A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) Administered Subcutaneously to Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
Phase: PHASE2
Conditions: Elevated Lipoprotein(a), Cardiovascular Disease
Sponsor: Akcea Therapeutics

 
Official Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
NCT Number: 
NCT03070782 
Document Date(s): 
Protocol Amendment Version 6: 25-January-2018 
Protocol Amendment Version 5: 30-May-2017 
Protocol Amendment Version 4: 5-January-2017 
Protocol Amendment Version 3: 9-December-2016 
 
 

 
 
 
Sponsor: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Collaborator: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
 
AKCEA THERAPEUTICS  
 
ISIS 681257-CS6 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
 
Protocol Amendment 6 – 25 January 2018 
  
 
EudraCT No:  2016-003373-18 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
3 
ISIS 681257-CS6 
Ionis Protocol Number ISIS 681257-CS6 
Protocol Amendment 6 
EudraCT No:  2016-003373-18 
Clinical Phase:  2 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
Trial Sponsor: 
Akcea Therapeutics, Inc. 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Key Sponsor Contact: 
 
 Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Phone:  
 
E-mail: 
 
Sponsor Medical Monitor: 
 MD, PhD 
 Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
Phone: 
 
Mobile: 
 
E-mail: 
 
Date: 
25 January 2018 
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. and Akcea Therapeutics 
that must not be disclosed to anyone other than the recipient study staff and members of the independent 
ethics committee, institutional review board, or authorized regulatory agencies.  This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc. and Akcea Therapeutics. 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study 
of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment: 
Amendment 6 
Date: 
25 January 2018 
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 681257 
Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established Cardiovascular 
Disease (CVD),” dated 25 January 2018, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on Good 
Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENTS ............................................................................................................... 10 
PROTOCOL SUMMARY OF CHANGES ............................................................................................ 11 
PROTOCOL SYNOPSIS ......................................................................................................................... 13 
STUDY DESIGN AND TREATMENT SCHEMA ................................................................................ 20 
1. 
OBJECTIVES .............................................................................................................................. 25 
1.1 
Primary Objective ...................................................................................................................... 25 
1.2 
Secondary Objective(s) ............................................................................................................. 25 
2. 
BACKGROUND AND RATIONALE ....................................................................................... 25 
2.1 
Overview of Disease.................................................................................................................. 25 
2.1.1 
Lipoprotein (a) ................................................................................................................... 25 
2.1.2 
Pathophysiology ................................................................................................................ 27 
2.1.3 
Current Treatment Options ................................................................................................ 27 
2.2 
Therapeutic Rationale ................................................................................................................ 28 
2.3 
ISIS 681257 ............................................................................................................................... 28 
2.3.1 
Mechanism of Action ........................................................................................................ 28 
2.3.2 
Chemistry .......................................................................................................................... 28 
2.3.3 
Preclinical Experience ....................................................................................................... 29 
2.3.4 
Clinical Experience ........................................................................................................... 30 
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 .......................................................................................................... 32 
3.3 
Number of Patients .................................................................................................................... 33 
3.4 
Overall Study Duration and Follow-up ..................................................................................... 33 
3.4.1 
Screening ........................................................................................................................... 33 
3.4.2 
Treatment .......................................................................................................................... 33 
3.4.3 
Post-Treatment .................................................................................................................. 33 
3.5 
End-of-Study ............................................................................................................................. 34 
3.6 
Data and Safety Monitoring Board ............................................................................................ 34 
4. 
PATIENT ENROLLMENT ........................................................................................................ 34 
4.1 
Screening ................................................................................................................................... 34 
4.2 
Randomization ........................................................................................................................... 34 
4.3 
Replacement of Patients ............................................................................................................ 35 
4.4 
Unblinding of Treatment Assignment ....................................................................................... 35 
5. 
PATIENT ELIGIBILITY ........................................................................................................... 35 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
6 
5.1 
Inclusion Criteria ....................................................................................................................... 35 
5.2 
Exclusion Criteria ...................................................................................................................... 36 
6. 
STUDY PROCEDURES ............................................................................................................. 37 
6.1 
Study Schedule .......................................................................................................................... 37 
6.1.1 
Screening ........................................................................................................................... 38 
6.1.2 
Treatment Period ............................................................................................................... 38 
6.1.3 
Post-Treatment Period ....................................................................................................... 38 
6.2 
Additional Study Assessments .................................................................................................. 39 
6.2.1 
Laboratory Assessments .................................................................................................... 39 
6.2.2 
Physical Exams and Vital Signs ........................................................................................ 40 
6.2.3 
Electrocardiography .......................................................................................................... 40 
6.2.4 
PK Sampling ..................................................................................................................... 40 
6.3 
Restriction on the Lifestyle of Patients...................................................................................... 41 
6.3.1 
Contraception Requirements ............................................................................................. 41 
6.3.2 
Other Requirements ........................................................................................................... 42 
7. 
STUDY DRUG ............................................................................................................................. 42 
7.1 
Study Drug Description ............................................................................................................. 42 
7.1.1 
ISIS 681257 ....................................................................................................................... 42 
7.1.2 
Placebo 42 
7.2 
Packaging and Labeling ............................................................................................................ 43 
7.3 
Study Drug Accountability ........................................................................................................ 43 
8. 
TREATMENT OF PATIENTS .................................................................................................. 43 
8.1 
Study Drug Administration ....................................................................................................... 43 
8.2 
Other Protocol-Required Drugs ................................................................................................. 44 
8.3 
Other Protocol-Required Treatment Procedures ....................................................................... 44 
8.4 
Treatment Precautions ............................................................................................................... 44 
8.5 
Safety Monitoring Rules ............................................................................................................ 44 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ......................................................... 45 
8.5.2 
Safety Monitoring for Renal Function .............................................................................. 46 
8.5.3 
