS 678354: 
• had no effects on cardiovascular (blood pressure [BP], heart rate [HR], electrocardiogram 
[ECG]), respiratory (respiration rate, arterial blood gases), or central nervous system 
(CNS) parameters in the monkey consistent with previous experience with 2ʹ-MOE ASOs 
(Kim et al. 2014). 
• was not genotoxic and did not increase the rate of mutations in the in vitro bacterial 
reverse mutation assay nor induce chromosomal abnormalities in mammalian cells 
Taken together, these data support the evaluation of ISIS 678354 as a potential new therapeutic 
approach to reduce hepatic apoC-III expression in patients with elevated TGs to reduce 
triglycerides, potentially improve their insulin sensitivity and reduce CVD risk. 
Lower doses afforded by the GalNAc3 technology will reduce overall drug exposure in plasma, 
non-hepatocyte cells in the liver, and kidney.  Therefore, ISIS 678354 has the possibility of 
delivering similar efficacy results with lower dose levels and thereby fewer class-related adverse 
effects. 


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2.3.4 
Clinical Experience  
Detailed information concerning the clinical study conducted with ISIS 678354 can be found in the 
Investigator’s Brochure. A summary of the study that has been conducted with ISIS 678354 is 
included below. 
ISIS 678354-CS1 was a Phase 1, double-blind, placebo-controlled, dose escalation study 
designed to assess the safety, tolerability and pharmacokinetics of single and multiple doses of 
ISIS 678354 administered by subcutaneous (SC) injection to healthy subjects (age 18 to 65).  In 
the single ascending dose (SAD) part of the study, five dose levels (10, 30, 60, 90, and 120 mg) 
were evaluated sequentially. In the multiple ascending dose (MAD) part, two dose levels (15 and 
30 mg) were evaluated at weekly dosing for 6 weeks and one dose level (60 mg) was evaluated 
at every 4-week dosing for 3 months.  The SAD and weekly MAD dose levels were studied in a 
cohort of 8 subjects, where 6 were randomized to active treatment with ISIS 678354 and 2 were 
randomized to placebo.  In the every 4-week MAD cohort 10 subjects were studied (6 active and 
4 placebo).  In the 90 and 120 mg SAD and all of the MAD cohorts, the pharmacodynamic 
effects of ISIS 678354 vs. placebo were examined in healthy subjects with elevated triglycerides 
(TG > 200 mg/dL).   
Results from the SAD portion of the Phase 1 study showed significant dose-dependent sustained 
reductions in fasting total apoC-III and TG levels.  ApoC-III reductions of -4%, -32%, -65%, -
78%, and -91%, and TG reductions of -12%, -11%, -43%, -68%, and -77% were observed with 
single doses of 10, 30, 60, 90 and 120 mg of ISIS 678354 respectively 14 days after dosing.  In 
the MAD cohorts, mean apoC-III reductions of -65%, -84%, and -83% and mean TG reductions 
of -61%, -71%, and -65% were observed in the 15 and 30 mg weekly and 60 mg every 4-week 
dosing cohorts, respectively, 1 week after the last dose.  Significant dose-dependent reductions of 
up to ~-30% in apoB and increases of up to ~100% in HDL-C were also observed.  There were 
no notable increases in LDL-C in any dose group.  Effects were sustained for at least 4 weeks 
after the last dose, consistent with the drug’s long terminal elimination half-life. 
Overall, ISIS 678354 was well tolerated and there were no safety concerns. There were no 
deaths, no serious adverse events related to ISIS 678354, no adverse events leading to treatment 
discontinuation, and no clinically-significant trends in laboratory assessments observed in any of 
the ISIS 678354 Phase 1 dose groups.  Elevations in ALT > 3x ULN were reported as treatment-
related in 2 ISIS-678354-treated subjects in MAD every-4-week cohort (60 mg).  Both subjects 
had prior history of ALT elevation. There were no other treatment related laboratory 
abnormalities in the liver, kidney function or platelet counts and no clinically significant changes 
in vital signs or ECGs in any cohort studied. 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 678354 doses of 15 mg and 30 mg given weekly and 60 mg 
given every 4 weeks that were found to be generally well-tolerated and to induce clinically-
relevant reductions in TG. Four dosing regimens are planned for the present study, which are 
proposed to provide total monthly drug exposures equivalent to 10, 30, 40, and 50 mg 
administered as 10 mg every 4 weeks, 15 mg every 2 weeks, 10 mg every week, and 50 mg 
every 4 weeks, respectively. These doses are predicted to provide reductions from Baseline in 
serum TG ranging from approximately 30% to 64% at the end of the dosing interval at steady-
state based on a preliminary PK/PD model developed using the available Phase 1 data. 


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The present study will evaluate the safety and efficacy of ISIS 678354 in a 5-fold range of drug 
exposure utilizing 3 different dosing frequencies:  every 4 weeks, every 2 weeks, and 
weekly. Patients with hypertriglyceridemia will require chronic treatment and thus every 2 weeks 
or every 4 weeks dosing regimens, if safe and well-tolerated, may provide advantages over 
weekly dosing in terms of convenience and compliance for patients.  The proposed range of 
doses are expected to provide sufficient data to characterize the dose- and exposure-response 
relationship. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  After 
an up to 4-week screening period, including an up to 2-week qualification period following an at 
least a 2-week diet stabilization period, where appropriate, approximately 100 eligible patients 
will be randomized in a 4:1 ratio to receive ISIS 678354 or placebo.  Patients on a stable diet 
known to the investigator and followed at the site may go from Screening to qualification period 
without a 2-week diet stabilization phase.  Study Drug (ISIS 678354 or placebo) will be 
administered by subcutaneous (SC) injection every week, every 2 weeks, or every 4 weeks, 
depending on cohort assignment, for up to 52 weekly doses, up to 26 every 2-week doses, or up 
to 13 every 4-week doses.  Minimum treatment duration is 6 months.  Maximum treatment 
duration is 12 months 
The treatment portion of the study will be complete when the last patient reaches 6 months of 
exposure.  All patients still on treatment will then enter a 13-week post-treatment follow-up 
period. Refer to Section 3.4.2 for additional detail regarding End of Treatment period and 
scheduling of End of Treatment Visits. 
The primary efficacy and safety analysis time point is at Week 25 for patients who received 
every 4-week dosing (Cohorts A and B) and at Week 27 for patients who received every 2-week 
or weekly dosing (Cohorts C and D, respectively).  For patients continuing treatment beyond the 
primary analysis time point additional supportive efficacy and safety analyses will be repeated at 
the completion of Study Drug treatment. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma TG levels (≥ 200 mg/dL (≥ 2.3 mmol/L) 
and ≤ 500 mg/dL (≥ 5.7 mmol/L)) and a clinical diagnosis of CVD or at high risk for CVD are 
eligible for enrollment upon meeting the study specific eligibility criteria.  Patients will be on 
standard-of-care preventative therapy for known CVD risk factors as per current guidelines. 
Clinical diagnosis of CVD is defined as documented coronary artery disease (CAD), stroke, or 
peripheral artery disease (PAD).  A diagnosis of CAD has to be documented by any of the 
following: 
• Angiographic evidence of ≥ 50% stenosis of 1 or more major epicardial coronary arteries 
• History of myocardial infarction documented by positive enzymes, and either symptoms 
of myocardial ischemia, or ECG changes (Thygesen et al. 2012) 
• History of coronary revascularization 


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• Evidence of cardiac ischemia on exercise testing, or imaging study 
Patients at a high risk for CVD are defined using the following criteria: 
• Type 2 Diabetes Mellitus requiring treatment, and  
• Age ≥50 years, and  
• at least one additional CV risk factor: 
o men ≥55 years of age and women ≥65 years of age, or 
o current cigarette smoker, or stopped smoking within 3 months prior screening, or 
o hypertension requiring antihypertensive treatment  
Patients will be evaluated for study eligibility during Screening, which takes place within 
4 weeks prior to Day 1 (the first day of Study Drug administration) and will include an at least a 
2-week diet stabilization period followed by an up to 2-week qualification period.  Patients on 
stable diet known to the investigator and followed at the site may go from Screening to 
qualification without a 2-week diet stabilization phase.  Patients who are determined to be 
eligible, based on screening assessments, will be enrolled in the study at Day 1 and randomly 
assigned to 1 of the 4 parallel dosing cohorts, with each cohort having a 4:1 ratio to receive ISIS 
678354 or matching volume of placebo, respectively, by SC injection for up to 52 weeks.   
Following the End-of-Treatment, patients will enter the 13-week post-treatment follow-up 
period. 
3.2 
Number of Study Centers 
This is a multicenter, multinational study. 
3.3 
Number of Patients 
Approximately 100 patients will be randomized in this study, with approximately 25 patients 
assigned to each of the 4 treatment cohorts. 
3.4 
Overall Study Duration and Follow-up 
The length of patients’ participation in the study may be up to approximately 16 months 
(69 weeks), which includes a 4-week screening period that includes a 2-week diet 
stabilization/run-in period for patients not already on a stable diet, and a 2-week qualification 
period, an up to 52-week treatment period, and a 13-week post-treatment follow-up period.  The 
treatment portion of the study will be complete when the last patient reaches 6 months of 
exposure. 
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Study 
Medical Monitor in consultation with the Investigator. 
3.4.1 
Screening 
Patient eligibility for the study will be determined within 4 weeks prior to study. 


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3.4.2 
Treatment 
For each patient, minimum treatment duration is 6 months and a maximum of 52 weeks.  
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
4 treatment cohorts.  On completion of the 6 months, patients will continue treatment within the 
same randomized cohort until the last patient reaches 6 months of exposure (for continuing 
safety assessments), with a maximal exposure period of 12 months.  The End of Treatment visits 
for all patients on treatment will be scheduled no later than the End of Treatment visit of the last 
patient to complete 6 months of exposure.   
The End of Treatment visit should be scheduled one dosing interval post last dose of study drug: 
one week post last dose for weekly dosing (Cohort D), 2 weeks post last dose for every 2-week 
dosing (Cohort C), and 4 weeks post last dose for every 4-week dosing (Cohorts A-B).  The 
procedures scheduled for the Week 53/ET visit (Appendix A) will be performed at the End of 
Treatment visit.  Following the End of Treatment visit patients will then enter a 13-week post-
treatment follow-up period.    
Eligible patients will report to the Study Center for assessments at specified intervals throughout 
the 52-week treatment period as detailed in the Schedule of Procedures in Appendix A.  During 
the Treatment, Study Drug (ISIS 678354 or placebo) will be administered by SC injection 
once-weekly, every 2 weeks, or every 4 weeks, depending on cohort assignment. 
3.4.3 
Post-Treatment 
Patients, when completed dosing, will enter the 13-week post-treatment follow-up period and 
will return to the Study Center for 3 follow-up visits at 4, 8, and 13 weeks post End of Treatment 
period as per Appendix A (Follow-up). 
The final study visit for each patient will be 13 weeks post End of Treatment period.  End of 
Treatment period is defined as one dosing interval post last dose. 
3.5 
End-of-Study 
The End-of-Study is defined as last patient, last visit.  
For individual patients, End-of-Study is defined as completion of their last study visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and efficacy (as needed) data collected on ISIS 678354 during this study.  Based on 
its ongoing assessment of the safety and tolerability of ISIS 678354, 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 Statistical Analysis Plan (SAP). 


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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 directed 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.  The screening number and 
patient identification number must remain constant throughout the entire trial.  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 
Patients will be randomized after all screening assessments have been completed and after the 
Investigator has verified that they are 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. 
Using an Interactive Web-Response System (IXRS), eligible patients will be randomized in a 
1:1:1:1 ratio to 1 of the 4 parallel-dose cohorts (Cohorts A, B, C, or D).  Within each dose cohort, 
patients will be randomized in a 4:1 ratio to receive ISIS 678354 or matching volume of placebo, 
respectively.   
A permuted block schedule will be used.  The randomization schedule will be generated and held 
by an independent vendor. 
4.3 
Replacement of Patients 
Patients who withdraw from the study 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 and until all patients have completed the study and the database has 
been locked.  However, if a patient has suffered an 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 using 
the IXRS.  The Sponsor will determine the point at which all treatment assignments will be 
unblinded.  The Sponsor or designee will be informed of the unblinding of a patient within 
24 hours.  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). 


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5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
within 4 weeks of Study Day 1 or at the time point specified in the individual eligibility criterion 
listed. 
5.1 
Inclusion Criteria 
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. Males or females aged ≥ 18 and ≤ 80 years old at the time of informed consent 
3. a.    Clinical diagnosis of CVD (defined as documented coronary artery disease, stroke, or 
peripheral artery disease; refer to Section 3.1), OR 
b.    High risk for CVD defined as: 
o Type 2 Diabetes Mellitus requiring treatment, and  
o Age ≥ 50 years, and  
o at least one additional CV risk factor: 
 men ≥ 55 years of age and women ≥ 65 years of age, or 
 current cigarette smoker, or stopped smoking within 3 months prior 
screening, or 
 hypertension requiring antihypertensive treatment  
4. Fasting serum TG ≥ 200 mg/dL (≥ 2.3 mmol/L) and ≤ 500 mg/dL (≥ 5.7 mmol/L) at 
Screening.  If the fasting TG value at Screening is < 200 mg/dL (< 2.3 mmol/L) but 
≥ 150 mg/dL (≥ 1.7 mmol/L) one additional test may be performed in order to qualify 
5. Fasting TG ≥ 200 mg/dL and ≤ 500 mg/dL at Qualification visit.  If fasting TG is 
< 200 mg/dL but ≥ 150 mg/dL one additional test may be performed in order to qualify 
6. Must be on standard-of-care preventative therapy for their known CVD risk factors (e.g., 
hyperlipidemia, hypertension, diabetes) 
7. Patients on the following medications must be on a stable regimen for at least 4 weeks 
prior to Screening and expected to remain on a stable regimen through the end of the 
post-treatment follow-up period: 
a. Lipid lowering drugs (statins, ezetimibe, PCSK9 inhibitors, niacin, fibrates, fish oil or 
other products containing omega-3 fatty acids including OTC preparations) 
b. Antiplatelet drugs 
c. Testosterone, estrogens, progesterone, growth hormone or progestins 
8. Females:  must be non-pregnant and non-lactating and either:  
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy); 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in 
females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous 
amenorrhea without an alternative medical cause and FSH levels in the 
postmenopausal range for the laboratory involved); 


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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 
678354 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 
9. Males must be surgically sterile 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 ISIS 678354 
5.2 
Exclusion Criteria 
1. Within 3 months of Screening:  acute coronary syndrome, major cardiac surgery, or 
stroke/transient ischemic attack  
2. Within 3 months of Screening:  coronary, carotid, or peripheral arterial revascularization, 
major non-cardiac surgery, or lipoprotein apheresis  
3. Heart failure NYHA class III and IV 
4. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
5. History of acute kidney injury within 12 months of Screening 
6. Uncontrolled hyper or hypothyroidism  
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
8. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C 
or chronic hepatitis B 
9. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated 
10. Patients at high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse  
12. Hypersensitivity to the active substance or to any of the excipients 
13. Clinically-significant abnormalities in screening laboratory values that would render a 
patient unsuitable for inclusion, including the following: 
a. Positive test (including trace) for blood on urinalysis.  In the event of a positive test, 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per 
high power field 
b. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  


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c. Estimated GFR ˂ 60 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation  
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN 
e. Bilirubin > 1.2 x ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. Alkaline phosphatase (ALP) > 1.5 x ULN 
g. Platelet count ˂ LLN 
h. LDL-C > 130 mg/dL (> 3.4 mmol/L)  
14. Type 1 diabetes mellitus 
15. Type 2 diabetes mellitus with any of the following: 
a. Newly diagnosed within 12 weeks of Screening 
b. HbA1c ≥ 9.0% at Screening 
c. Recent change in anti-diabetic pharmacotherapy (change in dosage or addition of new 
medication within 12 weeks of Screening [with the exception of ± 10 units of 
insulin]) 
d. Anticipated need to change dose or type of medication during the treatment period of 
the Study (with the exception of ± 10 units for insulin) 
e. Current use of GLP-1 agonists, if patient has history of pancreatitis 
16. Use of warfarin or other vitamin K antagonists, direct thrombin inhibitors or factor Xa 
inhibitors 
17. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
18. Treatment with any non-Akcea/non-Ionis oligonucleotide (including small interfering 
ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis oligonucleotide or 
siRNA within 9 months of Screening.  Patients that have previously received only 1 dose 
of an Ionis oligonucleotide as part of a clinical study may be included as long as 
≥ 4 months has elapsed since dosing 
19. BMI > 40 kg/m2  
20. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
21. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
22. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the patient unsuitable for inclusion, or could interfere with the patient participating 
in or completing the Study 


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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, and C. 
6.1.1 
Screening 
Written informed consent for the study will be obtained prior to the performance of any study-
related procedures including screening procedures.  An up to 4-week period is provided for 
completing screening assessments and determining patient eligibility for the study.  Abnormal 
screening results may be re-tested once for determination of patient eligibility after consultation 
with the Sponsor Medical Monitor.  Patients may be re-screened 1 time in order to determine 
eligibility. 
During the screening period, patients will undergo a medical history and physical examination 
including vital signs, 12-lead electrocardiogram (ECG) and have blood and urine samples taken 
for clinical laboratory testing.  Patients will be screened for HIV, hepatitis B, and hepatitis C. 
As part of the screening period, patients not already on a stable diet will have 2 weeks of diet 
run-in, followed by a qualification visit, during which final eligibility assessments will be 
performed.  Patients on a stable diet, known to the investigator and followed at the site, may go 
from Screening to qualification without a 2-week diet run-in.  At the qualification visit TGs will 
be measured.   
6.1.2 
Treatment Period 
Treatment period is defined as the time between the first and the last doses of study drug plus 
one dosing interval. During the treatment period, patients will report to the study center for clinic 
visits.  Patients will receive 10 mg doses of Study Drug administered by SC injection once every 
4 weeks for up to 49 weeks in Cohort A, 50 mg doses of Study Drug administered by SC 
injection once every 4 weeks for up to 49 weeks in Cohort B, 15 mg doses of Study Drug 
administered by SC injection once every 2 weeks for up to 51 weeks in Cohort C, or 10 mg doses 
of Study Drug administered by SC injection once per week (weekly) for up to 52 weeks in 
Cohort D (Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 678354 plasma concentrations, immunogenicity and 
biomarker samples, AEs and concomitant medication/procedure information will be performed 
according to the Schedule of Procedures in Appendix A. 
Extensive Pharmacokinetic (PK) Subgroup Only: 
Within each cohort, a subgroup of approximately 10 patients, who will consent to extensive PK 
sampling, will undergo additional PK sampling, in what is referred to as the PK Subgroup in this 
study.  Patients in this subgroup will have additional PK sampling time points in order to 
evaluate the plasma PK parameters of ISIS 678354.  Patients in this subgroup will have 
additional visits to the clinic during the treatment period in order to collect blood samples for PK 
assessment (Appendix C). 


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6.1.3 
Post-Treatment Period 
Each patient will be followed for safety assessments for 13 weeks post end of treatment period.  
During the post-treatment follow-up period, patients will return to the Study Center for 
3 outpatient visits as outlined in Appendix A for safety and clinical laboratory evaluations and 
for blood sampling for PK (Appendices A and C). 
6.2 
Additional Study Assessments 
6.2.1 
Laboratory Assessments  
Laboratory analyte samples will be collected throughout the study as per the Schedule of 
Procedures in Appendix A.  A list of these analytes is contained in Appendix B. 
Routine blood chemistry and urine samples should be taken after fasting for at least 10 hours and 
preferably not more than 12 hours.  Any confirmatory test, or test taken for safety reasons, may 
be taken at any time, irrespective of fasting status, but no later than 7 days after the initial result 
is obtained.  During preparation for fasting samples, the patient can drink water and they should 
ensure that they consume sufficient water in order to not become dehydrated.  
If tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or 
missing, a repeat blood or urine specimen should be re-drawn as soon as possible (ideally within 
1 week). 
While on treatment, hematology samples will be collected every 14 days (±2 days).  Each time a 
hematology lab is drawn and sent to the central laboratory for analysis, an additional sample 
should be collected in parallel and analyzed locally.  In the event that both the central and local 
samples are unreportable (e.g., due to hemolyzed or clumped blood samples), patient dosing 
cannot continue until another sample is repeated and determined not to have met a platelet 
stopping rule. 
If there is no reportable platelet count within 14 days of the last platelet count, the Investigator 
will contact the patient to hold dosing until a new platelet count is obtained and reviewed. 
While on treatment blood and urine samples for renal function testing will also be collected 
every 14 days (±2 days) and sent to the central laboratory for analysis for the first 3 months of 
the study treatment, and monthly thereafter during the Treatment Period per Section 8.5.2.  
While on treatment liver function testing will also be collected every 14 days (±2 days) and sent 
to the central laboratory for analysis for the first 3 months of the study treatment, and monthly 
thereafter during the Treatment Period per Section 8.5.1.   
All lab samples are to be sent to the central laboratory by overnight courier and processed.  Lab 
Alerts issued as per protocol safety monitoring requirements or stopping rules will indicate the 
applicable protocol section to facilitate review and will be immediately and simultaneously sent 
by email to the Investigator, the Sponsor and the CRO Medical Monitors, the Sponsor Drug 
Safety Physician, and the Clinical Trial Manager (CTM), and should be received by them within 
2 days from sample collection.  Hematology results from the site’s local laboratories are received 
by the study center staff per the local laboratories’ standard reporting time, and should be entered 
as soon as possible into the eCRF to inform the Sponsor and CRO study monitoring teams. 