Safety Monitoring for Platelet Count Results ................................................................... 47 
8.5.4 
Safety Monitoring for Minor Bleeding Events .................................................................. 48 
8.5.5 
Safety Monitoring for Constitutional Symptoms .............................................................. 48 
8.6 
Stopping Rules .......................................................................................................................... 48 
8.6.1 
Stopping Rules for Liver Chemistry Elevations ................................................................ 49 
8.6.2 
Stopping Rules for Renal Function Test Results ............................................................... 49 
8.6.3 
Stopping Rule for Platelet Count Results .......................................................................... 49 
8.7 
Adjustment of Dose ................................................................................................................... 52 
8.8 
Discontinuation of Study Drug .................................................................................................. 52 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
7 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from Post-Treatment 
Follow-up Period ............................................................................................................... 53 
8.9 
Withdrawal of Patients from the Study ..................................................................................... 53 
8.10 
Concomitant Therapy and Procedures ....................................................................................... 54 
8.10.1 
Concomitant Therapy ........................................................................................................ 54 
8.10.2 
Concomitant Procedures .................................................................................................... 54 
8.11 
Treatment Compliance .............................................................................................................. 55 
8.12 
Safety Monitoring Compliance ................................................................................................. 55 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .................................... 55 
9.1 
Sponsor Review of Safety Information ..................................................................................... 55 
9.2 
Regulatory Requirements .......................................................................................................... 55 
9.3 
Definitions ................................................................................................................................. 56 
9.3.1 
Adverse Event ................................................................................................................... 56 
9.3.2 
Adverse Reaction and Unexpected Adverse Reaction ...................................................... 56 
9.3.3 
Serious Adverse Event (SAE) ........................................................................................... 56 
9.3.3.1 
Adverse Events of Special Interest ............................................................................. 57 
9.4 
Monitoring and Recording Adverse Events .............................................................................. 57 
9.4.1 
Serious Adverse Events/Adverse Events of Special Interest ............................................. 57 
9.4.2 
Non-Serious Adverse Events ............................................................................................. 58 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ................................................ 58 
9.4.3.1 
Relationship to the Study Drug .................................................................................. 58 
9.4.3.2 
Severity....................................................................................................................... 58 
9.4.3.3 
Action Taken with Study Drug .................................................................................. 59 
9.4.3.4 
Treatment Given for Adverse Event........................................................................... 59 
9.4.3.5 
Outcome of the Adverse Event .................................................................................. 59 
9.5 
Procedures for Handling Special Situations .............................................................................. 60 
9.5.1 
Abnormalities of Laboratory Tests .................................................................................... 60 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ....................... 60 
9.5.3 
Dosing Errors .................................................................................................................... 61 
9.5.4 
Contraception and Pregnancy ............................................................................................ 61 
10. 
STATISTICAL CONSIDERATIONS ....................................................................................... 62 
10.1 
Study Endpoints, Subsets, and Covariates................................................................................. 62 
10.1.1 
Primary Endpoint(s) .......................................................................................................... 62 
10.1.2 
Secondary Endpoints ......................................................................................................... 62 
10.1.3 
Safety Endpoints................................................................................................................ 62 
10.1.4 
Dose Selection ................................................................................................................... 63 
10.2 
Sample Size Considerations ...................................................................................................... 63 
10.3 
Analysis Populations ................................................................................................................. 63 
10.4 
Definition of Baseline................................................................................................................ 64 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
8 
10.5 
Interim Analysis ........................................................................................................................ 64 
10.6 
Planned Methods of Analysis .................................................................................................... 64 
10.6.1 
Demographic and Baseline Characteristics ....................................................................... 64 
10.6.2 
Safety Analysis .................................................................................................................. 64 
10.6.2.1 
Adverse Events ........................................................................................................... 64 
10.6.2.2 
Clinical Laboratory Data ............................................................................................ 65 
10.6.2.3 
Vital Signs and Examinations .................................................................................... 65 
10.6.3 
Efficacy Analysis .............................................................................................................. 65 
10.6.3.1 
Analysis of Primary Efficacy Endpoint ...................................................................... 65 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints ................................................................ 65 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ............................................................... 66 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS .......................................................... 67 
11.1 
Informed Consent ...................................................................................................................... 67 
11.2 
Ethical Conduct of the Study ..................................................................................................... 67 
11.3 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) ................................. 67 
11.4 
Patient Confidentiality ............................................................................................................... 68 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .............................................................. 68 
12.1 
Protocol Amendments ............................................................................................................... 68 
12.2 
Study Termination ..................................................................................................................... 68 
12.3 
Study Documentation and Storage ............................................................................................ 68 
12.4 
Study Monitoring ...................................................................................................................... 69 
12.5 
Language ................................................................................................................................... 70 
12.6 
Compensation for Injury ............................................................................................................ 70 
13. 
REFERENCES ............................................................................................................................. 71 
14. 
APPENDICES .............................................................................................................................. 74 
Appendix A 
Schedule of Procedures .............................................................................................. 75 
Appendix B 
List of Laboratory Analytes ....................................................................................... 82 
Appendix C 
PK Sampling Schedule ............................................................................................... 84 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities ................ 87 
Appendix E 
Additional Laboratory Tests for Patients with Platelet Count ˂ 100,000/mm3 .......... 91 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
9 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ............................................................................................... 43 
Table 2 
Study Drug Dosing Information ....................................................................................... 44 
Table 3 
Actions in Patients with Low Platelet Count .................................................................... 51 
 