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All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator, or designee, to ensure that the count has not met the stopping rule and to determine 
whether the rate of decline is suggestive that the patient could be approaching the dose 
interruption rule of 75,000/mm3 as specified in Section 8.6.3.  Any case of a platelet count 
reduction to levels below 50,000/mm3 is considered an adverse event of special interest and must 
be reported in an expedited fashion to the Sponsor as per Sections 9.3.3.1 and 9.4.1. 
All liver and renal function tests must also be reviewed promptly (within 48 hours of receipt) by 
the Investigator, or designee, to ensure that the result has not met the stopping rule.  Any event 
meeting renal stopping rules criteria described in Section 8.6.2 is considered an adverse event of 
special interest and must be reported in an expedited fashion to the Sponsor as per 
Sections 9.3.3.1 and 9.4.1. 
All lab alerts received, including those related to platelet, liver, or renal function 
monitoring/stopping rules, are also reviewed promptly by the Sponsor and the CRO Medical 
Monitors who will agree on actions to be taken.  Within 24 hours of receiving an actionable lab 
alert the CRO Medical Monitor will communicate instructions to the Investigator and the study 
personnel by emailing them the Safety Surveillance Form that needs to be completed and signed 
by the Investigator/study personnel and promptly returned to the Sponsor and CRO Medical 
Monitor.  In urgent cases, such as platelets results below 50,000/mm3, or liver or renal test results 
reaching a critical stopping rule, the Investigator must also be contacted by phone.  
Further information on safety monitoring and actions to be taken by the Study Investigator in the 
event of reduced platelet count are provided in Sections 8.5.3 and 8.6.3. 
6.2.2 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure (BP), pulse rate, respiratory 
rate and body temperature.  BP and pulse rate will be recorded after the patient has been in a 
sitting position for at least 5 minutes.  BP should always be measured on the same arm 
(preferentially on the left arm).  Height will be measured at Screening. 
6.2.3 
Electrocardiography  
Electrocardiography (ECG) will be conducted at Screening, Day 1, (prior to the first dose of 
Study Drug), and again during the treatment period as follows per dosing cohort: 
• Cohorts A and B at Weeks 5, 13, 21, 25, 33, 41, 49, and 53  
• Cohorts C and D at Weeks 5, 13, 21, 25, 27, 33, 41, 49, and 53 
Patients assigned to the PK Subgroup will have additional ECGs conducted as indicated in the 
Schedule of Procedures (Appendix A).  In all cohorts, ECGs will be conducted during the post-
treatment follow-up period as outlined in Appendix A. 
ECGs will be recorded after the patient has been resting in a supine position for at least 
5 minutes.  ECGs will be performed in triplicate. 


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6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 678354 concentrations will be collected 
prior to dosing on Day 1 and at various times throughout the treatment and post-treatment 
follow-up periods as noted in the tables in Appendix C. 
Within each cohort, patients assigned to the PK Subgroup will have additional PK sampling time 
points and additional visits to the clinic during the treatment period in order to collect blood 
samples for PK assessment (Appendix C). 
6.3 
Restriction on the Lifestyle of Patients 
6.3.1 
Contraception Requirements 
All male patients and women of childbearing potential must refrain from sperm/egg donation and 
either be abstinent† or practice effective contraception from the time of signing the informed 
consent form until at least 13 weeks after their last dose of study treatment.   
Male patients engaged in sexual relations with a female of child-bearing potential must also 
encourage their female partner to use effective contraception from the time of signing the 
informed consent until 13 weeks after the patient’s last dose of study treatment. 
For the purposes of this study, women of childbearing potential are defined as any female who 
has experienced menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age or, 
in females ≤ 55 years, 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 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 and female partners of male patients: 
• Using 2 of the following acceptable methods of contraception:  surgical sterilization (e.g., 
bilateral tubal ligation), 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 


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†Note: 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. 
*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 
All patients will be required to fast for at least 10 hours and preferably not more than 12 hours 
before visits requiring fasted blood sampling. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 678354 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 678354 or Placebo) will be provided as 0.8 mL deliverable volume in 2 mL 
stoppered and sealed glass vials as a sterile solution.   
The Study Drug is clear to slightly yellow in color, it is for single use, contains no preservatives 
and must be stored between 2 to 8 °Celsius and be protected from light. 
7.1.1 
ISIS 678354 
ISIS 678354 vials contain 100 mg/mL ISIS 678354 in Water for Injection.  Additionally, sodium 
phosphate buffer and sodium chloride are added to control the measure of the acidity or basicity 
of the solution (pH) and tonicity, respectively.  The target pH is 7.4. 
7.1.2 
Placebo 
Placebo vials contain 0.9% sodium chloride in Water for Injection.  1.6 µg/mL riboflavin is 
added to ensure color matching of placebo vials to ISIS 678354 vials.  
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 678354 
Placebo 
Strength 
100 mg/mL  
Not Applicable 
Volume/Formulation 
0.8 mL solution per 
2.0 mL vial  
0.8 mL solution per  
2.0 mL vial 
Route of Administration 
SC 
SC 
SC = subcutaneous 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 678354 or placebo) 
labeled in accordance with specific country regulatory requirements. 


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7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 678354 or placebo) supplies provided by the Sponsor.  The patient must return all used and 
unused Study Drug to the Study Center for accountability.  The Study Center must return all 
used and unused Study Drug to the Sponsor or designee for destruction.  All used syringes must 
be disposed of as per the site’s hazardous waste destruction policy. 
8. 
TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
ISIS 678354 will be administered to patients by Study Center staff as follows: 
Cohort A: a single SC dose of 10 mg once every 4 weeks for up to 49 weeks and a 
maximum of 13 doses 
Cohort B: a single SC dose of 50 mg once every 4 weeks for up to 49 weeks and a 
maximum of 13 doses 
Cohort C: a single SC dose of 15 mg every 2 weeks for up to 51 weeks and a maximum of 
26 doses 
Cohort D: a single SC dose of 10 mg every week (weekly) for up to 52 weeks and a 
maximum of 52 doses 
Self-administration will be allowed after appropriate training of patient and/or caregiver. 
Patients in Cohorts A and B should receive 1 dose every 4 weeks, patients in Cohort C should 
receive 1 dose every 2 weeks and patients in Cohort D should receive 1 dose per week, with 
weeks always defined relative to Study Day 1.  For example, if a patient receives the first dose 
on a Monday, subsequent doses should be given on Mondays according to the respective dosing 
schedule, if possible.  If a patient misses an injection, or if dosing on the usual day is not 
possible, the patient can reschedule the injection provided that 2 doses are administered at least 
2 days apart. 
Every effort should be made to ensure the previous dose is given 7 days prior to a scheduled 
clinic visit. 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug (ISIS 678354 or placebo) preparation and administration. 


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Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 678354 
A 
10 mg ISIS 678354 
or placebo 
(Every 4 weeks) 
0.10 mL  
≤ 13 
≤ 130 mg 
B 
50 mg ISIS 678354 
or placebo 
(Every 4 weeks) 
0.50 mL  
≤ 13 
≤ 650 mg 
C 
15 mg ISIS 678354 
or placebo 
(Every 2 weeks) 
0.15 mL 
≤ 26 
≤ 390 mg 
D 
10 mg ISIS 678354 
or placebo 
(Every week) 
0.10 mL 
≤ 52 
≤ 520 mg 
8.2 
Other Protocol-Required Drugs 
No other Study Drug treatments are required by the protocol. 
8.3 
Other Protocol-Required Treatment Procedures 
No other treatment procedures are required by the protocol. 
8.4 
Treatment Precautions 
No specific treatment precautions are required. 
8.5 
Safety Monitoring Rules 
Stopping rules are described below in Section 8.6. 
Please refer also to the “Guidance for Investigator” section of the Investigator’s Brochure. 
For the purposes of safety monitoring Baseline is defined as the average of the pre-dose test 
closest to Day 1 and the Day 1 value itself. 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
In case of discrepancy between the test results from 2 sources, such as between the central and 
local lab, safety-mandated action must be initiated based on the more critical (lower or higher, as 
relevant) of the 2 values. 
Confirmation Guidance:  At any time during the study (treatment or post-treatment follow-up 
periods), the clinical laboratory results meeting any of the safety monitoring criteria presented 
below must be confirmed by performing measurements (ideally in the same laboratory that 
performed the initial measurement) on new specimens prior to administering the next dose of 
Study Drug (ISIS 678354 or placebo).  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  


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In addition, as described in Section 6.2.1 hematology labs should be sent in parallel to the central 
and local laboratory for analysis. 
Stopping Rule Guidance:  The Investigator may interrupt or permanently discontinue study 
treatment for any medical reason including changes in clinical laboratory results.   
In the event of an initial clinical laboratory result that meets a stopping criterion, study drug must 
not be administered again until a confirmatory test result has been reviewed by the Study 
Medical Monitor.  If any of the stopping criteria described below (refer to Sections 8.6.1 to 
8.6.3) are met and are confirmed, the patient will be permanently discontinued from further 
treatment with Study Drug (ISIS 678354 or placebo), evaluated fully as outlined below and in 
consultation with the Study Medical Monitor or appropriately qualified designee, and will be 
entered into the post-treatment evaluation portion of the study.  In general, patients who do not 
meet the stopping rules based upon retest may continue dosing.  However, the Investigator and 
the Study Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate. 
Additional Guidance:  If possible, a PK sample should be collected as soon as possible after an 
SAE has occurred (preferably within 2 weeks).  In addition, if a patient is asked to return to the 
clinic for additional evaluations due to an AE, then a PK sample should be taken at the time of 
the unscheduled visit. 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the FDA guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline, please refer to 
guidance in Section 8.5 above. 
All patients will have liver chemistry tests monitored every 14 days (±2 days) for the first 
3 months of the study treatment, and monthly thereafter during the Treatment Period.  Upon 
completion of the study treatment period, liver chemistry tests should be monitored as per visit 
schedule in Appendix A. 
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or 
eosinophilia > ULN) liver enzymes and bilirubin should be tested as soon as possible.  Testing at 
a lab that is local to the patient is permissible for this purpose. 
In the event of an ALT or AST measurement that is > 3 x ULN (or the greater of 2 x baseline 
value or 3 x ULN if the baseline value was > ULN) at any time during the study (treatment or 
post-treatment period), the initial measurement(s) should be confirmed as described in 
Section 8.5. 
Patients with confirmed ALT or AST levels > 3 x ULN should have their liver chemistry tests 
(ALT, AST, ALP, international normalized ratio [INR] and total bilirubin) retested at least 
once-weekly until ALT and AST levels become ≤ 1.2 x ULN. 


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All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.1. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 x ULN, the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A virus [HAV] immunoglobulin M [IgM], hepatitis 
B surface antigen [HBsAg], hepatitis C virus [HCV] antibody, Cytomegalovirus [CMV] 
IgM, and EBV antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
Sponsor Medical Monitor and the study DSMB.  Repetition of the above evaluations should be 
considered if a patient’s ALT and/or AST levels reach 5 x ULN. 
All routine liver function test results will be reviewed on an ongoing basis at the weekly safety 
review by the Medical Monitor.  
All lab alerts for abnormal liver function tests must be promptly reviewed by the Investigator 
(within 48 hours of receipt) and Medical Monitors (within 24 hours of receipt). 
Lab alerts for abnormal liver chemistry tests will be issued for:  1) ALT or AST > 3 x ULN; 
2) ALT or AST > 2 x baseline; 3) total bilirubin > ULN; 4) ALP > ULN.  These alert levels are 
set to anticipate the risk of a combined elevation of aminotransferases and bilirubin as per the 
FDA Guidance referenced in Section 8.5.1. 
8.5.2 
Safety Monitoring for Renal Function 
While on treatment all patients will have renal function tests monitored every 14 days (±2 days) 
for the first 3 months of the study treatment, and monthly thereafter during the Treatment Period.  
Upon completion of the study treatment period, urine renal biomarkers will be monitored as per 
visit schedule in Appendix A. 
In the event of appearance of symptoms or signs consistent with renal dysfunction such as 
hematuria, polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal 
function should be tested as soon as possible.  Testing at a lab that is local to the patient is 
permissible for this purpose. 
While on treatment during the course of the study, urinary surveillance will include urinalysis to 
include urine albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and 


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urinary red blood cells (RBCs), as well as serum creatinine and cystatin-C which will be 
monitored every 14 days (±2 days).  In addition, biomarkers of acute renal injury will also be 
measured every 14 days (±2 days) (Appendix B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than every 
14 days will be guided by consultation with a local nephrologist.  Any decision taken by the 
Investigator to discontinue study medication will be made taking into account all available and 
relevant data.  In addition, the decision to discontinue Study Drug may also be based on lesser 
changes in these parameters observed in isolation or in association with other renal-related 
abnormalities.  Any decision taken to restart study medication will be made in consultation with 
the Study Medical Monitor taking into account all available and relevant data.  
All renal function test results will be reviewed on an ongoing basis by the Medical Monitor. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.2. 
Lab alerts for abnormal renal tests will be issued for:   
• estimated GFR (eGFR) (by CKD-EPI formula) decrease from Baseline > 25%,  
• urine albumin/creatinine ratio (UACR) > 250 mg/g,  
• urine protein/creatinine ratio (UPCR) > 0.5 mg/mg, or  
• increase in serum creatinine from Baseline > 0.3 mg/dL 
These alert levels are set to anticipate and prevent the risk of a medically significant change in 
renal function while receiving Study Drug. If any of the above criteria are met, treatment should 
immediately be interrupted, and the Study Medical Monitor should be informed.  In addition, the 
result should be confirmed as soon as possible (as described in Section 8.5), but no later than 7 
days after the initial event. If the confirmatory test is negative (i.e. repeat sample taken within 7 
days is within normal limits), the patient may continue treatment upon consultation with the 
Study Medical Monitor. 
The Investigator should also review the patient’s concomitant medications for potentially 
nephrotoxic agents, and, with the results of these evaluations, review any decision to continue or 
discontinue the patient in consultation with the Study Medical Monitor and the medical area 
specialist consultant of the DSMB.  
Further instruction regarding treatment interruption and/or permanent stopping of study drug can 
be found in Section 8.6.2. 
8.5.3 
Safety Monitoring for Platelet Count Results 
All patients will have platelet counts monitored every 14 days (±2 days) for the duration of the 
study treatment period and must not receive Study Drug without an interpretable platelet count 
result in the prior 14 days.  Upon completion of the study treatment period, platelets will be 
monitored every 14 days (±2 days) for the first 6 weeks and then at 8 and 13 weeks post end of 
treatment period (as per visit schedule).  


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As described in Section 6.2.1, all platelet count results must be reviewed promptly (within 
48 hours of receipt) by the Investigator or the designee to ensure that the count has not met the 
stopping rule and to determine whether the rate of decline is suggestive that the patient could be 
approaching the dose interruption rule of 75,000/mm3 as specified in Section 8.6.3.  
Any case of a platelet count reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) is 
considered an adverse event of special interest and should be reported in an expedited fashion to 
the Sponsor.  In this case the Investigator should refer the subject to a hematologist to provide 
diagnostic and therapeutic management. 
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are 
< 140,000 mm3, 2) platelet count is ≥ 30% decreased from Baseline, or 3) the hematology 
sample is unreportable.  All these lab alerts, are reviewed promptly by the Medical Monitor and 
instructions are communicated to the Investigator and the study personnel within 24 hours of 
receiving an actionable lab alert as described in Section 6.2.1. 
Actions to be taken in the event of reduced platelet count are shown in Table 3 in Section 8.6.3. 
In the event of a platelet count ˂ 100,000/mm3 the laboratory tests outlined in Appendix E, 
should be performed as soon as possible.  Additional lab tests will be determined by the Sponsor 
Medical Monitor or designee in consultation with the Investigator. 
8.5.4 
Safety Monitoring for Bleeding Events 
Patients will be evaluated for occurrence of bleeding events continuously after the start of Study 
Drug treatment (Day 1) up to the end of the follow-up period for all cohorts.  All bleeding events 
are considered adverse events and reported on adverse event case report form. 
Bleeding events that are either major or clinically-relevant non-major bleeding (as defined 
below) will need to be monitored and treated, as needed, immediately.  Patients with a suspected 
bleeding event will undergo additional testing if deemed appropriate by the treating physician 
and an (S)AE case report form will be completed.  In addition, if bleeding is considered 
significant, hemoglobin (Hb), hematocrit (HCT), aPTT, PT, INR, and platelet count are to be 
obtained.  In addition, approximately 2 mL of K2EDTA anticoagulated blood will be collected 
and resulting plasma must be stored allowing for a centralized assessment of ISIS 678354 
concentrations.  
If a minor bleeding event occurs, the Investigator should notify the Sponsor Medical Monitor (or 
designee) and additional testing of coagulation parameters (aPTT, prothrombin time [PT], INR), 
platelet count, and platelet volume may be performed. 
Major bleeding (MB) is defined as one of the following (Büller et al. 2007):  
1. Fatal bleeding  
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or 
intramuscular with compartment syndrome  


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3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 20 g/L (1.24 mmol/L) or more within 24 hours  
Clinically-relevant non-major bleeding is defined as overt bleeding not meeting the criteria for 
major bleeding but that resulted, for example, in medical examination, intervention, or had 
clinical consequences for a subject (Büller et al. 2007).  
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (defined above), for example excess bruising, petechiae, 
gingival bleeding on brushing teeth.  
8.5.5 
Safety Monitoring for Constitutional Symptoms 
Patients will be instructed to promptly report any signs or symptoms of fever, constitutional 
symptoms, rash, arthralgia or joint swelling that may arise during the study and the Investigator 
should closely evaluate all potential causes, including concomitant illness.  Patients who 
experience persistent or increasing symptoms should be discussed with the Sponsor Medical 
Monitor or designee to determine whether additional monitoring or laboratory tests are required. 
8.5.6 
Safety Monitoring for Insulin, Oral Antidiabetic Medication and Glucose 
All patients on insulin will monitor their glucose levels with a glucometer as per standard 
practice guidelines and bring their glucometer or glucometer log printout to every clinic visit.  In 
addition, patients who are not on insulin but use a glucometer should also bring their glucometer 
and/or glucometer log printout to every clinic visit. 
• The Investigator or delegate will review the glucometer reading or printout at every clinic 
visit to evaluate if fasting pre-breakfast self-monitored plasma glucose values exceed 
threshold values as per the Safety Monitoring Rules for Hyperglycemia below 
All diabetic patients will note any changes in their insulin dose and /or oral antidiabetic 
therapy, as well as any hypoglycemic episode they may experience. 
• The Investigator or delegate will ask patients at every clinic visit if they made changes in 
their insulin dose or oral antidiabetic therapy, and if they experienced a hypoglycemic 
episode 
o Patients will be instructed on the monitoring and management of hypoglycemic 
episodes at each visit 
o Documented symptomatic hypoglycemic episodes should be captured as adverse 
events in the respective CRF.  Documented symptomatic hypoglycemia is defined as 
typical hypoglycemia symptoms accompanied by measured plasma glucose 
≤ 70 mg/dL (≤ 3.9 mmol/L) 
o Any changes in insulin dose or oral antidiabetic therapy should be captured into the 
Concomitant Medication CRF 
8.5.7 
Safety Monitoring for Documented Severe Hypoglycemia 
A documented severe hypoglycemic event is defined as one in which the patient requires 
assistance of another person to obtain treatment for the event and has a plasma glucose level       