TABLE OF FIGURES 
Page 
Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of apo(a) 
Covalently Bound to apoB ................................................................................................ 26 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
10 
PROTOCOL AMENDMENTS 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 
2 Study of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment Number: 
6 
Amendment Date: 
25 January 2018 
 
The following table summarizes the history and nature of amendments to the protocol ISIS 681257-CS6. 
None of the antecedent versions of the study protocol has been enacted clinically and therefore no patients 
have been enrolled prior to issuance of Amendment 4. 
Protocol Version 
Date 
Rationale for Amendments 
Original Protocol  
15 August 2016 
 
Amendment 1 
6 October 2016 
Regulatory advice on inclusion of more detailed 
description of processes for platelet monitoring, and 
more frequent monitoring of liver function. 
Amendment 2 
29 November 2016 
Regulatory advice on inclusion of biomarkers of 
renal damage and increased frequency of renal 
monitoring.  Addition of a DSMB. 
Amendment 3 
30 December 2016 
Adjustment of the frequency, and alert and 
intervention limits, for renal safety and adjustment of 
the frequency of liver safety testing.   
Amendment 4 
5 January 2017 
The study population was increased to 270 patients 
(54 per cohort) to support a statistical assessment 
of risk of platelet reduction in this population.  In 
addition, the 10 mg weekly treatment cohort has 
been modified to 20 mg every 2 weeks (biweekly). 
Amendment 5 
30 May 2017 
Regulatory advice on addition of exclusion criteria, 
reduced permitted timeframe for identifying critical 
laboratory results by the investigator and 
replacement of the AE definition.  In addition, 
Section 8.6.2 was edited for consistency. 
Amendment 6 
25 January 2018 
Updated platelet monitoring to allow for potential to 
return to every 2-week monitoring, clarified 
definition and scheduling of the follow-up period and 
End of Treatment visit for last patient to complete 
primary endpoint visit. 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
11 
PROTOCOL SUMMARY OF CHANGES 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 
2 Study of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment Number: 
6 
Amendment Date: 
25 January 2018 
 
The following modifications to Protocol ISIS 681257-CS6 Amendment 5 have been made. 
Minor changes (not included in the list of changes below) have been made throughout the protocol to 
correct errors and/or to improve the overall clarity of the original protocol but these changes do not 
impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the Amendment 5 of the protocol: 
Protocol Section 
Description of Change 
Rationale 
Throughout 
Updated Sponsor to Akcea 
Therapeutics and Collaborator to 
Ionis Pharmaceuticals, Inc. 
Sponsorship has been transferred 
from Ionis Pharmaceuticals, Inc. to 
Akcea Therapeutics 
Section 3.4.2 
Added detail around definition 
and scheduling of End of 
Treatment Visit 
Clarification and detail added to 
ensure definition of Treatment 
Period is clear. Additional 
clarification was also added around 
scheduling of the End of Treatment 
Visit for all patients once last patient 
is enrolled. 
Section 6.2.1 
Laboratory Assessments 
Added “should” to samples being 
collected and analyzed in parallel 
at the central and local lab. 
The word “should” was inadvertently 
left out of the sentence in a prior 
amendment. 
Section 8.5.3 
Safety Monitoring for Platelet Count 
Results 
Updated reference to Appendix 
from D to E for platelet counts  
< 100,000/mm3 
Correct Appendix is E 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
12 
Protocol Section 
Description of Change 
Rationale 
Section 8.6.3 
Stopping Rule for Platelet Count 
Results 
Table 3 
Actions in Patients with Low Platelet 
Count 
Changed language around 
weekly monitoring requirement to 
allow for return to every 2-week 
monitoring if 2 successive 
platelet values fall within the 
normal range.  
Given the episodic transient nature 
of mild platelet drops recorded to 
date, weekly platelet monitoring for 
the entire duration of the study even 
when the platelet count returns to 
the normal range is medically 
unjustified.  
Section 8.6.3 
Stopping Rule for Platelet Count 
Results 
Table 3 
Actions in Patients with Low Platelet 
Count 
Clarified platelet ranges and 
updated Section 8.6.3 
accordingly. 
Clarification to ensure no overlap in 
actions to be taken based on 
platelet value 
Appendix A 
Schedule of Procedures 
Clarified that follow-up visits 
should be timed to correspond 
with last visit of the treatment 
period 
Clarification to ensure alignment 
among sites in scheduling of follow 
up visits in relation to the last visit of 
the treatment period rather than the 
last dose. 
Appendix A 
Schedule of Procedures 
Added “(optional)” to genetic 
testing assessment 
This test is only required for patients 
who sign separate consent 
Appendix A 
Schedule of Procedures 
Clarified timing of study drug 
administration for weekly and 
every 2-week dosing 
Clarification to account for last dose 
variation between weekly and every 
2-week cohorts. 
Appendix A 
Schedule of Procedures 
Added footnote stating the last 
patient to reach 6 months of 
exposure will complete all 
assessments for primary 
endpoint visit (Week 25 or Week 
27 based on cohort) and for End 
of Treatment visit (Week53/ET), 
and will not receive a dose at 
that visit. 
Clarification that the last patient’s 
primary endpoint visit will count as 
Week 25/Week 27 and End of 
Treatment visit (Week53/ET)  
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
13 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of 
ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and 
Established Cardiovascular Disease (CVD)  
Study Phase 
2 
Indication 
Patients with hyperlipoproteinemia(a) and established CVD. 
Investigational Drug 
ISIS 681257 is a second generation 2ʹ-MOE modified, GalNAc3–conjugated antisense 
oligonucleotide inhibitor of apolipoprotein (a) [apo(a)]. 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of 
different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels 
in patients with hyperlipoproteinemia(a) and established CVD. 
Secondary Objective(s) To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein 
cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on 
apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose 
regimens in patients with hyperlipoproteinemia(a) and established CVD. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio to receive ISIS 681257 or 
placebo.  This number was chosen to provide statistical power for both efficacy and 
safety assessments.  Study Drug (ISIS 681257 or placebo) will be administered SC 
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 will then enter a 16-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-C) and at Week 27 for patients who received 
every 2-week or weekly dosing (Cohorts D and E, 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 (as needed) data collected on ISIS 681257 during this 
study, both individual events and aggregate data.   
Number of Subjects 
Approximately 270 
 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
25 January 2018 
14 
PROTOCOL SYNOPSIS Continued 
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.
Clinical diagnosis of CVD defined as documented coronary artery disease, stroke,
or peripheral artery disease
4.
Lp(a) plasma level ≥ 60 mg/dL
5.
Must be on standard-of-care preventative therapy for other than elevated Lp(a)
CVD risk factors
6.
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
7.
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 16 weeks after the last dose of Study 
Drug (ISIS 681257 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
8.
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 16 weeks after the last dose of ISIS 681257