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≤ 70 mg/dL (≤ 3.9 mmol/L).  The rescue treatment of hypoglycemia may include IV glucose or 
buccal or intramuscular glucagon. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  Note that “requires assistance” means that the 
patient could not help himself or herself.  Someone being kind that assists spontaneously the 
patient when not necessary does not qualify as “requires assistance.” 
Severe hypoglycemia will be qualified as a SAE only if it fulfills SAE criteria. 
If a patient presents with symptoms of hypoglycemia, the Investigator will need to take 
immediate action to confirm the patient’s glucose level and treat the patient accordingly. 
The experience of hypoglycemia may vary greatly from patient to patient.  However, there are 
certain classical signs and symptoms, of which patients should be aware as a clue that their blood 
glucose may be low.  Common symptoms include headache, heart pounding, confusion, 
disorientation, numbness or tingling, pale skin, shakiness or tremulousness, increased appetite, 
anxiousness or nervousness, lightheadedness or dizziness, sweating, and weakness.  Coma could 
occur if blood sugar correction is not performed.  
If patients suspect they might be having a hypoglycemia reaction, they should check their blood 
glucose using their meters as soon as possible, before treatment if possible, provided they feel it 
is safe to do so.  If there is doubt about safety they should treat the event first, using some sugar, 
milk, or juice for example, then obtain and record a blood glucose value as soon as possible 
thereafter.  The time and nature of treatment should be noted, and especially if any blood glucose 
result was before or after treatment.  It would be helpful for the patient to note if a contributory 
factor (e.g., missed or reduced meals, unaccustomed physical activity) occurred earlier in the day 
of the event. 
Instructions should be provided to all patients on the appropriate use of a glucose meter. 
8.5.8 
Safety Monitoring for Hyperglycemia in Patients with T2DM 
If medically appropriate, patients should remain on a stable regimen of anti-hyperglycemic 
therapy and have either upward dose titration and/or addition of any other anti-hyperglycemic 
agent(s) only when specific threshold values (listed below) are met and confirmed on subsequent 
testing (ideally within 1-week of the initial test).  Any change to the anti-hyperglycemic therapy 
should be discussed with the Sponsor Medical Monitor prior to introduction. 
Fasting plasma glucose (FPG) and HbA1c are monitored as per visit schedule in Appendix A 
(approximately every 3 months) throughout the study.  In addition, patients on insulin should 
self-monitor their plasma glucose (SMPG) routinely on a glucometer.  If a fasting pre-breakfast 
SMPG value exceeds the specific glycemic limit, the patient should check it again on the 
following 2 days.  If all the fasting pre-breakfast values on 3 consecutive days exceed the 
specific limit, the patient should contact the Investigator and an unscheduled central laboratory 
FPG measurement and HbA1c should be performed. 
The threshold values are defined as: 


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• FPG > 270 mg/dL (15.0 mmol/L) or 
• HbA1c > 9% (for patients with baseline HbA1c < 8%) and HbA1c increase of more than 
1% from Baseline (for patients with baseline HbA1c ≥ 8 and < 9%) 
In case of confirmed FPG/HbA1c above the threshold value, the Investigator should 
ensure that no reasonable explanation exists for insufficient glucose control and in 
particular that: 
• Plasma glucose was actually measured in the fasting condition (i.e., after at least 10 hours 
fast) 
• Absence of intercurrent disease which may jeopardize glycemic control.  In case of an 
emergency (e.g., surgery, infection), the Investigator can take appropriate measures for 
glycemic control 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, the 
Investigator should consider the following: 
• Investigation and treatment of intercurrent disease (to be reported in adverse event 
(AE)/concomitant medication parts of the e-CRF) 
• Stress on the absolute need to be compliant to treatment 
• Organize a specific interview with a Registered Dietician or other qualified nutrition 
professional and stress on the absolute need to be compliant to diet and lifestyle 
recommendations 
A FPG/HbA1c follow-up assessment should be arranged after appropriate action has been taken.  
8.6 
Stopping Rules  
Monitoring rules are described above in Section 8.5. 
For the purposes of stopping rules, Baseline is defined as the average of Day 1 pre-dose 
assessment and the last measurement prior to Day 1. 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of confirmed laboratory results meeting any of the following criteria, dosing of a 
patient with Study Drug will be stopped permanently: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline 
value was > ULN), which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 
4. ALT or AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 


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with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia (> ULN) felt by the Investigator to be 
potentially related to hepatic inflammation 
8.6.2 
Stopping Rules for Renal Function Test Results 
In the event that any of the renal monitoring rules summarized in Section 8.5.2 are met, 
treatment should immediately be interrupted and the abnormal result should be confirmed as 
soon as possible, but no later than 7 days after the initial event. In addition, upon consultation 
with the Study Medical Monitor, site will obtain any additional lab assessments necessary to 
determine any alternative etiologies that may account for the abnormal result. If results from 
additional testing confirm the initial abnormal lab result, future treatment of the patient will be 
determined per the guidelines below: 
• An alternative etiology is identified that may account for abnormal results:  
o Patient will have treatment interrupted until either: 
 Lab values have returned to baseline, and/or 
 Alternative etiology has resolved/recovered, AND 
 Study Medical Monitor has approved treatment to resume 
• An alternative etiology has not been identified that may account for abnormal results:  
o Patient will be permanently withdrawn from treatment 
The follow-up schedule and frequency of renal function monitoring after the initial event will be 
determined by the Study Medical Monitor in consultation with the Investigator and the medical 
area specialist on the DSMB.  The Investigator should consider consulting a local nephrologist 
for any change of renal function that presents a concern.  If a renal biopsy is performed, a sample 
specimen should be made available for examination by an independent renal pathologist who has 
been engaged by the Sponsor to review such specimens.  
8.6.3 
Stopping Rule for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 
In the event of any platelet count less than 50,000/mm3, or a platelet count less than 75,000/mm3 
that occurs while the patient is already on reduced dose, dosing of the patient with Study Drug 
will be stopped permanently (Table 3).  Platelet count will be monitored daily until 2 successive 
values show improvement then monitored every 2-3 days until platelet count is stable. 
Administration of glucocorticoids is recommended for patients whose platelet count is less than 
25,000/mm3.  Recovery in platelet count may be accelerated by administration of high dose 
glucocorticoids.  Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) 
recommend Dexamethasone 40 mg daily for 4 days every 2-4 weeks for 1-4 cycles; 
Prednis(ol)one 0.52 mg/kg/d for 2-4 weeks then taper; or methylprednisolone 30 mg/kg/day for 
7 days (note:  may require continuation with oral glucocorticoids after methylprednisolone). 
In the event of a platelet count ˂ 75,000/mm3 and ≥ 50,000/mm3, and in the absence of major 
bleeding or clinically-relevant non-major bleeding (defined below; Büller et al. 2007), dosing of 
a patient with Study Drug should be suspended temporarily until the platelet count has recovered 
to ≥ 100,000/mm3.  If dosing is continued, it must be at a reduced dose as shown in Table 3.  The 


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suitability of the patient for continued dosing will be determined by the Investigator in 
consultation with the Study Medical Monitor and will be based on factors such as the original 
rate of decline in the patient’s platelet count, whether any bleeding events were experienced by 
the patient, and the speed of recovery of platelet count after interruption of dosing. 
If, after reintroduction of Study Drug, the platelet count again falls below 75,000/mm3, then 
dosing of the patient with Study Drug will be stopped permanently.  
Once a patient commences weekly monitoring this frequency of monitoring should continue until 
the platelet count returns to the normal range (≥140K/mm3) for 2 successive values. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue.  
8.6.4 
Stopping Rule for Bleeding 
If an event of Major Bleeding or Clinically-Relevant Non-major Bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor (or designee) and the subject should be 
closely monitored (vital signs, lab tests such as Hb, HCT and platelet count, additional outpatient 
visits, overnight stays and coagulation tests may be needed) throughout the treatment and during 
the post-treatment evaluation period. 
In the event of Major Bleeding or Clinically-Relevant Non-major Bleeding (see definitions in 
Section 8.5.4) as assessed by the Investigator, dosing of a subject with Study Drug (ISIS 678354 
or placebo) may be stopped permanently.  The follow-up schedule for any events meeting this 
stopping criterion will be determined, including the suitability of the subject for resumption of 
dosing by the Investigator in consultation with the Sponsor Medical Monitor (or designee). 
Table 3 
Actions in Patients with Low Platelet Count  
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, 
≥140K/mm3 
No action 
Monitor every 14 days (±2 days) 
≥100K to <140K/mm3 
No action 
Closer observation 
Monitor every week*  
≥75K to <100K/mm3 
Permanently reduce as follows: 
For Cohort A:  reduce to 5 mg every 4 weeks  
For Cohort B:  reduce to 25 mg every 4 weeks 
For Cohort C:  reduce to 7.5 mg every 2 weeks 
For Cohort D:  reduce to 5 mg every week 
Closer observation 
Monitor every week* 
≥50K to <75K/mm3 
Pause dosing 
When platelet count returns to ≥ 100K/mm3 
restart dosing as follows only if approved by 
Sponsor Medical Monitor: 
For Cohort A:  reduce to 5 mg every 4 weeks  
For Cohort B:  reduce to 25 mg every 4 weeks 
For Cohort C:  reduce to 7.5 mg every 2 weeks 
For Cohort D:  reduce to 5 mg every week 
or 
Permanently discontinue Study Drug if it occurs 
while on already reduced dose  
Closer observation 
Monitor every 2-3 days until 2 successive 
values show improvement 
Consider discontinuation of antiplatelet 
agents/non-steroidal anti-inflammatory 
drug (NSAIDS) 


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Platelet Count on Rx 
Drug Dose 
Monitoring 
≥25K to ˂50K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive values 
show improvement then monitor every 2-3 
days until platelet count stable 
Discontinue antiplatelet agents/NSAIDS 
while platelet count ˂50K/mm3 if possible 
Refer to hematologist to provide 
diagnostic and therapeutic management 
˂25K/mm3 
Permanently discontinue Study Drug 
Closer observation: 
Monitor daily until 2 successive values 
show improvement then monitor every 2-3 
days until platelet count stable 
Steroids recommended** 
Consider need for hospitalization  
Discontinue antiplatelet agents/NSAIDS 
medication while platelet count ˂50K/mm3 
if possible 
Refer to hematologist to provide 
diagnostic and therapeutic management 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue until the platelet 
count returns to the normal range (≥140K/mm3) for 2 successive values. 
** 
Recovery in platelet count may be accelerated by administration of high dose glucocorticoids.  Treatment 
guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily for 
4 days every 24 weeks for 1-4 cycles; Prednis(ol-)one 0.5-2 mg/kg/d for 2-4 weeks then taper; or 
Methylprednisolone 30 mg/kg/day for 7 days (note:  may require continuation with oral steroids after 
methylprednisolone). 
8.7 
Adjustment of Dose  
Dose frequency adjustments for platelet count reduction must be made in accordance with 
Table 3 (above). 
Other dose adjustments, including dose interruptions, and/or decreasing the dose will be allowed 
for safety or tolerability after consultation with the Sponsor Medical Monitor.   
Patients may have their dose interrupted in response to AEs after consultation with Study 
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 AE that necessitates permanent discontinuation of Study Drug 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.4 
• When a platelet count of less than 50,000/mm3, or a platelet count less than 75,000/mm3 
while the patient is on a reduced dose. 


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The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period 
Any patient who discontinues early from the treatment period or from the post-treatment follow-
up period should be strongly encouraged to complete follow-up study visits, procedures and 
observations as described below. 
Any patient who discontinues early from the treatment period or from post-treatment follow-up 
period should be followed as per the platelet monitoring rules shown in Table 3, Section 8.6.3 for 
the first 6 weeks post end of treatment period and then at 8 and 13 weeks post end of treatment 
period (as per visit schedule).  
If a patient early terminates from the treatment period, an ET visit (Week 53 visit assessments) 
should be performed at the time of withdrawal, and ideally within 2 weeks from the last dose of 
Study Drug, and patients should start the 13-week post-treatment follow-up period to collect the 
study assessments in accordance with the Schedule of Procedures in Appendix A. 
If the patient early terminates from the post-treatment follow-up period, a final visit (assessments 
from the Week 13 of post-treatment follow-up period) should be performed at the time of 
withdrawal.  
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 
• The patient meets any of the Exclusion Criteria (see Section 5.2) after enrolling in the 
study that in the opinion of the Investigator represents a safety risk to the patient  
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 
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.  These patients should be 
encouraged to complete the ET visit (Week 53 visit assessments) and observations at the time of 
withdrawal (Appendix A). 


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For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the ET visit (Week 53 visit assessments) and observations at the time of withdrawal 
(Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  AEs related to administration of these therapies or procedures must also be documented 
on the appropriate eCRF. 
8.10.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including 
over-the-counter medications, herbal medications and vitamin supplements) administered from 
the time the patient has signed the informed consent at Screening to the end of the post-treatment 
follow-up period. 
Allowed Concomitant Therapy 
Use of the following is allowed only if the patient has been on a stable regimen for at least 
4 weeks prior to screening and is planned to remain on a stable regimen through the end of the 
post-treatment follow-up period:  
• Lipid lowering drugs (statins, ezetimibe, 0 inhibitors, niacin, fibrates, fish oil, other 
products containing omega-3 fatty acids (including OTC preparations) 
o The timing of PCSK9 inhibitor and study drug administration should be kept 
consistent with respect to lipid assessments. The first dose of ISIS 678354 (i.e., 
Study Day 1) will be scheduled for one day ahead of the next planned PCSK9 
inhibitor injection to establish a regular time span between the two medications.  
PCSK9 inhibitors should be administered one day after administration of the 
study drug for the whole duration of the study treatment. 
• Anti-platelet therapies 
• Testosterone, estrogens, progesterone, growth hormone, or progestins. 
Disallowed Concomitant Therapy 
Use of the following is disallowed: 
• Warfarin and other vitamin K antagonists, direct thrombin inhibitors or Factor Xa 
inhibitors 
• Other experimental agents during the study including investigational drug, biological 
agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, 
whichever is longer.  This includes marketed agents at experimental dosages 
• Treatment with any non-Ionis oligonucleotide (including siRNA) at any time or prior 
treatment with an Ionis oligonucleotide or siRNA within 9 months of Screening.  Patients 
that have previously received only 1 dose of an Ionis oligonucleotide as part of a clinical 
study may be included as long as ≥ 4 months has elapsed since dosing 


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• Lipoprotein apheresis 
Patients should consult with the Site Investigator or designee prior to initiating any new 
medication, including non-prescription or herbal compounds or any other non-drug therapy. 
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 
screening and the end of the post-treatment follow-up period. 
8.11 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and documented by the Study Center staff 
and recorded in the eCRF.   
Patients or Study Center Staff will record treatment administered in a dosing diary that will be 
reviewed by Study Center staff and entered into the eCRF. 
8.12 
Safety Monitoring Compliance 
Compliance with safety monitoring requirements and treatment stopping rules must be 
documented by the Study Center staff.   
Patients and the Study Investigators are required to adhere to a strict program of monitoring 
requirements and treatment stopping rules as described in Section 6.2.1, Sections 8.5.1-8.5.8, and 
Sections 8.6.1-8.6.4. 
While on treatment patients will be required to have platelet counts every 14 days (±2 days) for 
the duration of the study and must not receive Study Drug without an interpretable platelet count 
result in the prior 2 weeks, in which case the Investigator must contact the patient to hold dosing 
until a new platelet count is obtained and reviewed, and will document this contact. 
While on treatment patients will also be required to have renal function testing and assessment of 
biomarkers of renal damage every 14 days (±2 days) for the first 3 months of the study treatment, 
and monthly thereafter during the treatment period.  In such a case, the Investigator must contact 
the patient to hold dosing until these or new tests are obtained and reviewed. 
Adherence to the program will be closely monitored by the Sponsor, and patients and trial sites 
that are unable or unwilling to comply with this important risk mitigation program will be 
discontinued from the study.  
Patients should be informed of the possibility and risks of a reduction in platelet count, and of 
potential hepatic and renal risks, and the importance of adherence to the monitoring program.  
Any case of a platelet count reduction to levels below 50,000/mm3, or any event meeting renal 
stopping rules criteria described in Section 8.6.2 are considered adverse events of special interest 
and should be reported in an expedited fashion to the Sponsor. 


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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 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. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of relatedness.  While the 
Sponsor may upgrade an Investigator’s decision it is not permissible to downgrade the 
Investigator’s opinion for the purposes of determining whether the SAE meets the definition of a 
SUSAR. 
Appropriate personnel at the Sponsor or designee will unblind SUSARs for the purpose of 
regulatory reporting.  The Sponsor or designee will submit SUSARs to Regulatory Agencies in 
blinded or unblinded fashion according to local law.   
9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event (AE) 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 Unexpected Adverse Reaction 
Adverse reaction:  All untoward and unintended responses to an investigational medicinal 
product related to any dose administered. 
Unexpected adverse reaction:  an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., Investigator's Brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized 
product). 
9.3.3 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 


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• Is life threatening, that is, poses an immediate risk of death at the time of the event 
• An AE or 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 adverse reaction that, had it occurred in a more severe form, 
might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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 
9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 as well as any 
event meeting renal stopping rules criteria described in Section 8.6.2 are considered as AE of 
special interest and should be subject to expediting reporting to the Sponsor following the same 
requirements as for SAE reporting (Section 9.4.1). 
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/Adverse Events of Special Interest 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs and AEs 
of special interest (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.  An Initial Serious Adverse Event Form should be 
completed and a copy should be emailed or faxed to the Sponsor or designee.  The contact 
information for reporting SAEs is as follows:  
Attention:  
 
Email: 
 
 
Fax: 
 
 


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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 during the study period.  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. 
All SAEs considered treatment-related, as defined in Section 9.4.3.1, will be reported by the 
Sponsor to the DSMB as described in Section 3.6.  
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.  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 678354 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 678354 or placebo) administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions.  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 
The severity of AEs and SAEs will be graded based on criteria from the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D).  Any AE 
not listed in Appendix D will be graded as follows: 
• Mild:  The event is easily tolerated by the subject and does not affect the subject’s usual 
daily activities 


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• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug (ISIS 678354 or placebo) due to the event is characterized by 1 of 
the following. 
• None:  No changes were made to Study Drug (ISIS 678354 or placebo) administration 
and dose 
• Temporarily Interrupted, Restarted – Same Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the same dose 
• Temporarily Interrupted, Restarted Reduced Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the next lower dose  
• Permanently Discontinued:  Study Drug was discontinued and not restarted 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for an 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: 
• Ongoing:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious 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 that monitoring is no longer necessary.  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 clinical 
laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values and signatures. 
All platelet count results must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the count has not met the stopping rule and to 
determine whether the rate of decline is suggestive that the patient could be approaching the dose 
interruption rule of 75,000/mm3 as specified in Section 8.6.3. 
Any case of a platelet count reduction to levels below 50,000/mm3 is considered an adverse 
event of special interest and should be reported in an expedited fashion to the Sponsor as per 
Sections 9.3.3.1 and 9.4.1). 
All results of liver function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.1. 
All results of renal function tests must be reviewed promptly (within 48 hours of receipt) by the 
Investigator or the designee to ensure that the result has not met the stopping rules per 
Section 8.6.2. 
Any event meeting renal stopping rules criteria described in Section 8.6.2 is considered an 
adverse event of special interest and should be reported in an expedited fashion to the Sponsor as 
per Sections 9.3.3.1 and 9.4.1). 
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: 


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• 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 condition is documented in the patient’s medical history 
• 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 678354 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 was accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the patient takes a dose 
of Study Drug (ISIS 678354 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 contact the Sponsor or designee 
within 24 hours. 
9.5.4 
Contraception and Pregnancy 
Male and female patients of childbearing potential 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 by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours of occurrence. 
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 during the 
follow-up period), 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 
Investigator 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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after birth.  Follow-up will be performed to the extent permitted by the applicable regulations 
and privacy considerations. 
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, the Study Center and Sponsor may 
request access to the mother and infant’s medical records for an additional 8 weeks after 
birth.  Follow-up will be performed to the extent permitted by the applicable regulations and 
privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
The sections below indicate the overall structure and approach to the analysis of this study.  A 
detailed Statistical Analysis Plan (SAP) incorporating these sections below will be prepared 
separately.  The SAP will outline all data handling conventions, including software, and specify 
additional statistical methods to be used for analysis. 
The study objectives are listed in Section 1. 
10.1 
Study Endpoints, Subsets, and Covariates 
Efficacy and safety endpoints that will be evaluated after the last patient has completed the 
primary analysis time point are identified in the following sections. 
The primary efficacy and safety analysis time point is at Week 25 for patients who received 
every 4-week dosing (Cohorts A and B) and at Week 27 for patients who received weekly or 
biweekly dosing (Cohorts C and D).  For patients continuing treatment beyond the primary 
analysis time point additional supportive efficacy and safety analyses will be repeated at the 
completion of Study Drug treatment. 
10.1.1 
Primary Endpoint(s) 
The primary efficacy analysis for the primary endpoint will be the pairwise comparison of 
percent change from Baseline to the primary analysis time point in fasting TG between ISIS 
678354 treated groups and pooled placebo group in the FAS. 
The data will be analyzed using an ANCOVA model with the baseline TG level as a covariate. 
10.1.2 
Secondary Endpoints 
The secondary endpoints comprise the effect of ISIS 678354 as compared to placebo at the 
primary analysis time point on the following: 
• Percent change from Baseline in apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, 
apoB, and apoA-I 
• Proportion of patients who achieve serum TG ≤ 150 mg/dL (≤ 1.7 mmol/L) 
• Proportion of patients achieving TG ≤ 100 mg/dL (≤ 1.13 mmol/L) 
10.1.3 
Safety Endpoints 
The safety analysis will be performed using the following parameters: 




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10.3 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized, received at least 1 dose of Study 
Drug (ISIS 678354 or placebo), and have a Baseline TG assessment.  The FAS represents the 
practically-feasible intent-to-treat (ITT) population as delineated in ICH Guideline E9.  This 
population will be used for the primary analysis of efficacy.   
Per Protocol Set (PPS):  Subset of the FAS who received within 6 months at least 5 monthly 
doses of Study Drug for patients randomized in Cohorts A and B, or at least 11 every 2-week 
doses for patients randomized in Cohort C, or at least 22 weekly doses for patients randomized in 
Cohort D, and who have no major protocol violations that could compromise the interpretation 
of efficacy.  Major violations will be determined prior to unblinding for statistical analysis.  This 
population will be used for supportive inferences concerning efficacy. 
Safety Set:  All patients who are randomized and receive at least 1 dose of Study Drug.  This 
population will be used for all safety analyses.   
PK Population:  All patients who are randomized and received at least 1 dose of ISIS 678354, 
and have at least 1 evaluable concentration result post first dose.  This population will be used 
for analysis of PK data. 
10.4 
Definition of Baseline 
Baseline for TG, apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, apoA-I and other 
lipid measurements will be defined as the average of the pre-dose measurement on Day 1 and the 
last measurement closest to Day 1, prior to administration of Study Drug.  The baseline for other 
measurements is defined as the last non-missing assessment prior to the first dose of Study Drug. 
10.5 
Interim Analysis 
No interim efficacy analysis will be performed. 
10.6 
Planned Methods of Analysis 
Summary tabulations will be provided for disposition, demographic, baseline, efficacy, and 
safety data as noted in the following sections.  Hypothesis testing will be used for the primary 
efficacy endpoint and select secondary efficacy endpoints. 
All eCRF 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. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  The 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 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug (ISIS 678354 or placebo) received will be 
summarized by treatment group.  Patient incidence rates of all AEs will be tabulated by 
MedDRA system organ class, and by MedDRA preferred term.  Narratives of treatment-
emergent deaths, serious and significant AEs, including early withdrawals due to AEs, will also 
be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drug, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drug (ISIS 678354 or placebo) will be summarized. 
10.6.2.2 
Clinical Laboratory Data 
Laboratory tests to ensure patient safety including chemistry panel, complete blood count (CBC) 
with differential, coagulation panel, complement, etc., will be summarized by study visits for 
each treatment group.  These safety variables will also be presented as change and percent 
change from Baseline over time after Study Drug (ISIS 678354 or placebo) administration, as 
appropriate.  In addition, the number of patients who experience abnormalities in clinical 
laboratory evaluations will be summarized by treatment group. 
10.6.2.3 
Vital Signs and Examinations 
Vital sign and ECG measures will be tabulated by treatment group.   
10.6.3 
Efficacy Analysis 
10.6.3.1 
Analysis of Primary Efficacy Endpoint 
The primary efficacy analysis for the primary endpoint will be the pairwise comparison of 
percent change from Baseline to the primary analysis time point in fasting TG between ISIS 
678354 treated groups and pooled placebo group in the FAS.  The data will be analyzed using an 
ANCOVA model with the baseline TG level as a covariate.  Missing data may be handled by 
LOCF or multiple imputation methods (Schafer 1997, Schafer 1999). 
The primary efficacy analysis will take place after the last patient has completed the primary 
analysis time point, and the database has been locked,  
The following sensitivity analyses will be conducted: 
• The primary analysis will be repeated in the PPS 
• The primary efficacy endpoint will be analyzed using a Wilcoxon Rank Sum test on both 
FAS and PPS, and the treatment effect will be estimated using Hodges-Lehmann 
estimator 
Additional sensitivity analyses may be conducted as appropriate; the details of these analyses 
will be outlined in the SAP. 


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10.6.3.2 
Analysis of Secondary Efficacy Endpoints 
• Percent change from Baseline at the primary analysis time point in fasting apoC-III, TC, 
LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, and apoA-I will be compared between 
each ISIS 678354 treatment group and pooled placebo group using an ANCOVA model 
with baseline as covariate 
• Proportion of patients who achieve fasting TG ≤ 150 mg/dL (≤ 1.7 mmol/L) at the 
primary analysis time point will be compared between each ISIS 678354 treatment group 
and pooled placebo group using a logistic regression model with Baseline TG as a 
covariate.  Proportion of patients who achieve fasting TG ≤ 100 mg/dL (≤ 1.13 mmol/L) 
at the primary analysis time point will be analyzed similarly 
All analyses of secondary endpoints will be performed on the FAS as primary and PPS as 
supportive. 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
For all patients, trough and post-treatment concentrations of ISIS 678354 in plasma (as total full 
length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 678354) will be determined and summarized by treatment with and without stratification by 
subject immunogenicity (IM) status using descriptive statistics. In addition, plasma terminal 
elimination half-life of ISIS 678354 will be calculated using the post-treatment follow-up data if 
data permits. 
Additionally, for patients in the PK subgroup only, PK parameters will be calculated using non-
compartmental methods. The maximum plasma concentration (Cmax) and time to reach Cmax 
(Tmax) values will be obtained directly from the plasma concentration-time data. The area under 
the plasma concentration-time curve (AUC) values after the first dose and steady-state dose will 
be calculated using the trapezoidal rule. Other PK parameters may be calculated at the discretion 
of the PK scientist. Plasma PK parameters will be summarized using descriptive statistics with 
and without stratification by subject IM status. 
Exposure-response relationships between selected PD [e.g., TG] and PK measures (e.g., plasma 
trough concentrations) may be explored (including with and without stratification by IM status) 
in this study, or in a separate population PK analysis combined with other clinical studies. 
The immunogenicity (IM) of ISIS 678354 will be assessed before, during, and after treatment 
with Study Drug (ISIS 678354 or placebo).  The IM incidence (number) and incidence rate 
(percent) will be summarized at each evaluated study time point and at the patient level by 
treatment and dose, as the total number of and percent of evaluated patients with antibody 
negative, positive, and unknown status.  Study patients with positive anti-ISIS 678354 antibody 
status may be further classified (when applicable) as being either ‘persistent’, ‘transient’, or not 
determinable.  Potential relationships of immunogenicity with selected efficacy, safety, and PK 
measures may be evaluated. 
Additional details regarding the PK and immunogenicity analysis will be described in the SAP. 


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11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
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 or legally acceptable representative 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 678354 or placebo) are 
administered. 
Importantly, patients should be informed of the possibility and risks of a reduction in platelet 
count and other potential risks, in particular hepatic and renal risks, and the importance of strict 
adherence to the monitoring program.  The patient or legally acceptable representative must be 
given sufficient time to consider whether to participate in 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 or a legally acceptable 
representative 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 or legally acceptable representative. 
The sponsor shall maintain all records referred to in the applicable Regulations for a period of 
25 years. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2013 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 (IEC)/Institutional Review Board (IRB) 
A copy of the protocol, proposed informed consent forms, other written patient information, and 
any proposed advertising material must be submitted to the IEC/IRB for written approval.  A 
copy of the written approval of the protocol and informed consent form must be received by the 
Sponsor or designee before recruitment of patients into the study and shipment of Study Drug.  A 
copy of the written approval of any other items/materials that must be approved by the Study 
Center or IEC/IRB must also be received by the Sponsor or designee before recruitment of 
patients into the study and shipment of Study Drug.  The Investigator’s Brochure must be 
submitted to the IEC/IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 


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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 in accordance with local procedures.   
11.4 
Patient Confidentiality 
The Investigator and Sponsor must ensure that the patient’s confidentiality is maintained.  On the 
case report forms 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. 
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 ET.  An Investigator who terminates participate is required to send a copy of the IEC/IRB 
notification to the Sponsor or designee. 
12.3 
Study Documentation and Storage 
Source documents are original documents, data, and records from which the patient’s case report 
form 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, 
eCRF 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 


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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 case report forms, 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 case report forms must be 
maintained and be readily available for the duration required by GCP or local regulatory 
requirements, whichever is longer. 
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, in 
accordance with GCP. 
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., case report forms and other pertinent data) provided that 
patient confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case report forms 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 case report forms.  Source data should be attributable, legible, 
contemporaneous, original, and accurate (ALCOA) and must meet the regulatory requirements 
for recordkeeping. 
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 case report forms, 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 


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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 case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content in 
accordance with the general investigational plan. 
12.5 
Language 
Case report forms must be completed in English.  Whenever possible, the trade name rather than 
the generic name for concomitant medications should be recorded and if possible, in English.  
Generic names are acceptable if the trade name is unknown.  Combination medications should be 
recorded using their trade name in English if possible. 
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 
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to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Atzmon G, Rincon M, Schechter CB, et al. Lipoprotein genotype and conserve pathway for exceptional longevity in 
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Austin MA, McKnoght B, Edwards KL, et al. Cardiovascular disease mortality in familial forms of 
hypertriglyceridemia:a 20-year prospective study. Circulation 2000; 101:2777-2782. 
Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A report from the 
American Heart Association. Circulation 2017; 135 (10):e145-e603. 
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Breyer ED, Le N-A, Li X, et al. Apolipoprotein C-III displacement of apolipoprotein E from VLDAL: Effect of 
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Brown RJ, Lagor WR, Sankaranaravanan S, et al. Impact of combined deficiency of hepatic lipase and endothelial 
lipase on the metabolism of both high-density lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 
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Bruns GA, Karathanasis SK, Breslow JL. Human apolippoprotein A-I-C-III gene complex is located on 
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versus moderate statin therapy. J Am Coll Cardiol 2006; 48 (3): 438-445. 
Cannon CP, Blazing MA, Giugliano RP et al. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after 
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Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. 
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Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
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(Therothrombosis intervention in metabolic syndrome with low HDL/high triglycerides and impact on global health 
outcomes). J Am Coll Cardiol 2013; 62 (17): 1580-1584. 


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Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
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and risk of ischemic vascular disease. NEJM 2014 Jul 3; 371(1): 32-41. 
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coronary events in diabetic patients. Arterioscler Thromb Vasc Biol 2003; 23: 853-858. 
Lemieux I, Salomon H, Després JP. Contribution of apo CIII reduction to the greater effect of 12-week micronized 
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Mendivil CO, Rimm EB, Furtado J et al. Low-density lipoproteins containing apolipoprotein C-III and the risk of 
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Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile 
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Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using 
triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 2014 Jul; 42: 8796-8807. 
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primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Roncaglioni MC, Tombesi M, Avanzini F et al. N-3 fatty acids in patients with multiple cardiovascular risk factors. 
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Sabatine MS, GiuglianoRP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular 
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Sacks FM. The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and 
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Sacks FM, Alaupovic P, Moye LA, et al. VLDL, apolipoproteins B, CIII and E and risk of recurrent coronary events 
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Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL-cholesterol reduction with 
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Schafer JL. Analysis of Incomplete Multivariate Data, New York: Chapman and Hall 1997. 
Schafer JL. Multiple imputation: a primer, Statistical Methods in Medical Research 1999; 8: 3–15. 
Staels B, Vu-Dac N, Kosykh V, et al. Fibrates downregulate apolipoprotein C-III expression independent of 
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14. 
APPENDICES 
 
 


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Appendix A   Schedule of Procedures 
 
Schedule of Procedures for Weekly and Every 2-Week Dosing Cohorts 
Schedule of Procedures for Every 4-Week Dosing Cohorts 
 


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Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing 
 
Screening 
Treatment Period 
Follow-up Period 
Run-
in# 
Qual* 
Study Week 
-4 to -
2 
-2 to 
-1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27q 
29 
33 
37 
41 
45 
49 
53/ 
ET 
4** 
8** 
13** 
Study Day 
-28 to  
-15 
-14 to  
-7 
1 
2a 29 57 85 113 141 169 170a 171a  176a 
183 
197 225 253 281 309 337 365 
**Weeks from 
the end of 
treatment 
periodp 
Visit and Testing Window +/- Days 
0 
0 
-3b 0 
2 
2 
2 
3 
3 
3 
0 
0 
 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
X1 X2 
X 
 
X 
 
X 
X1 
X2 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Extended Urinalysis e 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Biomarkers g 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and Cys-C i, j 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel j,k 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology j, k 
X 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS (+/- 2 days) f, k 
Xh 
Xh  
Xh  
Coagulation 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing Continued 
 
Screening 
Treatment Period 
Follow-up Period 
Run-
in# 
Qual
* 
Study Week 
-4 to -
2 
-2 to  
-1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27q 
29 
33 
37 
41 
45 
49 
53/ 
ET 
4** 
8** 
13** 
Study Day 
-28 to  
-15 
-14 to  
-7 
1 
2a 29 57 85 113 141 169 170a 171 a  176a 
183 
197 225 253 281 309 337 365 
**Weeks from the 
end of treatment 
periodp 
Visit and Testing Window +/- Days 
0 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c, HOMA-IR, Fructosamine, 
Glycated Albumin 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 678354 l 
 
 
X1 X2 
X 
X 
X 
X 
X 
X1 
X2 
X3 
X 
X4 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 678354 Antibodies 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) j, m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test m 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archived Serum & Plasma 
Samples j, n 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid Panel j 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study Drug:  SC Injection 
 
 
WEEKLY AND EVERY 2-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG  
(Week 1 through Week 52/Day 358 for Weekly Cohort; Week 1 through Week 51/Day 351 for Every 2-
Week Cohort)o 
 
 
 
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 Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Qual = Qualification 
# Patients on stable diet known to the investigator and followed at the site may go from Screening to qualification without the diet run-in period.  
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
81 
Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing Continued 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Visit only required for patients in PK subgroup. 
b 
Day 1/Baseline assessments can be performed up to 3 days (-3 days) prior to the actual Day 1 visit, which is the day of first Study Drug dose. 
c 
Patient charts will be reviewed in order to collect disease associated medical history data such as CVD history. 
d 
Height only required at Screening. 
e 
All tests listed in Appendix B under Extended Urinalysis should be performed, including routine urinalysis, urine microscopy, UACR and UPCR. 
f 
Assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Patient Study Center visits must be no more than 
4 weeks apart during the treatment period. 
g 
Urine samples for renal biomarkers will be collected.  Sample analysis will be conducted in accordance with Safety Monitoring for Renal Function. 
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days for 6 weeks after treatment period, then at the Week 8 and Week 13 
Follow-up visits.  
i 
Serum Creatinine and Cys-C will be collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone samples at time 
points when a chemistry panel is not performed. 
j 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
k 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
l 
Refer to Appendix C for PK Sampling schedule. 
m 
Women who are not surgically sterile or post-menopausal. 
n 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the final 
study report. 
o 
Patients will continue treatment in the study for 12 months, or until the last patient reaches 6 months of exposure.  When this milestone is met, all patients still 
on treatment will have an End of Treatment visit, then enter a 13-week post-treatment follow-up period. 
p 
End of treatment period is defined as one dosing interval post last dose. 
q  
The last patient to reach 6 months of exposure will also be the last patient to complete the End of Treatment (EOT) visit. Therefore, the Week 27 visit will 
count as the EOT visit for all patient whose EOT visit would have been scheduled to occur later than the EOT visit for the last patient to reach 6 months of 
exposure. No dose will be administered at this visit.   
 
Time (time is in reference to Study Drug administration): 
1 
Pre-dose for all patients and pre-dose 1, 2, 4, 8 hours post SC injection for patients on PK subgroup only  
2 
24-hr from previous dose of Study Drug for patients on PK subgroup only 
3 
48-hr from previous dose of Study Drug for patients on PK subgroup only 
4 
Pre-dose for Cohort C (every 2-week dosing) patients on PK subgroup only 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
82 
 
Appendix A Schedule of Procedures – Every 4-Week Dosing 
 
Screening 
Treatment Period 
Follow-up Period 
Run-
in# 
Qual* 
Study Week 
-4 to -
2 
-2 to  
-1 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25q 
29 
33 
37 
41 
45 
49 
53/ 
ET 
4** 
8** 
13** 
Study Day 
-28 to  
-15 
-14 to  
-7 
1 
2a 29 57 85 113 141 142 a 143a 148a 
155a 
169 
197 225 253 281 309 337 365 
**Weeks from 
the end of 
treatment 
periodp 
Visit and Testing Window +/- Days 
0 
0 
-3b 
0 
2 
2 
2 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outpatient Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
 
X1 X2 
X 
 
X 
 
X1 
X2 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Extended Urinalysis e 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal Biomarkers g 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine and Cys-C i, j 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Panel j, k 
X 
 
EVERY 14 DAYS  
(+/- 2 days) f 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology j, k 
X 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS (+/- 2 days) f, k 
Xh 
Xh 
Xh 
Coagulation  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
83 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
84 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
Screening 
Treatment Period 
Follow-up 
Period 
Run-
in# 
Qual* 
Study Week 
-4 to -
2 
-2 to  
-1 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25q 
29 
33 
37 
41 
45 
49 53/ 
ET 
4** 
8** 13** 
Study Day 
-28 to  
-15 
-14 to -
7 
1 
2a 
29 
57 
85 
113 141 142 a 143a 148a 155a 169 197 225 253 281 309 337 365 
**Weeks from 
the end of 
treatment 
periodp 
Visit and Testing Window +/- Days 
0 
0 
-3b 
0 
2 
2 
2 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c, HOMA-IR, Fructosamine, 
Glycated Albumin 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 678354 l 
 
 
X1 
X2 
X 
X 
X 
X 
X1 
X2 
X3 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 678354 Antibodies 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
FSH (women only, if applicable) j, m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test m 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archived Serum & Plasma 
Samples j, n 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid Panel j 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study Drug:  SC Injection 
 
 
EVERY 4-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 through Week 49/Day 337)o 
 
 
 
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 Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Qual = Qualification 
# Patients on stable diet known to the investigator and followed at the site may go from Screening to qualification without the diet run-in period.  
 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
85 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
Visit only required for patients in PK subgroup. 
b 
Day 1/Baseline assessments can be performed up to 3 days (-3 days) prior to the actual Day 1 visit, which is the day of first Study Drug dose. 
c 
Patient charts will be reviewed in order to collect disease associated medical history data such as CVD history. 
d 
Height only required at Screening. 
e 
All tests listed in Appendix B under Extended Urinalysis should be performed, including routine urinalysis, urine microscopy, UACR and UPCR. 
f 
Assessments and procedures to be conducted by either a home healthcare service or the Study Center.  Patient Study Center visits must be no more than 
4 weeks apart during the treatment period. 
g 
Urine samples for renal biomarkers will be collected.  Sample analysis will be conducted in accordance with Safety Monitoring for Renal Function 
h 
During follow-up period, hematology sampling for platelet values are taken every 14 days for 6 weeks post treatment period and then at the Week 8 and 13 
Follow-up visits. 
i 
Serum Creatinine and Cys-C will be collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone samples at time 
points when a chemistry panel is not performed. 
j 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours, unless tests are repeated for safety reasons. 
k 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen should be re-drawn as soon as possible (ideally within 7 days).  All platelet count results will be reviewed promptly (within 48 hours of receipt) by the 
Investigator.  Any case of a platelet count < 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
l 
Refer to Appendix C for PK Sampling schedule. 
m 
Women who are not surgically sterile or post-menopausal. 
n 
Serum and plasma samples will be collected and stored for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or 
chemokine levels, measurement of additional markers of kidney function, measurement of antibodies, etc.) and will be retained until completion of the final 
study report. 
o 
Patients will continue treatment in the study for 12 months, or until the last patient reaches 6 months of exposure.  When this milestone is met, all patients still 
on treatment will have an End of Treatment visit, then enter a 13-week post-treatment follow-up period. 
p 
End of treatment period is defined as one dosing interval post last dose. 
q 
The last patient to reach 6 months of exposure will also be the last patient to complete the End of Treatment (EOT) visit. Therefore, the Week 25 visit will 
count as the EOT visit for all patient whose EOT visit would have been scheduled to occur later than the EOT visit for the last patient to reach 6 months of 
exposure. No dose will be administered at this visit.     
 