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
15 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria 
1. 
Within 6 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 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 with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse  
12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions  
13. Hypersensitivity to the active substance or to any of the excipients 
14. Clinically-significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion, including the following: 
a. 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
protein measurement of ˂ 300 mg/24-hr 
b. 
Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
albumin measurement of ˂ 150 mg/24-hr 
c. 
Estimated GFR ˂ 60 mL/min as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
d. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)  
> 2.0 x ULN 
e. 
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > ULN  
g. 
Platelet count ˂ LLN 
15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
16. Treatment with another investigational drug, biological agent, or device within 
1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol 
 
25 January 2018 
 
16 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria 
17. Treatment with any 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 
18. BMI > 40 kg/m2  
19. Blood donation of 50-499 mL within 30 days of screening or of > 499 mL within 
8 weeks of Screening 
20. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator 
21.  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 5 parallel cohorts: 
Cohort A (n = 54): Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort B (n = 54):  Patients will be randomized 5:1 to receive 40 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort C (n = 54):  Patients will be randomized 5:1 to receive 60 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort D (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every 2 weeks for up to 26 doses. 
Cohort E (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every week for up to 52 doses. 
Cohort 
Treatment 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 or placebo  
(Every 4 weeks) 
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 or placebo 
(Every 2 weeks) 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 or placebo 
(Every week) 
≤ 52 
≤ 1040 mg 
 
 
 
 

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PROTOCOL SYNOPSIS Continued  
Study Drug Dosage 
and Administration 
The Sponsor will provide ISIS 681257 in a concentration of 100 mg/mL and matching 
volume placebo: 
Cohort A:  20 mg every 4 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort B:  40 mg every 4 weeks ISIS 681257 or placebo (0.4 mL) 
Cohort C:  60 mg every 4 weeks ISIS 681257 or placebo (0.6 mL) 
Cohort D:  20 mg every 2 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort E:  20 mg every week ISIS 681257 or placebo (0.2 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 681257 doses of 10 mg, 20 mg, and 40 mg given 
weekly that were found to be generally well-tolerated and to induce clinically-relevant 
reductions in Lp(a).  The range of dosing proposed for the present study will provide the 
equivalent drug exposure of 5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and 
is predicted (based on modelling of PK/PD data obtained in Phase 1 study) to result in 
mean reductions from baseline in plasma Lp(a) ranging from approximately 60% to 85% 
at steady-state.  
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to 
bring almost all patients with hyperlipoproteinemia(a) into the normal range 
(Lp(a) ≤ 30 mg/dL). 
 Rationale for Dose and 
Schedule Selection 
Continued 
The present study will also evaluate safety and efficacy at different dosing 
frequencies:  every 4 weeks, every 2 weeks, and weekly.  Patients with 
hyperlipoproteinemia(a) 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.  Dosing regimens of 
20 mg every 2 weeks and 40 mg every 4 weeks will test if similar monthly exposure, at 
different frequencies of administration, will achieve similar safety and similar level of 
Lp(a) reduction since the reduction achieved by a given dose level is principally driven 
by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety. 
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. 
 
 
 

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PROTOCOL SYNOPSIS Continued 
Study Visit Schedule 
and Procedures  
Detailed information regarding the study procedures are outlined in Section 6, 
Appendices A and C. 
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may 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
•
An up to 52-week treatment period during which Study Drug will be
administered per assigned cohort by SC injection
•
A 16-week post-treatment follow-up period
Patients in Cohorts A through C will receive up to 13 SC doses of ISIS 681257 or 
placebo every 4 weeks.  Patients in Cohort D will receive up to 26 SC doses of 
ISIS 681257 or placebo every 2 weeks and patients in Cohort E will receive up to 52 SC 
doses of ISIS 681257 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).  
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 and use of concomitant 
medications.  Safety and tolerability results in patients dosed with ISIS 681257 will be 
compared with those dosed with placebo. 
Efficacy Evaluations 
The primary analysis time point is at Week 25 for patients who received every 4-week 
dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly 
dosing (Cohorts D and E). 
The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary 
analysis time point for ISIS 681257 treatment groups compared to placebo. 
The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at 
the primary analysis time point on the following: 
•
Percent change from baseline in LDL-C
•
Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L)
•
Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL (≤ 75 nmol/L)
•
Percent change from baseline in apoB
•
Percent change from baseline in OxPL-apo(a)
•
Percent change from baseline in OxPL-apoB