Time (time is in reference to Study Drug administration): 
1 
Pre-dose for all patients and pre-dose 1, 2, 4, 8 hours post SC injection for patients on PK subgroup only  
2 
24-hr from previous dose of Study Drug for patients on PK subgroup only 
3 
48-hr from previous dose of Study Drug for patients on PK subgroup only 
  


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
86 
Appendix B   List of Laboratory Analytes 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
87 
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 678354 or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Uric Acid 
• Total bilirubin 
• Direct (conjugated) 
bilirubin 
• Indirect 
(unconjugated) 
bilirubin 
• ALT 
• AST 
• ALP 
• Creatinine kinase 
• GGT 
• Cys-C 
Screening Tests 
• Hepatitis B surface 
antigen 
• Hepatitis C antibody 
• HIV antibody 
• FSH (women only) 
• Serum βhCG 
(women only) 
• TSH 
• Free T4 
• HbA1c 
 
Coagulation 
• aPTT 
• PT 
• INR 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL 
• ApoC-III 
• Non-HDL-C 
• ApoA-1 
• Lp(a) 
• ANGPTL3 
Hematology 
• Red blood cells 
• Hemoglobin 
• Hematocrit 
• MCV, MCH, MCHC 
• Platelets 
• White blood cells (WBC)  
• WBC Differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Pharmacokinetics1 
• ISIS 678354 (total full 
length ASO) levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 678354 
antibodies 
 
Other assessments 
• HbA1c 
• HOMA-IR 
• Fructosamine 
• Glycated albumin 
 
Inflammatory 
• hs-CRP  
 
Extended Urinalysis 
• Routine Urinalysis 
- 
Color 
- 
Appearance 
- 
Specific gravity 
- 
pH 
- 
Protein 
- 
Blood 
- 
Glucose 
- 
Ketones 
- 
Bilirubin 
- 
Urobilinogen 
- 
Leukocyte esterase 
- 
Nitrate 
• Microscopic examination 
• P/C Ratio (UPCR) 
• A/C Ratio (UACR) 
  
Renal Urine Biomarkers 
2 
• NGAL  
• NAG 
• KIM-1 
• Cys-C 
 
 
1 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 678354 with plasma 
constituents 
2 
All samples will be collected, handled and stored under the conditions specified for the assays. Please refer to 
the study Laboratory Manual for details on the appropriate handling and storage methods for biomarker and 
other samples.   
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
88 
Appendix C   PK Sampling Schedule 
 
Sampling Schedule for Weekly and Every 2-Week Dosing Cohorts 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
89 
Appendix C PK Sampling Schedule  
Blood samples for the determination of plasma ISIS 678354 concentrations will be collected prior to dosing, and at various times 
throughout the dosing and post-treatment follow-up period as noted in the tables below.  Plasma PK samples may also be used for 
profiling of drug binding proteins, bioanalytical method validation purposes, stability and metabolite assessments, immunogenicity 
testing (or possibly for purposes of immunogenicity assay development and/or validation), or to assess other actions of ISIS 678354 
with plasma constituents.  Extensive PK samples will be collected in PK subgroup only (approximately 10 patients per cohort) (see 
tables below): 
Sampling Schedule for Weekly and Every 2-Week Dosing Cohorts 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
37 
53/ET 
4* 
8* 
13* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
170 
171 
176 
183 
197 
253 
365 
*Weeks from the end of 
treatment period4 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
for 
Weekly 
Only 
Pre-
dose, 
1, 2, 
4, & 8-
hr1 
24-
hr2 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 
4, & 
8-hr1 
24-
hr2 
48-
hr3 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
for 
Every 2-
Week 
Only 
Pre-
dose, 
1, 2, 
4, & 8-
hr1 
24-
hr2 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 
4, & 
8-hr1 
24-
hr2 
48-
hr3 
Any-
time 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
Anytime 
1 
8-hr from previous dose of Study Drug. Window of (-) 2 hrs 
2 
24-hr from previous dose of Study Drug.  Window of (+/-) 4 hours 
3 
48-hr from previous dose of Study Drug.  Window of (+/-) 6 hours 
4 
End of treatment period is defined as one dosing interval post last dose 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
90 
Appendix C PK Sampling Schedule Continued 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
1 
5 
9 
13 
17 
21 
22 
23 
25 
29 
37 
53/ET 
4* 
8* 
13* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
142 
143 
148 
155 
169 
197 
253 
365 
*Weeks from the end of 
treatment period4 
All 
Patients 
Pre-
dose NA Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
only 
Pre-
dose, 
1, 2, 
4, 
and 
8-hr1 
24-
hr2 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 4, 
and 
8-hr1 
24-hr2 48-hr3 Anytime Anytime 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
Anytime 
1 
8-hr from previous dose of Study Drug. Window of (-) 2 hours allowed 
2 
24-hr from previous dose of Study Drug.  Window of (+/-) 4 hours allowed 
3 
48-hr from previous dose of Study Drug.  Window of (+/-) 6 hours allowed 
4 
End of treatment period is defined as one dosing interval post last dose 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
91 
Appendix D   Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
92 
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 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
93 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
94 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
95 
Appendix E   Additional Laboratory Tests for Patients with Platelet 
Count ˂ 100,000/mm3


ISIS 678354-CS2 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
12 June 2019 
 
96 
Appendix E Laboratory Tests to Be Performed in the Event of a Platelet Count 
˂ 100,000/mm3  
*Labs only need to be performed once.  Labs may be collected over multiple visits, if blood 
requirements are a concern, as per Investigator discretion. 
Note:  The following labs may change as additional data is assessed, and sites will be updated 
regarding any changes. 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes 
Folate (folic acid) 
Vitamin B12 
Fibrinogen 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
von Willebrand factor (vWF) Antigen 
Helicobacter pylori 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
 


Official Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 678354 Administered Subcutaneously to 
Patients with Hypertriglyceridemia and Established Cardiovascular 
Disease (CVD) or at High Risk for CVD 
NCT Number: 
NCT03385239 
Document Date: 
SAP Version 1: 17 December 2019 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 1 of 44 
  
 
 
 
 
 
Sponsor:  
Akcea Therapeutics, Inc.  
22 Boston Wharf Road, 9th Floor 
Boston, MA 02210 
 
 
Statistical Analysis Plan 
 
ISIS 678354–CS2 
 A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 678354 Administered Subcutaneously to 
Patients with Hypertriglyceridemia and Established 
Cardiovascular Disease (CVD) or at High Risk for CVD 
 
 
 
 
Date:  December 17, 2019  
 
Final Version:  1.0 
 
Collaborator:  
Ionis Pharmaceuticals, Inc.  
2855 Gazelle Court  
Carlsbad, CA 92010  






Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 4 of 44 
  
Table of Contents 
1 
INTRODUCTION ..............................................................................................................9 
1.1 
Study Overview .......................................................................................................... 10 
1.2 
Objectives .................................................................................................................. 11 
1.2.1 
Primary Objective ........................................................................................................... 11 
1.2.2 
Secondary Objectives ..................................................................................................... 11 
1.2.3 
Exploratory Objectives ................................................................................................... 11 
1.3 
Hypotheses ................................................................................................................ 11 
1.4 
Endpoints .................................................................................................................. 11 
1.4.1 
Primary Efficacy Endpoint ............................................................................................. 12 
1.4.2 
Secondary Efficacy Endpoints ........................................................................................ 12 
1.4.3 
Exploratory Endpoints .................................................................................................... 12 
1.4.4 
Safety Endpoints ............................................................................................................. 12 
2 
PROCEDURES ................................................................................................................ 13 
2.1 
General Overview of Procedures ................................................................................ 13 
2.1.1 
Screening Period ............................................................................................................. 13 
2.1.2 
Treatment Period ............................................................................................................ 13 
2.1.3 
Post-Treatment Follow-Up Period .................................................................................. 13 
2.2 
Randomization and Treatment Allocation ................................................................... 14 
2.3 
Conduct ..................................................................................................................... 14 
2.4 
Data Monitoring ........................................................................................................ 14 
2.4.1 
Safety Data Monitoring .................................................................................................. 14 
2.4.2 
Data Safety Monitoring Board ........................................................................................ 15 
2.5 
Data Management ..................................................................................................... 15 
2.5.1 
Case Report Form (CRF) Data ....................................................................................... 15 
2.5.2 
Laboratory Data .............................................................................................................. 15 
2.5.3 
Pharmacokinetics and Anti-drug Antibody Data ............................................................ 15 
2.5.4 
Other Data ....................................................................................................................... 15 
3 
ANALYSIS PLANS .......................................................................................................... 16 
3.1 
Statistical Design Summary........................................................................................ 16 
3.2 
General Overview of Analyses .................................................................................... 16 
3.2.1 
General Conventions ...................................................................................................... 16 
3.2.2 
Reporting Conventions ................................................................................................... 16 
3.2.2 
Patient Population Analyzed ........................................................................................... 19 
 
 20 
3.2.4 
Baseline and Endpoint Definition ................................................................................... 21 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
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Related to:  SOP-GDO-WW-019                                                                                                        Page 5 of 44 
  
3.2.5 
Patient Characteristics .................................................................................................... 21 
3.3 
Primary Analyses ....................................................................................................... 24 
3.3.1 
Primary Endpoint Definition .......................................................................................... 24 
3.3.2 
Primary Efficacy Analysis .............................................................................................. 24 
3.3.3 
Sensitivity Analyses of Primary Endpoint ...................................................................... 25 
3.3.4 Subgroup Analyses of Primary Endpoint ........................................................................... 26 
3.4 
Secondary Efficacy Analyses ...................................................................................... 27 
3.5 
Exploratory Efficacy Analyses ................................................................................... 27 
3.6 
Pharmacokinetic and Anti-Drug Antibody analysis ..................................................... 30 
3.6.1 
Pharmacokinetic Data Analysis ...................................................................................... 30 
3.6.2 
Anti-Drug Antibody Data Analysis ................................................................................ 30 
3.7 
Safety Analyses ......................................................................................................... 30 
3.7.1 
Imputation of Missing/Partial Dates ............................................................................... 31 
3.7.1.1 
Adverse Events ...................................................................................................... 31 
3.7.1.2 
Prior/Concomitant Medications ............................................................................. 32 
3.7.2 
Adverse Events ............................................................................................................... 32 
3.7.2.1 
Treatment Emergent Adverse Events at Injection Site .......................................... 33 
3.7.2.2 
Treatment Emergent Flu-Like Reactions ............................................................... 34 
3.7.2.3 
Adverse Events of Special Interest ........................................................................ 35 
3.7.3 
Vital Signs Measurements .............................................................................................. 35 
3.7.4 
Laboratory Measurements .............................................................................................. 35 
3.7.5 
12-Lead Electrocardiogram ............................................................................................ 39 
3.8 
Interim Analysis ........................................................................................................ 40 
4 
REFERENCES ................................................................................................................. 41 
5 
APPENDICES .................................................................................................................. 42 
Appendix A – Efficacy Measurement Analysis Visit Window and Selection Rules .................... 42 
Appendix B – Repeated Measures Efficacy Visit Mapping Instructions for Sensitivity Analysis 6 
and Model ............................................................................................................................. 44 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 6 of 44 
  
REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
1.0 
17Dec2019 
New document 
 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 7 of 44 
  
LIST OF ABBREVIATIONS 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANGPTL3 
Angiopoietin-Like 3 
apoA-I 
Apolipoprotein A-I 
apoB 
Apolipoprotein B 
apoC-III 
Apolipoprotein C-III 
aPTT 
Activated Partial Thromboplastin Time 
ASO 
Antisense Oligonucleotide 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CVD 
Cardiovascular Disease 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EoT 
End of Treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Agency 
FLR 
Flu-Like Reaction 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HbA1c 
Glycated Hemoglobin 
HDL-C 
High-Density Lipoprotein Cholesterol 
HIV 
Human Immunodeficiency Virus 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
hsCRP 
C-Reactive Protein Measured by High Sensitivity Assay 
ICH 
International Council on Harmonisation 
INR 
International Normalized Ratio 
ISR 
Injection Site Reaction 
LCRIS 
Local Cutaneous Reactions at Injection Site  
LDL-C 
Low-Density Lipoprotein Cholesterol 
LLN 
Lower Limit of Normal 
Lp(a) 
Lipoprotein(a) 


Akcea Therapeutics, Inc. 
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December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
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Related to:  SOP-GDO-WW-019                                                                                                        Page 8 of 44 
  
LSM 
Least Squares Mean 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRL 
Medpace Reference Laboratories 
OTC 
Over-The-Counter 
PAT 
Primary Analysis Time Point 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SS 
Safety Set 
TC 
Total Cholesterol 
TEAE 
Treatment-Emergent Adverse Events 
TSH 
Thyroid Stimulating Hormone 
UACR 
Urine Albumin/Creatinine Ratio 
UAT 
User Acceptance Testing 
ULN 
Upper Limit of Normality 
ULQ 
Upper Limit of Quantification 
UPCR 
Urine Protein/Creatinine Ratio 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
WBC 
White Blood Cells 
WHODD 
World Health Organization Drug Dictionary 
βhCG 
Serum Beta-Subunit of Human Chorionic Gonadotropin 
 
 
 
 
 
 
 
 
 
 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 9 of 44 
  
1 
INTRODUCTION 
Hypertriglyceridemia is associated with increased risk of first or secondary cardiovascular (CV) 
events even in patients with well controlled LDL-C levels. Elevated triglyceride levels are thought to 
play an important role in development of atherosclerosis and subsequently CV disease (CVD) due to 
accumulation of triglyceride-rich lipoproteins (TRL) and their remnant cholesterol in the arterial wall 
(Nordestgaard and Varbo, 2014). 
Apolipoprotein C-III (apoC-III), a 79 amino acid glycoprotein synthesized principally in the liver, is a 
key regulator of plasma triglyceride-rich lipoprotein (TRL) metabolism. ApoC-III determines serum 
triglyceride levels by two main mechanisms, by inhibiting lipoprotein lipase (LPL) activity as well as 
by directly inhibiting hepatic uptake of TRL, thus leading to increased levels of chylomicrons and 
TRLs (Norata et al. 2015). Genome wide significance studies have shown that individuals with loss of 
function mutations in APOC3 gene exhibited reduced serum triglyceride levels, reduced coronary 
heart disease, and increased longevity, thus providing the evidence for APOC3 gene as a target for 
CVD risk reduction (Jorgensen et al. 2014). 
AKCEA-APOCIII-LRx (ISIS 678354) is a second-generation antisense oligonucleotide (ASO) drug 
targeted to apoC-III that has been covalently bonded to triantennary N-acetyl galactosamine 
(GalNAc3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor to form an 
ASO-GalNAc3 conjugate. This GalNAc3-conjugate approach results in enhanced ASO delivery to 
hepatocytes vs. non-parenchymal cells, therefore increases ASO potency and allows to achieve a 
therapeutic benefit at a lower dose (Crooke et al. 2019). In the Phase 1 study in subjects with 
hypertriglyceridemia treatment with AKCEA-APOCIII-LRx significantly decreased plasma apoC-III 
protein levels and triglyceride levels by over 90% and over 70%, respectively at the highest dose 
used. 
Therefore, the present study was designed to evaluate this new approach to lowering triglycerides by 
reducing apoC-III levels, specifically in high-risk patients, those with established CVD or at high risk 
for CVD, whose LDL-C levels are controlled by standard therapeutic strategies but whose elevated 
triglyceride levels place them at continued risk of CV events. 
This document provides a description of the statistical methods and procedures to be implemented for 
the analyses of data from the Akcea Therapeutics, Inc. study with Protocol Number ISIS 678354-
CS2. The analyses described in this statistical analysis plan (SAP) are based upon the following study 
documents: 
• 
Study Protocol, Amendment 3 (June 12, 2019) 
• 
electronic Case Report Form (eCRF), Version 6.0 (March 06, 2019) 
Section 1 discusses study design, objectives, and endpoints; Section 2 provides the study procedures; 
and, Section 3 provides the detailed plan for the statistical analyses. Any deviations from the final 
version of this Statistical Analysis Plan will be substantiated by sound statistical rationale and will be 
documented in the final clinical study report. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 10 of 44 
  
1.1 
Study Overview 
The study ISIS 678354-CS2 is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging study being conducted at approximately 32 sites in the United States and Canada. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma triglyceride levels (≥ 200 mg/dL (≥ 2.3 
mmol/L) and ≤ 500 mg/dL (≥ 5.7 mmol/L)) and a clinical diagnosis of established CVD, or at high 
risk for CVD (as defined in the study protocol), will be eligible for enrollment upon meeting the study 
specific eligibility criteria. Patients will be on standard-of-care preventative therapy for known CVD 
risk factors as per current guidelines. The study is comprised of the following periods: 
• 
Screening: An up to 4 week Screening Period, including an up to 2-week qualification period 
following an at least 2-week diet stabilization period, where appropriate. Patients on a stable 
diet known to the investigator and clinically followed at the site may go from Screening to 
the qualification visit without a 2-week diet stabilization phase.  
• 
Treatment Period: Following qualification, up to approximately 100 eligible patients will be 
randomized in a 1:1:1:1 ratio to one of the 4 dosing cohorts as shown in Table 1, with each 
cohort having a 4:1 ratio to receive ISIS 678354 or matching volume of placebo, respectively, 
by SC injection.  
Table 1: 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 678354 
A 
10 mg ISIS 678354 
or placebo 
(Every 4 weeks) 
0.10 mL  
≤ 13 
≤ 130 mg 
B 
50 mg ISIS 678354 
or placebo 
(Every 4 weeks) 
0.50 mL  
≤ 13 
≤ 650 mg 
C 
15 mg ISIS 678354 
or placebo 
(Every 2 weeks) 
0.15 mL 
≤ 26 
≤ 390 mg 
D 
10 mg ISIS 678354 
or placebo 
(Every week) 
0.10 mL 
≤ 52 
≤ 520 mg 
 
The minimum treatment duration for all patients is 6 months and the maximum is 12 months. 
The treatment portion of the study will be complete when the last patient reaches 6 months of 
exposure, at which time patients still receiving Study Drug (ISIS 678354 or placebo) will 
transition to the Post-Treatment Follow-up Period. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 11 of 44 
  
The End of Treatment (EoT) visit for all patients should be scheduled no later than the EoT 
visit of the last patient to reach 6 months of exposure. The EoT visit should be scheduled to 
occur at one dosing interval post last dose of Study Drug: one week post last dose for weekly 
treatment (Cohort D), 2 weeks post last dose for every 2-week treatment (Cohort C), and 4 
weeks post last dose for every 4-week treatment (Cohorts A-B). For any patient whose EoT 
visit would occur later than the EoT visit for the last patient to reach 6 months of exposure, 
the primary endpoint visit (Week 25 or Week 27 depending on Cohort) will count as the EoT 
visit. 
• 
Post-Treatment Follow-up Period: After the EoT visit has been completed, patients will 
enter the 13-week post-treatment follow-up period and will return to the Study Center for 3 
follow-up visits at 4, 8, and 13 weeks post EoT visit.  
1.2 
Objectives 
1.2.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 678354 and to assess the efficacy of different 
doses and dosing regimens of ISIS 678354 for reduction of serum triglyceride levels in patients with 
hypertriglyceridemia and established CVD or at a high risk for CVD. 
1.2.2 
Secondary Objectives 
To evaluate the efficacy of ISIS 678354 on serum levels of apolipoprotein C-3 (apoC-III), total 
cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol 
(HDL-C), non-high density lipoprotein cholesterol (non-HDL-C), very low density lipoprotein 
cholesterol (VLDL-C), apolipoprotein B100 (apoB) and apolipoprotein A-1 (apoA-I).  
To evaluate pharmacokinetics (PK) of ISIS 678354 across different doses and dose regimens in 
patients with hypertriglyceridemia and established CVD or at a high risk for CVD. 
1.2.3 
Exploratory Objectives 
To evaluate the efficacy of ISIS 678354 on serum levels of lipoprotein(a) [Lp(a)], remnant 
cholesterol, and angiopoietin-like 3 (ANGPTL3). 
1.3 
Hypotheses 
The study hypothesis is that ISIS 678354 can significantly reduce the serum triglyceride levels and is 
well-tolerated for patients with established CVD or at a high risk for CVD.  
1.4 
Endpoints 
The primary analysis time point (PAT) is at Week 25 for patients who received every 4-week dosing 
(Cohorts A and B) and at Week 27 for patients who received weekly or biweekly dosing (Cohorts C 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 12 of 44 
  
and D). For patients continuing treatment beyond the PAT additional supportive efficacy and safety 
analyses will be repeated at the completion of Study Drug treatment. A final analysis will be 
conducted after all patients have completed their post-treatment follow-up visits. 
1.4.1 
Primary Efficacy Endpoint 
Percent change in fasting triglyceride level from Baseline to the PAT.  
1.4.2 
Secondary Efficacy Endpoints 
The secondary endpoints are the following at the PAT: 
• 
Percent change from Baseline in apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, 
apoB, and apoA-I  
• 
Proportion of patients who achieve serum triglycerides ≤ 150 mg/dL (≤ 1.7 mmol/L)  
• 
Proportion of patients who achieve triglycerides ≤ 100 mg/dL (≤ 1.13 mmol/L)  
1.4.3 
Exploratory Endpoints 
Percent change in Lp(a), remnant cholesterol, and ANGPTL3 from Baseline to the PAT. 
Remnant cholesterol will be calculated using the following formula:  
       Remnant cholesterol = TC – (LDL-C+HDL-C) 
1.4.4 
Safety Endpoints  
The safety analysis will be performed using the following parameters: 
• 
Adverse events (AEs)  
• 
Vital signs and weight 
• 
Physical examinations  
• 
Clinical laboratory tests (serum chemistry, hematology, coagulation, urinalysis) 
• 
Proportion of patients with platelet drop by severity, including platelet drop below lower limit 
of normal (LLN), platelet drop greater than 30% from baseline, or any platelet drop meeting 
stopping rules. 
• 
Proportion of patients with liver adverse events by severity, number of patients meeting liver 
stopping rules, and change in liver function tests by severity. 
• 
Proportion of patients with renal adverse events by severity, number of patients meeting renal 
stopping rules, and change in renal function tests by severity. 
• 
Electrocardiograms (ECGs) (including serial ECGs in a subgroup of patients undergoing 
serial PK sampling) 
• 
Use of concomitant medications  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 13 of 44 
  
2 
PROCEDURES 
The study for an individual patient will generally consist of the following periods (see also Section 
1.1):  
• 
A Screening Period (up to 4 weeks), including an up to 2-week qualification period following 
an at least 2-week diet stabilization phase, where appropriate  
• 
A Treatment Period (up to 52 weeks) during which Study Drug will be administered per 
assigned cohort by SC injection  
• 
A Post-treatment Follow-up Period (13 weeks)  
2.1 
General Overview of Procedures 
2.1.1 
Screening Period 
Written informed consent for the study will be obtained prior to the performance of any study-related 
procedures including screening procedures. An up to 4-week period is provided for completing 
screening assessments and determining patient eligibility for the study. Abnormal screening results 
may be re-tested once for determination of patient eligibility after consultation with the Sponsor 
Medical Monitor. Patients may be re-screened 1 time in order to determine eligibility. During the 
screening period, patients will undergo a medical history and physical examination including vital 
signs, 12-lead ECG and have blood and urine samples taken for clinical laboratory testing. Patients 
will be screened for Human Immunodeficiency Virus (HIV), hepatitis B, and hepatitis C. 
 2.1.2 Treatment Period 
Patients will receive the Study Drug (ISIS 678354 or placebo) administered by SC injection as shown 
in Table 1. Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters, ISIS 678354 plasma concentrations, anti-drug antibody (ADA) and biomarker 
samples, AEs and concomitant medication/procedure information will be performed according to the 
Schedule of Procedures in Protocol Appendix A. A list of laboratory analytes required for the study is 
contained in Protocol Appendix B. Protocol Appendix C details the PK sampling schedules. Within 
each cohort, a subgroup of approximately 10 patients, who will consent to extensive PK sampling, 
will undergo additional PK sampling, in what is referred to as the PK Subgroup in this study. Patients 
in this subgroup will have additional PK sampling time points, additional ECG assessments, and 
additional clinic visits during the treatment period according to the PK Sampling Schedule in Protocol 
Appendix C.  
2.1.3 
Post-Treatment Follow-Up Period 
Following the end of the treatment period, patients will enter a 13-week Post-Treatment Follow-up 
Period and return to the Study Center for 3 outpatient visits outlined in the Schedule of Procedures in 
Protocol Appendix A and C.  


Akcea Therapeutics, Inc. 
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December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
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Related to:  SOP-GDO-WW-019                                                                                                        Page 14 of 44 
  
2.2 
Randomization and Treatment Allocation 
Patients will be randomized after all screening and qualification assessments have been completed 
and after the Investigator has verified, they are eligible per criteria in the protocol sections 5.1 and 
5.2. No patient may begin treatment prior to randomization and assignment of a unique patient 
identification number. 
Using an Interactive Web-Response System (IWRS), eligible patients will be randomized in a 1:1:1:1 
ratio to 1 of the 4 parallel-dose cohorts (Cohorts A, B, C or D). Within each dose cohort, patients will 
be randomized in a 4:1 ratio to receive ISIS 678354 or matching volume of placebo, respectively.  
A permuted block schedule will be used. The randomization schedule will be generated and held by 
an independent vendor. Patients who withdraw from the study will not be replaced. The study is 
planned to randomize approximately 100 patients. 
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 Agency (FDA) Code of Federal Regulations, 
and all other local regulatory requirements. 
2.4 
Data Monitoring 
In order to ensure maintenance of the study blind, the results of efficacy parameters consisting of lipid 
panel results including apoA-I, apoB, apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, 
triglycerides, ANGPTL3 and Lp(a) will be blinded to the Akcea study team, Clinical Research 
Organization (CRO) study team, Investigators, Study Center personnel and patients until after 
database lock for EoT. After Sponsor’s unblinding post completion of treatment period, blinded study 
personnel will continue to oversee the study until all patients completed the study. 
2.4.1 
Safety Data Monitoring 
Safety information will be collected, reviewed, and evaluated by Akcea (or designee) in accordance 
with the Safety Management Plan throughout the conduct of the clinical trial.  
In addition to the standard monitoring of clinical safety parameters, there are individual monitoring 
rules for the selected parameters related to renal, liver function, platelet count, bleeding events, 
constitutional symptoms, and glycemic control, described in the Protocol Section 8.5. The stopping 
rules and adjustment of dose are specified in protocol Sections 8.6 and 8.7  
Akcea (or designee) is responsible for regulatory submissions and reporting to the Investigators of 
suspected unexpected serious adverse reactions (SUSARs) per ICH guidelines. Processing of serious 
adverse events (SAEs) is delegated to a third-party vendor although Akcea remains accountable for 
this activity and process. AEs and SAEs are reviewed according to standard operating procedures. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 15 of 44 
  
The Study Medical Monitor will review all AEs and SAEs on an ongoing basis throughout the study. 
Monitoring of AEs are outlined in the Protocol section 9.4 
2.4.2 
Data Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and efficacy (as needed) data collected on ISIS 678354 during this study. Based on its 
ongoing assessment of the safety and tolerability of ISIS 678354, the DSMB will provide 
recommendations to Akcea 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. 
2.5 
Data Management 
2.5.1 
Case Report Form (CRF) Data 
Bioclinica® is responsible for creating the Electronic Data Capture (EDC) data entry screens, 
database and edit checks using definitions developed by the Sponsor (or designee). 
Trennic Data Services, a data management vendor contracted by Akcea, is responsible for creating 
CRF Completion Guidelines (CCGs) and will oversee the development of the Electronic Data 
Capture (EDC) system by the EDC hosting vendor. Akcea (or designee) is responsible for the review, 
querying, and locking of the database. 
2.5.2 
Laboratory Data 
Trennic Data Services is responsible for the format of the laboratory electronic data transfers and the 
transfer schedule. Akcea is responsible for the review of the clinical laboratory data. Central lab data 
managed by Medpace Reference Laboratories (MRL) are not stored in the EDC system but will be 
transferred to Trennic Data Services. Investigator sites have access to this data via lab reports sent 
directly from MRL. 
2.5.3 
Pharmacokinetics and Anti-drug Antibody Data 
PPD and Charles River Laboratories are responsible for the production of PK and anti-drug antibody 
(ADA) data respectively. Akcea is responsible for the review of the data. This process involves 
reviewing the patient and visit identifiers with the clinical data collected in the EDC system. The PK 
and ADA results are not stored in the EDC system but will be transferred to Akcea Therapeutics, Inc. 
or designee as external data. 
2.5.4 
Other Data 
Almac manages and produces randomization code. The User Acceptance Testing (UAT) data will be 
delivered prior to the database lock for pre-programming. The actual data will be delivered after 
database lock. Data will not be stored in the EDC system, but will be transferred to Parexel as 
external data. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 16 of 44 
  
3 
ANALYSIS PLANS 
3.1 
Statistical Design Summary 
This is a multi-center, randomized, double blind, placebo-controlled study. 
The study hypotheses will be formally evaluated at the planned EoT analysis on data obtained 
through the data cut-off date, defined as the date of the last EoT visit. The database will be queried, 
and data cleaning performed on all data, with database interim lock of all data, at which point the 
treatment code is unblinded and the EoT analysis is performed. 
The primary analysis model will be an Analysis of Covariance (ANCOVA) model for percent change 
from baseline to the PAT in fasting triglycerides. Missing data will be imputed by a multiple 
imputation method as the primary analysis and will be supported by various sensitivity analyses. 
The treatment groups proposed in this analysis are defined as follows: 
• 
ISIS 678354 10 mg every 4 weeks (Q4W) 
• 
ISIS 678354 50 mg every 4 weeks (Q4W) 
• 
ISIS 678354 15 mg every 2 weeks (Q2W) 
• 
ISIS 678354 10 mg every week (QW) 
• 
Pooled Placebo, defined as the combined group of placebo patients from the 4 randomized 
cohorts 
A final analysis will be performed after all data from the 13-week post treatment follow-up period are 
collected and locked. 
 
3.2 
General Overview of Analyses 
This analysis plan describes the reporting of data at 1) all patients completed the primary analysis 
time point 2) all patients completed the study. 
3.2.1 
General Conventions 
All reporting will be performed in SAS version 9.3 or higher.   
All eCRF data and lab data transfers, as well as 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, and will be sorted by treatment group, patient ID, visit, and time point (where appropriate).  
3.2.2 
Reporting Conventions 
Efficacy results will be summarized under the treatment to which patients were randomized. Safety 
and PK results will be summarized under the treatment which patients actually received. Should there 
be any cases after unblinding in which a patient received treatment other than what the patient was 


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randomized to, such cases will be discussed in the study report and noted in footnotes where 
applicable. 
All tables will present the population frequencies in each treatment group and/or subgroup (where 
appropriate) and will indicate the number of patients with non-missing data and the denominators for 
percentages.    
Descriptive summary statistics including n, mean, median, standard error, standard deviation SD, 
interquartile range (25th percentile, 75th percentile), range (minimum, maximum), mean 95% 
confidence interval (CI) for continuous variables, and counts and percentages for categorical 
variables, will be used to summarize data by treatment group. Summaries of PK concentrations and 
parameters will also include coefficient of variation (CV%), geometric mean, and geometric CV%. 
Where appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided 
tests with 5% Type I error rates unless otherwise stated. 
Except summaries for PK parameters, precision for displays will use the following conventions.  
Means, percentiles (e.g., median, 25th and 75th percentile), least squares means, difference in least 
squares means will be displayed to one more decimal place than measured values. Standard 
deviations and standard errors will be displayed to two more decimal places than measured values. 
The minimum, maximum and confidence intervals will be displayed using the same number of 
decimal places as the recorded values.  All raw values presented in listings will be displayed to the 
measured precision.  Percentages will be displayed to one decimal place. For PK concentrations and 
parameters, mean, standard deviation, standard error, geometric mean, median, minimum, and 
maximum values will be presented to 3 significant digits and CV% and geometric CV% will be 
presented to one decimal place. p-value will be displayed to 4 decimal places.  p-value less than 
0.0001 will be presented as “<0.0001”. p-value greater than 0.9999 will be displayed as “>0.9999”. 
Confidence intervals will be presented using a comma separator rather than a dash. 
Age will be presented in years.  Weight will be presented in kg.  Height will be presented in cm. 
Temperature will be presented in °C. Laboratory listings will be presented using original unit. 
Summary tables of lab results will be based on original unit. For multiple original units within the 
parameters, the results will be converted to the majority of units as reported.  Lab shift tables and 
abnormalities tables will be based on mock shell displays. 
The lab data will be reported using central lab and/or local lab depending on the type of outputs or 
values. Table 2 and Table 3 outline which data source, lab unit and visits should be used for the 
specific outputs and values.  
Table 2: 
Summary of Lab Data Source per Type of outputs 
Type of Outputs 
Data source 
Unit 
Visits 


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Listings 
Listings of lab data 
Central and local 
lab in separate 
listings 
Original Unit 
SCH + USCH 
visits 
Tables, 
Figures 
All efficacy endpoints 
(primary, secondary, 
exploratory) 
Central lab  
Original Unit 
analysis SCH + 
USCH within 
visit window 
Descriptive summary of 
platelet count data 
Central and local 
lab, separate tables 
and figures   
Original Unit 
(cells/mm3) 
nominal SCH 
visits  
Descriptive summary 
safety lab data other than 
platelet counts 
Central lab 
Original Unit 
nominal SCH 
visits 
Safety shift tables  
Central and local 
lab  
Per mock shells nominal SCH + 
USCH visits 
Abnormalities lab tables 
Central and local 
lab  
Per mock shells nominal SCH + 
USCH visits 
SCH: scheduled; USCH: unscheduled 
 
Table 3: 
Summary of Lab Data Source per Type of Values 
Type of values 
Data source 
Unit 
Visits 
Baseline for platelet 
count 
Central and local lab 
Original Unit 
(cells/mm3) 
SCH + USCH visits prior to 
the first dose of Study Drug 
Baseline for other 
safety labs 
Central lab  
Original Unit 
nominal based on SCH + 
USCH visits; selected as last 
non missing prior to first dose 
of Study Drug 
Confirmed lab value 
Central and local lab 
Per mock shells 
nominal SCH + USCH visits 
SCH: scheduled; USCH: unscheduled 
Efficacy assessments (i.e. lipid panel) will be mapped to an analysis visit per the analysis visit 
windows as specified in Appendix A and summarized by analysis visit. The selection rule of analysis 
visits is specified in Appendix A as well.  


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Safety assessments will be summarized by nominal visit as collected in CRF. For summary tables by 
nominal visit, only scheduled visits will be used. For multiple records at the nominal (scheduled) 
visit, the average will be used for continuous values, or the worst will be used for categorical values.  
For summary tables of platelet counts by nominal visit, scheduled visits from central lab data and 
separately, from local lab data will be used. For multiple records at the nominal (scheduled) visit, the 
average will be used for continuous values, or the worst will be used for categorical values. 
3.2.2 
Patient Population Analyzed 
The following analysis sets will be used for the analysis of data as described within each analysis set. 
Screened Patients are defined as the patients who sign an informed consent form. 
Randomized Patients are defined as the patients who receive a randomization assignment.  
Full Analysis Set (FAS): All patients who are randomized and received at least 1 dose of Study Drug 
(ISIS 678354 or placebo). The FAS represents the practically-feasible intent-to-treat (ITT) population 
as delineated in International Conference on Harmonisation (ICH) Guideline E9. This population will 
be used for the analysis of efficacy.  
Per Protocol Set (PPS): Subset of the FAS who received prior to the Primary Analysis Timepoint at 
least 5 monthly doses of Study Drug for patients randomized in Cohorts A and B, or at least 11 every 
2-week doses for patients randomized in Cohort C, or at least 22 weekly doses for patients 
randomized in Cohort D, and who have no major protocol deviations that could compromise the 
interpretation of efficacy. Major deviations will be determined prior to unblinding for statistical 
analysis. This population will be used for supportive inferences concerning efficacy.  
Safety Set (SS): All patients who are randomized and received at least 1 dose of Study Drug. This 
population will be used for all safety analyses.  
PK Population: All patients who are randomized and received at least 1 dose of ISIS 678354, and 
have at least 1 evaluable concentration result post first dose. This population will be used for analysis 
of PK data.  
PK Subgroup:  A subset of PK population who will undergo additional PK sampling after dose 
administration on Day 1 and Week 21 (Cohorts A and B) / Week 25 (Cohorts C and D) to evaluate 
the plasma PK parameters of ISIS 678354. 
Patients in PK subgroup will also have additional ECGs conducted as indicated in Table 4.  
Table 4: Additional PK Sampling and ECG Schedule for PK Subgroup 
Cohort  
Additional PK Sampling 
Additional ECGs 


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Cohort A and B 
Week 1 (1, 2, 4, 8, 24 hr post-dose),  
Week 21 (1, 2, 4, 8, 24, 48 hr post-dose), 
Week 22 (Anytime),  
Week 23 (Anytime) 
Week 1 (1, 2, 4, 8, 24 hr post-dose), 
Week 21 (1, 2, 4, 8, 24 hr post-dose) 
Cohort C 
Week 1 (1, 2, 4, 8, 24 hr post-dose),  
Week 25 (1, 2, 4, 8, 24, 48 hr post-dose), 
Week 26 (Anytime),  
Week 27 (pre-dose) 
Week 1 (1, 2, 4, 8, 24 hr post-dose), 
Week 25 (1, 2, 4, 8, 24 hr post-dose) 
Cohort D 
Week 1 (1, 2, 4, 8, 24 hr post-dose),  
Week 25 (1, 2, 4, 8, 24, 48 hr post-dose), 
Week 26 (pre-dose) 
Week 1 (1, 2, 4, 8, 24 hr post-dose), 
Week 25 (1, 2, 4, 8, 24 hr post-dose) 
PK-ECG Set: All patients who provide baseline ECG data and at least one post-baseline matched PK 
before onset of anti-drug antibody and ECG record. This population will be used to analyze the 
exposure-QTcF relationship.  Patients determined to have a pacemaker rhythm will be excluded from 
the PK-ECG Set. 
All primary and secondary efficacy endpoints will be assessed in the FAS and PPS, with the former 
being the basis for the primary efficacy analysis. All exploratory efficacy endpoints will be assessed 
in the FAS. All safety assessments will be performed on the SS. PK endpoints will be assessed in the 
PK Population and PK Subgroup as applicable.   
Patients in randomization populations, FAS and PPS will be analyzed in the treatment group to which 
they were randomized. Patients in SS, PK Population, PK Subgroup, and PK-ECG Set will be 
analyzed in the group with actual treatment they received. 
 
 
 
 
 
 
 
 


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3.2.4 
Baseline and Endpoint Definition 
For platelet count data, central and local lab will be used in baseline derivation. For other lab data, 
only central lab will be used in baseline derivation.  
Baseline for lipid panel is defined as the average of Day 1 fasting pre-dose assessment and the last 
non-missing fasting measurement prior to Day 1 pre-dose assessment.  If 1 of the 2 measurements is 
missing, then the other measurement will be assigned as the baseline value.  If both are missing, then 
the baseline will be set as missing.  Note that if on Day 1, there are multiple pre-dose assessments, 
then the last assessment with non-missing value will be used as the Day 1 pre-dose assessment.  
Baseline for platelet is defined as the average of all assessments prior to the first dose of Study Drug. 
Baseline for ECG is the average of the triplicate taken on Day 1 pre-dose for ECG summary over 
time and abnormal ECG parameters tables. If only one or two assessments are available, the single 
assessment or average of the two assessments will be used. If ECG results on Day 1 pre-dose is 
missing, results at screening visit will be used as baseline. 
Baseline for other measurements is defined as the last non-missing assessment prior to the first 
dose of Study Drug.  
3.2.5 
Patient Characteristics 
Disposition and Analysis Population 
The number of patients screened, randomized, dosed, number of patients included in each analysis 
set, the number of patients who completed treatment, discontinued treatment along with reasons for 
discontinuing treatment, entered post-treatment follow-up, completed post-treatment follow-up, and 
discontinued post-treatment follow-up, along with reasons for early terminating post-treatment 
follow-up, will be presented in screened patients by treatment group to which they were randomized, 
and overall. 
Listings of patient disposition will also be provided for all randomized patients. 
Protocol Deviation 


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Major protocol deviations will be summarized by deviation category for randomized patients. 
Reasons for excluding patients from PPS will be summarized for randomized patients. All protocol 
deviations (major and minor) will be provided in a data listing for randomized patients. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group and overall in FAS, 
including age, sex, race, ethnicity. Baseline characteristics include number of patients with 
established CVD vs. high risk for CVD, weight, height, body mass index (BMI), triglycerides, apoA-
I, apoB, apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, ANGPTL3, remnant cholesterol, 
and Lp(a). 
Medical History 
Medical history will be coded by Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
Version 20.1 and will be summarized by System Organ Class (SOC) and Preferred Term (PT) by 
treatment group and overall for the FAS.  Medical history will also be provided in a data listing. 
Cardiovascular history will be tabulated by ISIS 678354 treatment group and pooled placebo group. 
A by-patient data listing will also be provided. 
Prior/Concomitant Medications 
All medications will be coded by World Health Organization Drug Dictionary (WHODD) Version 
DEC2017.  The start and stop dates of medications that are recorded on the Concomitant Medications 
CRF will be used to determine whether the medications are prior or concomitant to the treatment 
period. Missing or partial dates will be imputed as outlined in Section 3.7.1.  Prior medications 
include medications that started prior to the first dose of Study Drug from the time the patient has 
signed the informed consent, regardless whether continued while on treatment or not. A concomitant 
medication is any drug or substance (including over-the-counter (OTC) medications, herbal 
medications and vitamin supplements) administered between first administration of study drug and 
the end of the post-treatment follow-up period.  A prior medication with an imputed stop date that is 
missing or on or after date of first dose of Study Drug will also be considered as a concomitant 
medication. Medications will be classified based on imputed start and imputed stop dates as follows: 
1) Prior Medication 
Start Date 
End Date 
< FDD 
≥ Inform Consent Date 
Missing 


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FDD = Date of First Dose of Study Drug 
2) Concomitant Medication  
Start Date 
End Date 
< FDD 
≥ FDD 
Missing 
≥ FDD  
Any non-missing stop date 
Missing 
FDD = Date of First Dose of Study Drug 
Prior or concomitant medications will be summarized separately for all Safety Set by Anatomical 
Therapeutic Chemical (ATC) class, Preferred Term, treatment group and overall with counts and 
percentages, sorting by decreasing frequency of all patients.  The concomitant medications in on-
treatment and on-study period will be summarized respectively. 
Prior or concomitant medications will be displayed in patient listings for all Randomized Patients.  A 
listing of ancillary procedures will also be provided. Note that imputed dates will be used for prior 
and concomitant medications classification. Originally reported dates will be used for listings. 
Treatment Exposure and Compliance 
Treatment duration and amount of Study Drug received will be summarized by treatment group and 
overall in Safety Set.  Compliance to Study Drug will be summarized by descriptive statistics by 
treatment group and overall. 
Compliance (%) will be calculated as follows:  
100 x (total volume of Study Drug) / (total volume of Study Drug scheduled during the 
treatment period).  
For early withdrawals/terminations, the volume of Study Drug will be calculated for the period up to 
their withdrawal/termination. 