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PROTOCOL SYNOPSIS Continued 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all patients for the measurement of ISIS 681257 
plasma trough levels throughout treatment and during the post-treatment follow-up 
period.  In addition, in a subset of patients (approximately 12 patients per cohort), more 
frequent plasma samples will be taken following the first and Day 169 (for Cohorts A, B, 
and C) or Day 183 (for Cohorts D and E) dose to determine PK parameters.  Plasma 
sample collection time points are detailed in Appendices A and C. 
The plasma ISIS 681257 levels over time will be descriptively summarized by treatment 
with stratification by subject immunogenicity status.  Apparent terminal elimination 
half-life will be calculated in patients who received ISIS 681257 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 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 Lp(a) between 
ISIS 681257 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the baseline Lp(a) 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 plasma Lp(a) 
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. 
Sample Size Considerations: 
Efficacy: 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the 
standard deviation of the percent change in Lp(a) is approximately 20%.  With 
23 patients in each ISIS 681257 treatment group and 23 in placebo group there would 
be approximately 90% power to detect a 20% difference in percent change in Lp(a) 
levels between the ISIS 681257 treatment groups and placebo group at an alpha level of 
0.05, assuming 30% reduction in the ISIS 681257 patients and 10% reduction in the 
placebo patients. 
Safety: 
Based upon prior clinical trial experience with ISIS ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in 
the ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, 
with 45 patients in each ISIS 681257 treatment group, there would be approximately 
80% power to detect at least 1 event. 
A total of approximately 270 patients (54 patients per cohort, including 45 patients per 
cohort treated with ISIS 681257) will be randomized to ensure that both the safety and 
efficacy of ISIS 681257 will be adequately characterized in the study. 
Sponsor/Collaborator 
Akcea Therapeutics/Ionis Pharmaceuticals 

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STUDY DESIGN AND TREATMENT SCHEMA 
 
SCREENING PERIOD 
Weeks -4 to -1 
TREATMENT PERIOD 
Weeks 1 to 52* 
Dosing per assigned cohort: 
Cohorts A, B, and C:  Every 4 weeks SC 
administration of 20, 40, or 60 mg ISIS 681257 or 
placebo 
Cohort D:  Every 2 weeks SC administration of 
20 mg ISIS 681257 or placebo 
Cohort E:  Every week SC administration of 20 mg 
ISIS 681257 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 
Weeks 4, 10, and 16 after Treatment 
Period 
3 clinical visits for safety, efficacy,  
PK and PD assessments 
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 (16 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 
apo(a) 
apolipoprotein(a) 
apoB 
apolipoprotein B 
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 
CVD 
cardiovascular disease 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
 
 
 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
Cys C 
Cystatin C 
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 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 681257 
antisense inhibitor of apolipoprotein (a) 
IV 
intravenous(ly) 
IXRS 
interactive voice/internet response system 
KIM-1 
kidney injury molecule 1 
kg 
kilogram 
 
 
 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
L 
liter 
m2 
square meter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
MI 
myocardial infarction 
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 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OxPL 
oxidized phospholipids 
PAD 
peripheral arterial disease 
PBS 
phosphate buffered saline 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLA2 
Lp(a)-associated Lp-phospholipase A2 
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 
 
 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
SC 
subcutaneous(ly) 
Study Drug 
ISIS 681257 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
Tg 
transgenic 
Tmax 
time to maximal concentration 
UACR 
urine albumin -creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein- creatinine ratio 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 

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1.
OBJECTIVES
1.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses 
and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels in patients with 
hyperlipoproteinemia(a) and established cardiovascular disease (CVD). 
1.2 
Secondary Objective(s) 
To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol (LDL-C), 
apolipoprotein B (apoB), oxidized phospholipids (OxPL) on apolipoprotein (a) [apo(a)] [OxPL-apo(a)] 
and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in in 
patients with hyperlipoproteinemia(a) and established CVD. 
2.
BACKGROUND AND RATIONALE
2.1 
Overview of Disease 
2.1.1 
Lipoprotein (a) 
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein (Figure 1, Koschinsky and Marcovina 2004) in which 
the apoB component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], the distinct 
protein component of Lp(a) that is mainly responsible for its signature structural and functional properties 
(Dubé et al. 2012; Kronenberg and Utermann 2013).  Lp(a) is now recognized as an independent, genetic, 
causal risk factor for coronary artery disease (CAD), stroke, peripheral arterial disease (PAD), and 
calcific aortic stenosis (Erquo et al. 2009; Nordestgaard et al. 2010; Thanassoulis et al. 2013). 

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Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of apo(a) 
Covalently Bound to apoB 
Apo(a) contains 10 unique units of kringle IV repeats, of which KIV2 are present in variable copies (1 to > 40) 
conferring structural heterogeneity to Lp(a).  Apo(a) also contains kringle V and an inactive protease-like (P) 
domain.  In this model, 4 KIV2 repeats are shown.  Lp(a) also contains OxPL in the lipid phase of apoB as 
well as covalently bound to apo(a). 
Plasma levels of Lp(a) vary substantially among individuals, and most of this variation reflects the effects 
of genetic variation in the LPA gene which encodes the apo(a) protein. 
A second contributor to plasma-level variability are LPA single nucleotide polymorphisms (SNPs) that 
can be associated with either higher or lower Lp(a) levels (Clarke et al. 2009; Li et al. 2011).  Significant 
associations exist between 2 particular LPA variants, rs10455872 and rs3798220, increased Lp(a) levels, 
CVD, and aortic stenosis, with the CVD risk primarily mediated by Lp(a) plasma levels rather than an 
independent effect of the SNPs (Clarke et al. 2009; Li et al. 2011). 
Lp(a) plasma levels are generally inversely associated with apo(a) size, and can vary by > 1,000-fold 
(0.1 to > 250 mg/dL or ˂ 0.25 to > 625 nmol/L) between individuals (Merki et al. 2011).  Despite this 
inter-individual variation, intra-individual Lp(a) levels are thought to be generally stable over time along 
a pre-set genetically determined levels without significant impact from dietary or environmental factors, 
mediating CVD risk throughout the patient’s lifetime. 

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2.1.2 
Pathophysiology 
Lp(a) adheres to plaque sites and is retained in the artery wall and has proatherogenic and 
pro-inflammatory properties due to its LDL and apo(a) components  
(Spence and Koschinsky 2012).  In addition, Lp(a) may be prothrombotic by inhibiting fibrinolysis 
because of its structural similarity to plasminogen and its enhancement of platelet aggregation 
(Rand et al. 1998).  In vitro studies have provided evidence for both of these pathogenic mechanisms, but 
in vivo data are not definitive (Dubé et al. 2012).  In humans, Lp(a) is the main lipoprotein carrier of 
OxPL, which may drive the risk associated with Lp(a) (Bergmark et al. 2008; Leibundgut et al. 2013; 
Tsimikas et al. 2014).  In fact, OxPL measured on apoB (OxPL-apoB), which largely reflect the OxPL on 
Lp(a), have been shown to be a prognostic indicator for future CV events (Tsimikas et al. 2010; Tsimikas 
et al. 2012; Tsimikas et al. 2014).  OxPL associated with Lp(a) can be subjected to degradation by the 
Lp(a)-associated Lp-phospholipase A2 (PLA2), implicating Lp(a) in novel proinflammatory and 
atherogenic pathways (Kiechl et al. 2007). 
Hyperlipoproteinemia(a) in humans is associated with increased risk of cardiac death, myocardial 
infarction (MI), stroke, aortic stenosis, and peripheral arterial disease (PAD), particularly in subjects with 
small apo(a) isoforms (Bennett 2008; Erqou et al. 2009; Erqou et al. 2010; Bertoia et al. 2013; 
Thanassoulis et al. 2013).  Although prospective, randomized, controlled outcomes studies have not been 
conducted, epidemiological, genome-wide association and Mendelian randomized controlled study data to 
date provide supporting evidence for a role of Lp(a) as a risk factor for CVD (Kamstrup et al. 2009).  For 
example, in the Copenhagen City Heart Studies of 42,000 subjects with a 15-year follow-up (Kamstrup et 
al. 2009) using a Mendelian randomization approach, higher Lp(a) levels were related to risk of MI. 
2.1.3 
Current Treatment Options 
In 2010, the European Atherosclerosis Society (EAS) Consensus Panel recommended screening for 
elevated Lp(a) in people at moderate to high risk of CVD to reach a treatment goal of ˂ 50 mg/dL (125 
nmol/L), after therapeutic management of LDL-C (Nordestgaard et al. 2010).  Approximately 20% of 
people are estimated to have plasma Lp(a) levels over 50 mg/dL (125 nmol/L) and approximately 0.3% to 
have levels over 175 mg/dL (438 nmol/L).  There are no gender differences in Lp(a) concentrations but 
racial differences have been observed, with whites and Asians having lower levels while blacks and 
Hispanics generally have somewhat higher levels (Nordestgaard et al. 2010). 
Lifestyle and diet are thought to have little impact on an individual’s Lp(a) level.  Current treatment 
recommendations from the EAS Consensus Panel are limited to the use of 1 to 3 g of niacin (nicotinic 
acid) daily which could result in an up to 30% reduction in Lp(a).  However, niacin is associated with side 
effects (e.g., flushing) that reduce patient tolerability and compliance (Parker et al. 2006; Guyton 2007). 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are neither indicated nor formally 
recommended for treatment of hyperlipoproteinemia(a) but have been reported to reduce Lp(a) levels by 
~20%-35% in patients with hypercholesterolemia (Desai et al. 2013; Raal et al. 2015). 
The other current option for patients with significantly elevated Lp(a) levels (≥ 60 mg/dL) is lipoprotein 
apheresis, either general lipoprotein apheresis (Jaeger et al. 2009; Leebmann et al. 2013; Rosada et al. 
2014) or Lp(a)-specific apheresis (Safarova 2012).  While very effective at acutely lowering Lp(a) (acute 