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3.3 
Primary Analyses  
3.3.1 
Primary Endpoint Definition 
The primary endpoint is the percent change in fasting triglycerides from baseline to the primary 
analysis time point. The primary analysis time point is Week 25 for patients in Cohort A and B, and 
Week 27 for Cohort C and D.  
3.3.2 
Primary Efficacy Analysis  
The primary efficacy analysis for the primary endpoint will be the pairwise comparison of percent 
change from baseline to the primary analysis time point in fasting triglycerides between ISIS 678354 
treated groups and pooled placebo group in the FAS.  
The percent change from baseline in triglycerides will be analyzed using an ANCOVA model with 
treatment group as a fixed factor and log-transformed baseline triglycerides as a covariate. The 
ANCOVA model will use log(Y/X) as dependent variable, where Y is the post-baseline value of 
triglycerides and X is the baseline value of the triglyceride. The model will provide an estimate of the 
log ratio, which will then be converted back to the original ratio scale. The percent change from 
baseline will then be estimated based on the estimated ratio. Patients with missing primary endpoint 
will have their fasting triglyceride value imputed using the multiple imputation method described 
below. 
Missing data for the primary efficacy endpoint will be handled by a multiple imputation model that 
contains the following variables: log-transformed baseline fasting triglyceride value, log-transformed 
fasting post-baseline triglyceride values, stratified by treatment (Schafer 1997; Schafer 1999). 
Imputation of missing data will be conducted under a working assumption of missing at random 
(MAR), meaning that the propensity for a data point to be missing is not related to the missing data, 
but it is related to some of the observed data. 
The imputations will be performed for post-baseline visits. The Markov Chain Monte Carlo (MCMC) 
method will be used under the multivariate normality assumption to impute the missing primary 
endpoint by treatment group (ISIS 678354 treatment group or pooled placebo treatment group). In 
order to be compliant with the normality assumption, baseline and post-baseline triglyceride data will 
be log-transformed prior to the imputation process and will be reverted when creating the imputed 
dataset. The MCMC method will impute 100 datasets in order to estimate the treatment effect, where 
the median value across the imputed datasets will be used for patients with missing endpoint. 
The primary endpoint will be compared between each ISIS 678354 treatment group and the pooled 
placebo group for each of the 100 imputed datasets. The estimates from the 100 fitted models will be 
combined to provide an overall estimate, with corresponding CIs and p-value (Little and Rubin, 
2002).  Results from the ANCOVA model will be tabulated by ISIS 678354 treatment groups 
compared to the pooled placebo group. 
For fasting triglycerides, observed value, change from baseline and percentage of change will be 
summarized by analysis visit using descriptive statistics in FAS. 


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Mean (SD) percent change over time in fasting triglycerides will be plotted by ISIS 678354 treatment 
group and pooled placebo group, until there are fewer than 10% of the FAS/PPS population at a given 
visit. Waterfall plots of by-patient percent changes from baseline to the primary analysis time point 
will also be provided. 
The primary efficacy analysis will take place after the last patient has completed the primary analysis 
time point, and the database has been locked. 
All primary efficacy data will be provided in data listings.   
The sample SAS code for the ANCOVA model can be found below: where the baseline and post-
baseline values will be log-transformed first. Log (post-baseline/baseline) calculated as log (post-
baseline) – log (baseline) will be subjected to the ANCOVA model. 
********************************************************************* 
* Note:   
*  Base= baseline                                                                  
*  Y=Post-baseline  
*  TRTP = Treatment group: Pooled Placebo, 10 mg Q4W, 50 mg Q4W, 15 mg Q2W, 10 mg QW      
********************************************************************* 
ods output lsmeans=lsm diffs=diff; 
proc mixed data = dataset; 
class TRTP (ref=’pooled placebo’) ; 
model log (Y/base) = TRTP  log(Base) /solution cl;  
lsmeans TRTP/ diff cl;    
run; 
3.3.3 
Sensitivity Analyses of Primary Endpoint 
In addition to the primary efficacy analysis, the following sensitivity analyses will be conducted on 
the FAS. 
Sensitivity Analysis 1 (Per Protocol Set): The primary efficacy analysis will be repeated, using the 
PPS population. 
Sensitivity Analysis 2 and 3 (Non-Parametric Analyses): The primary efficacy endpoint will be 
analyzed using a non-parametric Wilcoxon Rank Sum test using both the FAS and the PPS. Missing 
data will be handled using the same MCMC multiple imputation method as the primary analysis. The 


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treatment effect will be estimated using the Hodges-Lehmann estimator of the location shift between 
ISIS 678354 treatment groups and the pooled placebo group. Asymptotic 95% CI and corresponding 
p-values will be provided. 
Sensitivity Analysis 4 (FAS) Using controlled imputations (pattern mixture models [PMM] with 
ANCOVA) will be conducted to assess the robustness of the missing at random assumption. With this 
approach, missing not at random (MNAR) is assumed, and the mean function for the missing data 
from patients treated with ISIS 678354 who discontinue the study is pre-specified. Missing 
triglycerides for placebo patients will be imputed using the same MCMC multiple imputation method 
as the primary analysis. Patients treated with ISIS 678354 who discontinue the study due to AE or 
lack of efficacy will have their post-discontinuation triglyceride values imputed using estimates from 
the placebo patients using the copy increment from reference (CIR) approach, detailed in (Carpenter 
et al. 2013). The assumption is based on the premise that when a patient discontinues treatment due to 
informative missing data, at the time of discontinuation they would progress in a similar manner as 
placebo-treated patients. Otherwise, non-informative missing data will be imputed using the same 
MCMC method as the primary analysis, since it is assumed that those patients would have continued 
in a similar manner to similar patients in their own treatment group who remained on the study. 
Therefore, the missing data for these patients is expected to be missing at random.  
Sensitivity Analysis 5 (FAS) An ANCOVA will be performed on the primary efficacy endpoint 
without applying any imputation for missing data.    
Sensitivity Analysis 6 (FAS) A repeated measures analyses will be performed on the fasting 
triglyceride endpoint.  The percent change from baseline in triglycerides will be analyzed using an 
MMRM model with treatment group as a fixed factor, log-transformed baseline triglycerides and 
timepoint as covariates. If log transformation is applied, the analysis will carry the same conditions as 
the primary efficacy analysis for back transformation.  No imputation of data is applied to this 
analysis. Analysis visits beyond PAT (Week 29, 37, 45, and 53) will be included only if the total n at 
the analysis visit is at least 10% of the overall FAS. Visit mapping is provided in Appendix A and 
SAS code is outlined in Appendix B.  
3.3.4 Subgroup Analyses of Primary Endpoint 
Subgroup analyses (with log-transformation and imputation method) for the primary endpoint are 
planned as follow:  
• 
Gender: Male, Female 
• 
Age: <65 and ≥65 years old 
• 
CV history: established CVD (All patients enrolled in original protocol and protocol 
amendment 1, and Patients enrolled in protocol amendment 2 per Inclusion Criteria 3a), at risk 
for CVD (Patients enrolled in protocol amendment 2 per Inclusion Criteria 3b) 


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• 
Concomitant drugs used in diabetes: yes, no (ATC code: A10, ATC2 text: Drugs Used in 
Diabetes) 
• 
Concomitant use of insulin and insulin analogues: yes, no (ATC code: A10A, ATC3 text: 
Insulins and Analogues) 
• 
Concomitant use of triglyceride lowering drugs (fibrates, omega-3 fatty acids): yes, no to 
include ATC code: C10AB, ATC4 text: Fibrates, and ATC code: C10AX, ATC4 Text: Other 
Lipid Modifying Agents, Preferred Term: EICOSAPENTAENOIC ACID ETHYL ESTER, FISH 
OIL, FISH OIL;OMEGA-3 FATTY ACIDS, FISH OIL;TOCOPHEROL, OMEGA-3 FATTY 
ACIDS, OMEGA-3-ACID ETHYL ESTER. 
3.4 
Secondary Efficacy Analyses  
All analyses of secondary endpoints will be performed on the FAS as primary and PPS as supportive. 
Secondary efficacy analyses are based on the data collected at the primary analysis time point.    
• 
Percent change from baseline at the primary analysis time point in fasting apoC-III, TC, 
LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, and apoA-I will be compared between each 
ISIS 678354 group and pooled placebo group using an ANCOVA model with log-
transformed baseline as covariate. The ANCOVA model without applying any imputation for 
missing data will use log(Y/X) as dependent variable, where Y is the post-baseline lipid value 
and X is the baseline lipid value.  
• 
Proportion of patients who achieve fasting triglycerides ≤ 150 mg/dL (≤ 1.7 mmol/L) at the 
primary analysis time point with MCMC imputation will be compared between each ISIS 
678354 treatment group and pooled placebo group using a logistic regression model with 
baseline triglycerides as a covariate.  
• 
Proportion of patients who achieve fasting triglycerides ≤ 100 mg/dL (≤ 1.13 mmol/L) at the 
primary analysis time point with MCMC imputation will be compared between each ISIS 
678354 treatment group and pooled placebo group using a logistic regression model with 
baseline triglycerides as a covariate. 
Summary statistics of the observed value, change and percent change from baseline by analysis visit 
will be performed for fasting apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apoB, and apoA-
I on FAS. 
3.5 
Exploratory Efficacy Analyses  
All analyses of exploratory endpoints will be performed on the FAS.  Percent change from baseline at 
the primary analysis time point in fasting Lp(a), remnant cholesterol, and ANGPTL3 as log- 
transformed ratio of post-baseline to baseline value will be compared between each ISIS 678354 
group and pooled placebo group using an ANCOVA model with log-transformed baseline as 
covariate. Summary statistics including observed value, change and percent change from baseline by 
analysis visit will also be performed. 


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Table 5 outlines the analysis methods used in each efficacy analysis. 
 
 


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Table 5 Summary of Analysis Methods in Efficacy Analyses 
Endpoint  
Analysis 
Type  
Log-
Transformed 
Data  
MCMC 
imputation  
Population  Model  
Primary 
Endpoint 
Primary 
Analysis  
Yes 
Yes, assume 
MAR 
FAS 
ANCOVA 
Sensitivity 
Analysis 1 
Yes 
Yes, assume 
MAR 
PPS 
ANCOVA 
Sensitivity 
Analysis 2 
Yes 
Yes, assume 
MAR 
FAS 
non-parametric Wilcoxon 
Rank Sum test 
Sensitivity 
Analysis 3 
Yes 
Yes, assume 
MAR 
PPS 
non-parametric Wilcoxon 
Rank Sum test 
Sensitivity 
Analysis 4 
Yes 
Yes,  
Placebo: 
assume MAR. 
  
ISIS 678354: 
missing before 
discontinuation, 
assume MAR;  
missing after 
discontinuation 
assume CIR  
FAS 
ANCOVA 
Sensitivity 
Analysis 5 
Yes 
No 
FAS 
ANCOVA 
Sensitivity 
Analysis 6 
Yes 
No 
FAS 
MMRM 
Subgroup 
Analysis  
Yes 
Yes 
FAS 
ANCOVA 
Secondary 
Endpoints  
Secondary 
Analysis  
Yes 
Yes for 
triglycerides; 
No for other 
endpoints 
FAS and 
PPS 
ANCOVA 
Exploratory 
Endpoint 
Exploratory 
Analyses 
Yes 
No 
FAS 
ANCOVA 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 30 of 44 
  
3.6 
Pharmacokinetic and Anti-Drug Antibody analysis 
3.6.1 
Pharmacokinetic Data Analysis 
All PK data analysis will be conducted using the PK Population except the listing of PK 
concentrations which will be conducted on the Safety Set. 
The concentrations of ISIS 678354 in plasma expressed as ISIS 678354-equivalent (as total 
full-length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 678354) will be summarized by nominal visit by treatment group with and without stratification 
by patient ADA status using descriptive statistics. In addition, plasma terminal elimination half-life of 
ISIS 678354 will be calculated using the post-treatment follow-up data if data permits. 
Additionally, for patients in the PK subgroup only, PK parameters will be calculated using non-
compartmental methods. The maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) 
values will be obtained directly from the plasma concentration-time data. The area under the plasma 
concentration-time curve (AUC) values after the first dose (AUC0-24h) and steady-state dose (AUC0-24h 
and AUCtau) will be calculated using the linear trapezoidal rule. Other PK parameters may be 
calculated at the discretion of the Sponsor. Plasma PK parameters will be summarized using 
descriptive statistics with and without stratification by patient ADA status. 
Exposure-response relationships between selected lipid and PK measures (e.g., plasma trough 
concentrations) may be explored in a separate population PK/PD analysis combined with other 
clinical studies. 
3.6.2 
Anti-Drug Antibody Data Analysis 
All ADA data analysis will be conducted using the Safety Set. 
The ADA of ISIS 678354 will be assessed before, during, and after treatment with Study Drug 
(ISIS 678354 or placebo). The ADA incidence will be summarized by nominal visit and at the patient 
level by treatment group, as the total number of and percent of evaluated patients with ADA negative, 
positive, and unknown status. Patient ADA status (positive, negative or unknown) for all evaluable 
patients, along with the study day associated with the first emergence of ADA positivity (i.e., onset of 
ADA), the last positive ADA status observed, and peak ADA titer will be listed by treatment group. 
Potential relationships of ADA with selected efficacy, safety, and PK measures may be evaluated. 
3.7 
Safety Analyses 
All safety analyses will use the Safety Set unless otherwise specified. Unless noted otherwise, 
denominators for all tables will be number of patients in the SS. Safety endpoints including laboratory 
assessments and vital signs will be analyzed by nominal visit collected on CRF. 
Adverse events, concomitant medications, safety shift tables, and all tables related to safety 
monitoring/stopping rules will be summarized by 2 periods: on-treatment and on-study. On-treatment 
assessment is defined as the assessment from the first dose to the last dose of Study Drug plus one 
dosing interval. For Cohorts A and B, on-treatment period spans time from first dose to the last dose 
+ 28 days; For Cohort C, on-treatment period spans time from first dose to the last dose + 14 days; 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 31 of 44 
  
For Cohort D, on-treatment period spans time from first dose to the last dose + 7 days. On-study 
assessment is defined as the assessment from the first dose to the last visit in post-treatment follow-up 
period.   
3.7.1 
Imputation of Missing/Partial Dates 
3.7.1.1 Adverse Events 
For AEs, the following imputation rules will be applied to impute start dates under conservative 
principles: 
• 
If year, month and day are all missing then assign the date of first dose of Study Drug 
• 
If month and day are missing, and year is: 
o the same as the year of the first dose of Study Drug then assign the month-day of first 
Study Drug 
o earlier than the year of the first dose of Study Drug then assign December 31 
o after the year of the first dose of Study Drug then assign January 1 
• 
If only day is missing, and month-year is: 
o the same as the month-year of the first dose of Study Drug then assign the day of first 
Study Drug  
o earlier than the month-year of the first dose of Study Drug then assign the last day of the 
month 
o after the month-year of the first dose of Study Drug then assign the first day of the month 
Imputation will be performed for the end date only if the day or month is missing (i.e., year is 
present) for a resolved AE as follows: 
• 
If month and day are missing, and year is 
o the same as the year of the last dose of Study Drug then assign the month-day of the last 
dose of Study Drug  
o otherwise, assign December 31 
• 
If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to the 
imputed end date. 
Analysis period (on-treatment and on-study) will be assigned by comparing the imputed AE start date 
with the period start/end date. 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 32 of 44 
  
3.7.1.2 Prior/Concomitant Medications 
For prior/concomitant medications, the following imputation rules will be applied to impute start 
dates under conservative principles: 
• 
If year, month and day are all missing, then assign the date of first dose of Study Drug  
• 
If month and day are missing and year is: 
o earlier than the year of the first dose of Study Drug then assign December 31 
o otherwise, assign January 1 
• 
If only day is missing, and month-year is: 
o earlier than the month-year of the first dose of Study Drug then assign the last day of the 
month 
o otherwise, assign the first day of the month 
Imputation will be performed for the end date only if the day or month is missing (i.e., year is 
present) for a stopped prior/concomitant medication as follows: 
• 
If month and day are missing, then assign December 31 
• 
If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to the 
imputed end date. 
Analysis period will be assigned by comparing the imputed medication start/end date with the period 
start/end date. 
3.7.2 
Adverse Events 
All AEs will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1.  
Missing or partial dates will be imputed as outlined in Section 3.7.1.   
Treatment-emergent adverse events (TEAEs) are defined as adverse events that occurred after the 
first dose of Study Drug. If the imputed onset date/time is the same as or after the date/time of the 
first dose of Study Drug, then the event is treatment emergent. An AE with a completely missing start 
date will be assumed to be treatment emergent. 
In the situation where change in severity (but no change in seriousness) occurs for an AE, study sites 
are instructed to enter an end date for the original AE and start a new record for the AE with a new 
severity reported. In the new record, the changed severity is to be recorded and the start date will be 
set to be the end date of the previous record. 
When counting the total number of treatment-emergent events for table display, events reporting an 
increase in severity will be counted as separate events.  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 33 of 44 
  
AE summary tables by treatment group and overall will be presented in 2 periods separately: on-
treatment and on-study. The frequency of patients with any incidence of AEs and the number of 
events will be summarized by SOC and PT for: 
• 
TEAEs 
• 
TEAEs related to Study Drug. Related is defined as “Related”, “Possible”, or missing 
relationship to Study Drug 
• 
TEAEs by severity. At each level of patient summarization, a patient with multiple events is 
counted only once according to the worst reported severity. Adverse events with missing 
severity will be categorized as “Missing” for this summary. 
• 
TEAEs related to Study Drug by severity  
• 
Most common TEAEs. Most Common TEAE is defined as treatment-emergent adverse 
events with an incidence of 10% or more within any treatment groups at PT level. 
• 
Treatment Emergent SAEs 
• 
Treatment Emergent SAEs related to Study Drug 
• 
TEAEs leading to permanent treatment discontinuation 
• 
TEAEs leading to death. 
Summary tables will be sorted by decreasing frequency of SOC and then by decreasing frequency of 
PT within SOC in pooled ISIS 678354 group. If the frequency is the same for multiple PTs, sort 
alphabetically. 
An overview of AEs will be provided for all TEAEs. Treatment-emergent AEs, treatment-emergent 
SAEs, TEAEs related to Study Drug, treatment-emergent SAEs related to Study Drug, TEAEs that 
lead to Study Drug discontinuation, TEAEs that lead to Study Drug interruption, TEAEs that lead to 
dose reduction, and TEAEs leading to death will be listed. Note that imputed dates will be used for 
defining TEAEs and classification of TEAEs into analysis periods.  
Listings of all AEs, TEAEs related to Study and Treatment Emergent SAEs related to Study will be 
presented. Originally reported dates will be used in listings.  
3.7.2.1 Treatment Emergent Adverse Events at Injection Site 
Treatment Emergent AEs at injection site will follow two definitions: 
Definition 1: Local cutaneous reactions at injection site (LCRIS) are defined as injection site 
erythema, injection site swelling, injection site pruritus, injection site pain, or injection site tenderness 
that started on the day of injection and persisted for at least two days (i.e. event onset date on the day 
of injection and resolution date not on the day of injection or the day after injection) will be included. 
Events on the day of the injection with a missing resolution date will also be included. 
Definition 2: Injection Site Reactions (ISR) are defined as any AE with PT or verbatim term 
containing ‘Injection Site’ that persisted for at least two days (i.e. event onset date on the day of 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 34 of 44 
  
injection and resolution date not on the day of injection or the day after injection) will be included. 
Events with a missing resolution date will also be included.  
Treatment Emergent LCRIS will be summarized by SOC and PT and by severity in on-treatment 
period only. Treatment Emergent ISRs will be summarized by SOC and PT and by severity in on-
treatment and on-study periods.   
Additionally, the following will be summarized using Definition 2 (i.e., ISRs):   
• 
Percentage of injections leading to ISR for overall and preferred term will be summarized 
using descriptive statistics for on-study period only. Percentage of injections leading to ISR 
will be calculated as follows for each patient: (A/B) *100, where A = number of injections 
leading to ISR, and B = total number of injections. 
• 
ISRs by injection location for on-study period only 
• 
Incidence of ISR and time to first ISR for on-study period only 
• 
ISRs by treatment time interval (<=13 weeks, >13-26 weeks, >26-39 weeks, and 
>39-52 weeks) for on-treatment period only 
An additional table summarizing ISRs (definition 2) on-treatment by SOC and PT and by severity 
within cohort will be presented. 
3.7.2.2 Treatment Emergent Flu-Like Reactions 
Treatment Emergent Flu-Like Reactions (FLRs) will follow two definitions:  
• 
Definition 1: TEAEs with either (i) influenza like illness or (ii) at least one of following PTs: 
pyrexia, feeling hot, or body temperature increased, plus at least two of the following PTs: chills, 
myalgia, and arthralgia, starting on the day of injection or the next day.  
• 
Definition 2: TEAEs with following PTs or verbatim: influenza like illness, chills, myalgia, 
arthralgia, pyrexia, feeling hot, or body temperature increased, starting on the day of injection or 
the next day. 
Note that imputed dates will be used for defining.  
Treatment Emergent FLRs defined in definition 1 will be summarized by category (i) or (ii). 
Treatment Emergent FLRs defined in definition 2 will be summarized by SOC and PT. Both 
definitions will be presented in on-treatment period. 
Percentage of injections leading to FLRs (definition 2) for overall and by preferred term will also be 
summarized using descriptive statistics. Percentage of injections leading to FLRs will be calculated 
for each patient as (A/B)*100, where A is the number of injections associated with FLRs, and B is the 
total number of injections. 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 35 of 44 
  
3.7.2.3 Adverse Events of Special Interest  
The TEAEs of bleeding based on the Haemorrhages (SMQ) Export from MedDRA version 20.1 will 
be summarized by SOC and PT and by severity in on-treatment and on-study period respectively. 
The TEAEs of bleeding in presence or absence of concomitant antithrombotic medication (ATC3 
Text: Antithrombotic agents) will be summarized by SOC and PT in on-treatment period. The TEAEs 
of bleeding in presence or absence of concomitant antithrombotic medication will be listed as well. 
An additional table summarizing treatment-emergent bleeding AEs on-treatment by SOC and PT 
within cohort will be presented. 
3.7.3 
Vital Signs Measurements 
Vital signs include weight, BMI, body temperature, heart rate, respiratory rate, systolic and diastolic 
blood pressure. Vital signs will be summarized using the descriptive statistics (n, mean, standard 
error, standard deviation, median, P25, P75, minimum, maximum, and mean 95% CI) for observed 
values, change from baseline and percent change from baseline at each nominal study visit. 
Scheduled visits will be used for summary table. A listing of vital signs with scheduled and 
unscheduled visits will also be provided. 
3.7.4 
Laboratory Measurements 
The following is the list of lab analytes that will be collected throughout the study: 
• 
Chemistry:  sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, 
magnesium, phosphorus, glucose, blood urea nitrogen (BUN), creatinine, glomerular 
filtration rate, uric acid, total bilirubin, direct bilirubin, indirect bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), 
creatine kinase, GGT, Cystatin-C 
• 
Hematology:  red blood cells, hemoglobin, hematocrit, mean corpuscular hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC), platelets, white blood cells (WBCs), and WBC differential (percentage and 
absolute count), neutrophils, eosinophils, basophils, lymphocytes, and monocytes  
• 
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT), and 
international normalized ratio (INR) 
• 
Inflammatory Panel:  C-reactive protein measured by high sensitivity assay (hsCRP) 
• 
Test Performed at Screening Only: Hepatitis B surface antigen, Hepatitis C antibody, HIV 
antibody, follicle-stimulating hormone (FSH) (women only), serum beta-subunit of human 
chorionic gonadotropin (βhCG) (women only), thyroid stimulating hormone (TSH), free T4. 
The screening test data will only be displayed in patient listings 
• 
Urinalysis:  color, appearance, specific gravity, pH, protein, red blood cell, ketones, glucose, 
urobilinogen, bilirubin, leukocytes esterase, nitrate. For expanded urinalysis at certain visits, 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 36 of 44 
  
additional measurements will be performed including: microscopic examination, urine 
protein/creatinine ratio (UPCR), urine albumin/creatinine ratio (UACR). 
• 
Renal Urine Biomarkers:  NGAL, NAG, KIM-1, Cystatin-C   
• 
Other assessments (glycemic control): plasma insulin, fasting plasma glucose, homeostatic 
model assessment of insulin resistance (HOMA-IR) as provided in the central laboratory data, 
fructosamine, glycated albumin, and glycated hemoglobin (HbA1c)  
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 neutrophil 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. 
Quantitative laboratory measurements reported as ‘< X’, i.e. below the lower limit of quantification 
(BLQ), or ‘> X’, i.e. above the upper limit of quantification (ULQ), i.e. outside the limit of 
quantification, will be converted to X (or limit of quantification) for the purpose of quantitative 
summaries. If urine albumin/creatine ratio (UACR) or urine protein/creatinine ratio (UPCR) is 
‘Cannot calc’ indicating urine albumin or urine protein in the below quantification range, UACR and 
UPCR will be calculated as the ratio of urine albumin or urine protein to urine creatinine after 
converting urine albumin or urine protein to the limit of quantification. 
Estimated Glomerular Filtration Rate (eGFR) is based on the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation and is provided as a parameter in the central 
laboratory data. 
Chemistry, hematology, inflammatory panel, coagulation, other assessments, renal biomarkers, and 
quantitative urinalysis (observed value, absolute and percent change from baseline) will be 
summarized using descriptive statistics (n, mean, standard error, standard deviation, median, P25, 
P75, minimum, and maximum, mean 95% CI) by scheduled nominal visit. HOMA-IR and plasma 
insulin will be summarized only in patients not treated with insulins or insulin analogues. Qualitative 
urinalysis will be summarized using counts and percentages by scheduled nominal visit. Lab 
summary table except for platelet count will be based on the scheduled visits in central lab data only 
with the results in original unit. The summary table of platelet count will be based on the scheduled 
visits in central and separately in local lab data with the results in original unit. 
All laboratory test results will be listed separately for local and central labs at scheduled and 
unscheduled visits with results in original unit.  
A confirmed laboratory value is based on consecutive lab values performed on a different day to, but 
within 7 days (no matter central lab data or local lab data). If consecutive value is same or worse, then 
the initial value is confirmed. If the consecutive value is better, then the initial value is confirmed 
using consecutive value.  If there is no retest within 7 days, then the initial value is presumed 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 37 of 44 
  
confirmed. If there are multiple results on the same day (no matter central lab data or local lab data), 
then the worst value will be utilized in the analysis. 
The following lab results will be graded based on Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007).  Number 
and proportion of patients with shift from baseline to worst post-baseline values by toxicity grade will 
be tabulated for on-treatment and on-study periods. Post-baseline lab results are defined as any 
assessment taken after the first dose no matter central lab or local lab data.  If a patient has no 
baseline value but has a post-baseline value, then the baseline assessment will be labeled as 
“unknown”.  Likewise, if a patient has a baseline value but has no post-baseline value, then the worst 
value will be labeled as “unknown”. Shift tables for eGFR, ALT, AST and total bilirubin will be 
provided using original and confirmed values. 
• 
Hemoglobin:  shift from Baseline to minimum post-baseline value 
• 
WBCs:  shift from Baseline to minimum post-baseline value  
• 
Platelets:  shift from Baseline to minimum post-baseline value  
• 
BUN:  shift from Baseline to maximum post baseline value 
• 
Creatinine:  shift from Baseline to maximum post-baseline value   
• 
eGFR:  shift from Baseline to minimum post-baseline value 
• 
Proteinuria:  shift from Baseline to worst post-baseline value 
• 
ALT:  shift from Baseline to maximum post-baseline value   
• 
AST:  shift from Baseline to maximum post-baseline value   
• 
Alkaline phosphatase:  shift from Baseline to maximum post-baseline value   
• 
Total bilirubin:  shift from Baseline to maximum post-baseline value 
eGFR will be graded using the following criteria: 
• 
≥ 90 mL/min/1.73m2 
• 
≥ 60 mL/min/1.73m2 to < 90 mL/min/1.73m2 
• 
≥ 30 mL/min/1.73m2 to < 60 mL/min/1.73m2 
• 
≥ 15 mL/min/1.73m2 to < 30 mL/min/1.73m2 
• 
< 15 mL/min/1.73m2 
The number and percent of patients who stopped treatment because they met a protocol-defined 
safety monitoring rule(s) and stopping rule(s) (see Protocol Section 8.6 for details) will be tabulated 
by treatment group. A listing will be provided for patients who met protocol-defined safety 
monitoring rules and for patients who terminated treatment due to a protocol-defined stopping rule as 
well. 
Additional investigation of abnormalities in liver chemistry, platelet counts, and renal functions will 
be performed for on-treatment and on-study periods as below.  


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 38 of 44 
  
Abnormalities in liver chemistry: The number and percent of patients falling in each of the 
following categories (using available central and local laboratory assessments) will be tabulated 
based on worst post-baseline assessments by treatment group and for pooled ISIS 678354. 
• 
The higher of ALT > 3 x upper limit of normality (ULN) or ALT > 2 x Baseline 
• 
ALT/AST > 3 x ULN 
• 
ALT/AST > 5 x ULN 
• 
ALT/AST > 8 x ULN 
• 
ALT > 3 x ULN - ≤ 5 x ULN 
• 
ALT > 5 x ULN - ≤ 8 x ULN 
• 
Total bilirubin > 2 x ULN 
• 
ALP > 2 x ULN and (baseline ALP < 2 x ULN or baseline ALP missing) 
The number and percent of patients falling in each of the following categories based on confirmed 
worst post-baseline assessments will be tabulated by treatment group and for pooled ISIS 678354. 
• 
ALT/AST > 8 x ULN, which is confirmed 
• 
ALT/AST > 5 x ULN, which is confirmed and persist for at least 2 weeks 
• 
ALT/AST > 3 x ULN (or the greater of 2 x Baseline value or 3 x ULN if the Baseline value 
was > ULN), which is confirmed and either: 
• 
Total bilirubin > 2 x ULN, or 
• 
INR > 1.5, or 
• 
Temporal association with symptoms of fatigue, nausea, vomiting, right upper 
        quadrant pain or tenderness (PT: abdominal pain or abdominal pain upper), 
        fever, rash, or eosinophilia (PT: Eosinophilia and the corresponding lab value >ULN 
        within the interval of associated Eosinophilia start and end date); and where temporal 
        will be defined as the report date of the confirmed laboratory parameter occurring 
        within the interval of the associated adverse event start and stop dates 
For patients having confirmed 3-fold or greater elevations above the ULN for ALT or AST, a listing 
of all ALT, AST, total bilirubin, INR, and alkaline phosphatase records will be provided. 
Abnormalities of platelet counts: The number and percentage of patients falling in each of the 
following categories (using available central and local laboratory assessments) based on worst post-
baseline assessments will be provided: 
• 
Any 2 occurrences of platelet count < 140,000 cells/mm3 
• 
Any single occurrence of platelet count < 100,000 cells/mm3 
• 
Any 2 occurrences of platelet count < 140,000 cells/mm3 or any single occurrence of value < 
100,000 cells/mm3 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 39 of 44 
  
The nadir platelet count will be summarized by following categories: 
• 
Decrease ≥ 30% from baseline 
• 
Decrease ≥ 50% from baseline 
• 
100,000 cells/mm3 to < 140,000 cells/mm3 
• 
75,000 cells/mm3 to < 100,000 cells/mm3 
• 
50,000 cells/mm3 to < 75,000 cells/mm3 
• 
25,000 cells/mm3 to < 50,000 cells/mm3 
• 
0 to < 25,000 cells/mm3 
All categories of abnormalities in platelet count will be summarized based on confirmed values for 
on-study period as well. 
Abnormalities of renal function: The number and percentage of patients falling in each of the 
following categories (using available central and local laboratory assessments) based on confirmed 
worst post-baseline assessments will be provided: 
• 
eGFR by CKD-EPI > 25% decrease from baseline 
• 
UACR > 250 mg/g 
• 
UPCR > 0.5 g/g  
• 
Serum creatinine increase of > 0.3 mg/dL from baseline  
 
3.7.5 
12-Lead Electrocardiogram 
ECGs will be performed in triplicate at the visits indicated in the Protocol Appendix A. Patients in PK 
Subgroup will have additional ECG conducted during the treatment period. Patients determined to 
have a pacemaker rhythm will be excluded from summary tables. 
The ECG data include ventricular rate, PR interval, QRS duration, QT and corrected QT intervals. 
For the continuous variables, the average of measurements at a given visit will be used for analysis. 
For the continuous variables above, descriptive statistics (n, mean, standard error, standard deviation, 
median, P25, P75, minimum,  maximum, and mean 95% CI) of the observed values, as well as the 
change from baseline to each nominal study visit, will be presented by treatment group and for pooled 
placebo in summary tables. The summary table will be presented in SS and in PK Subgroup 
separately. Scheduled visits will be used for all summary tables. 
The number and percent of patients who have the following reported events will be tabulated by 
treatment group and for pooled ISIS 678354. 
• 
Absolute QT/QTcF/QTcB >450 msec 
• 
Absolute QT/QTcF/QTcB >480 msec 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 40 of 44 
  
• 
Absolute QT/QTcF/QTcB >500 msec 
• 
Increase from baseline in QT/QTcF/QTcB >30 msec 
• 
Increase from baseline in QT/QTcF/QTcB >60 msec 
• 
Increase from baseline in PR ≥50% (if absolute baseline <200 msec) 
• 
Increase from baseline in PR ≥25% (if absolute baseline >200 msec) 
• 
Increase from baseline in QRS ≥50% (if absolute baseline <100 msec) 
• 
Increase from baseline in QRS ≥25% (if absolute baseline >100 msec) 
QTcB (msec) = QT (msec) / (RR)1/2; if RR is missing, use QT (msec) * (HR(bpm)/60)1/2 
QTcF (msec) = QT (msec) / (RR)1/3; if RR is missing, use QT (msec) * (HR(bpm)/60)1/3 
All the ECG data with scheduled and unscheduled visits will be listed. 
An exploratory exposure-response analysis will be performed in PK-ECG Set to evaluate the 
relationship between QTcF and plasma concentration of ISIS 678354. The relationship between 
ISIS 678354 concentration and change from baseline QTcF (ΔQTcF) and placebo-corrected change 
from baseline QTcF (ΔΔQTcF) will be investigated using a linear mixed-effects modeling approach 
on time-matched ECG and ISIS 678354 concentration data. 
ΔQTcF or ΔΔQTcF = α + β1 x [ISIS 678354 concentration] + β2 x [baseline QTcF] + γ x [patient 
effect] 
ΔΔQTcF = (ΔQTcF for ISIS 678354 treated patient) − (mean of ΔQTcF for pooled placebo group).  
Matching of ECG and ISIS 678354 concentration (PK) data will be based on the following algorithm, 
in the sequence provided: 
1. Time of ECG and PK must be within 60 minutes (±60 minutes) of each other. 
2. If there are multiple records within the 60 minutes range, the closest match will be chosen. 
3. If there is more than one closest match identified in the previous step, the recorded pair with 
the ECG time point after the PK time point will be chosen. 
Plots of ΔQTcF or ΔΔQTcF versus ISIS 678354 concentration including all patients in PK-ECG Set 
will be generated. 
3.8 
Interim Analysis 
There is no interim analysis planned for the study. 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 41 of 44 
  
4 
REFERENCES 
Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: From pathophysiology to 
pharmacology. Trends Pharmacol Sci 2015;36(10):675-87. 
Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384(9943):626-
35. 
Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations 
in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41. 
Crooke ST, Baker BF, Xia S, Yu RZ, Viney NJ, Wang Y, Tsimikas S, Geary RS. Integrated 
assessment of the clinical performance of galnac3-conjugated 2'-o-methoxyethyl chimeric antisense 
oligonucleotides: I. Human volunteer experience. Nucleic Acid Ther 2019;29(1):16-32. 
Schafer JL. Analysis of Incomplete Multivariate Data. Chapman and Hall, A CRC Press Company, 
US 1997.  
Shaffer HJ, Hall MN, Vander Bilt J. Estimating the Prevalance of Disordered Gambling Behavior in 
the United States and Canada: A Research Synthesis. Am J Public Health. 1999 Sep; 89(9):1369-76. 
Roderick J. A. Little Donald B. Rubin. Statistical Analysis with Missing Data. John Wiley & Sons, 
Inc, 2002. 
Carpenter J, Roger J, and Kenward M. Analysis of longitudinal trials with protocol deviations: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. Journal of 
Biopharmaceutical Statistics 2013; 23: 1352-1371. 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 42 of 44 
  
5 
APPENDICES 
Appendix A – Efficacy Measurement Analysis Visit Window and Selection Rules 
• 
Primary Efficacy: Fasting triglycerides 
• 
Second Efficacy: Fasting apoA-I, apoB, apoC-III, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C 
• 
Exploratory Efficacy:  Fasting ANGPTL3, Lp(a) and remnant cholesterol (per TC, HDL-C and 
LDL-C) 
Cohort A/B 
Period 
Study Week 
Target Day 
Study Day Window 
Screening 
Run-in 
-28 to -15 
≤ -15 
Qualification 
-14 to -7 
-14 to < 1 
Treatment 
Week 1 
1 
1 
Week 5 
29 
2 to 43 
Week 9 
57 
44 to 71 
Week 13 
85 
72 to 99 
Week 17 
113 
100 to 127 
Week 21 
141 
128 to 155 
Week 25 (PAT) 
169 
156 to 183 
Week 29 
197 
184 to 211 
Week 37 
253 
240 to 267 
Week 45 
309 
296 to 323 
Week 53 
365 
352 to 379 
Data collected under visit labels containing follow up will not be mapped to analysis week.  
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 43 of 44 
  
Cohort C/D 
Period 
Study Week 
Target Day 
Study Day Window 
Screening 
Run-in 
-28 to -15 
≤ -15 
Qualification 
-14 to -1 
-14 to < 1 
Treatment 
Week 1 
1 
1 
 
Week 5 
29 
2 to 43 
Week 9 
57 
44 to 71 
Week 13 
85 
72 to 99 
Week 17 
113 
100 to 127 
Week 21 
141 
128 to 155 
Week 27 (PAT) 
183 
156 to 190 
Week 29 
197 
191 to 211 
Week 37 
253 
240 to 267 
Week 45 
309 
296 to 323 
Week 53 
365 
352 to 379 
Data collected under visit labels containing follow up will not be mapped to analysis week. 
Record selection rules to identify analysis visit will be based on the following algorithm, in the 
sequence provided: 
1. Records must be fasting  
2. If there are multiple records with fasting, the closest record to target day will be chosen. 
3. If there are multiple records within same range to target day, the record prior to the target day 
will be chosen. 
4. If there is more than one record on the same day prior to the target day, the average of these 
records will be chosen. 
 
 


Akcea Therapeutics, Inc. 
CONFIDENTIAL 
December 17, 2019 
Statistical Analysis Plan V1.0 
ISIS 678354-CS2 
 
TP-GDO-WW-016-07.a 
CONFIDENTIAL           Project Document Version No. Final 1.0 
Effective Date:  30 Jan 19                                              Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019                                                                                                        Page 44 of 44 
  
Appendix B – Repeated Measures Efficacy Visit Mapping Instructions for Sensitivity Analysis 6 
and Model  
For the MMRM analysis of triglycerides, we will map the visits per Appendix A for assignment to the 
analysis visits.  For the MMRM we should only include the following analysis visit timepoints in the 
model: Week 5, 9, 13, 17, 21, 25/27 (PAT). Also include Week 29, 37, 45, and 53 only if total n at 
the analysis visit is at least 10% of the overall FAS. 
 
In order to use the same visit number in the model for primary analysis time point, Week 25 in cohort 
A and B will be re-numbered to Week 27. 
The sample SAS code for the repeated measures analysis can be found below: 
********************************************************************* 
* Note:  
* Base represents baseline triglycerides value                                                                
* Y represents post-baseline triglycerides value                                           
* TRTP represents treatment group (pooled placebo, 10 mg Q4W, 50 mg Q4W, 15 mg Q2W, 10 mg 
QW) 
*AVISIT represents the visit variable (Week 5, 9, 13, 17, 21, PAT, and potentially 29, 37, 45, and 53)      
*SUBJID represents the variable identifying the patients  
********************************************************************* 
ods output lsmeans=lsm diffs=diff; 
proc mixed data = dataset; 
 
class TRTP AVISIT SUBJID; 
 
model log(Y/base) = TRTP log(BASE) AVISIT TRTP*AVISIT; 
 
repeated AVISIT / subject=SUBJID (TRTP) type=un;  
 
lsmeans TRTP*AVISIT/E CL DIFF=CONTROL ("pooled placebo" "Week xx"); 
run; 
ods output close;