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and interval Lp(a) reductions of > 60% and > 30% respectively), this treatment option is expensive, 
burdensome for patients, and unavailable/not reimbursed in many countries and regions. 
2.2 
Therapeutic Rationale 
Therapeutic modalities to reduce Lp(a) levels in humans are few, and there are no drugs currently 
available that specifically target Lp(a) alone.  Antisense oligonucleotides (ASOs) are emerging as viable 
therapeutic agents to treat disorders where overexpression of proteins is associated with a disease process.  
Apo(a) is synthesized primarily in the liver, a target organ for ASOs, where it is subsequently covalently 
linked to the apoB-100 component of LDL to form the Lp(a) lipoprotein.  The goal of treatment with 
ISIS 681257 is to reduce the production of apo(a) in the liver and thus, the level of Lp(a) lipoprotein by 
using an ASO directed against the messenger ribonucleic acid (mRNA) of apo(a).  It has been 
hypothesized that a pharmacologic reduction in Lp(a) could slow down or reverse CVD by reducing 
thrombotic, atherogenic, or inflammatory events in patients with elevated Lp(a) levels (Nordestgaard et 
al. 2010). 
Importantly, there is no evidence that lowering Lp(a) will result in adverse consequences in individuals, 
and there are no reports linking very low Lp(a) to any deleterious effects. 
2.3 
ISIS 681257 
Please refer to the ISIS 681257 Investigator’s Brochure for more details on ISIS 681257 mechanism of 
action, chemistry, pre-clinical and clinical experience.  The summary is provided below. 
2.3.1 
Mechanism of Action 
ISIS 681257 is a second-generation ASO drug targeted to apo(a) that has been covalently bonded to 
triantennary N-acetyl galactosamine (GalNAc3), a high-affinity ligand for the hepatocyte-specific 
asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc3 conjugate.  This GalNAc3-conjugate 
approach results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells and has 
increased ASO potency by approximately 10-fold compared to unconjugated ASOs in mice (Prakash 
et al. 2014). 
The ASO portion of ISIS 681257 is complementary to a region spanning the Exon 24-25 splice site at 
position 3901 of apo(a) transcript sequence (NM_005577.2) and binds to the mRNA by Watson and 
Crick base pairing.  The hybridization (binding) of ISIS 681257 to the cognate mRNA results in the 
Ribonuclease H1 (a non-specific endonuclease that catalyzes the cleavage of RNA via hydrolytic 
mechanism RNase H1-mediated degradation of the apo(a) mRNA, thus preventing production of the 
apo(a) protein).  Maximal antisense-mediated reduction of target mRNA levels is typically greater than 
90% of control levels in sensitive tissues (Zhang et al. 2010).  Furthermore, reduction in target mRNA 
levels using this approach correlates directly with a subsequent reduction in target protein levels.  
ISIS 681257 does not have any complementary homology to plasminogen mRNA (Graham et al. 2016). 
2.3.2 
Chemistry 
Chemically, ISIS 681257 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are connected 
sequentially by phosphorothioate and phosphodiester linkages (mixed backbone design).  The mixed 

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backbone design reduces the total number of phosphorothioate linkages, which reduces non-specific 
interactions with proteins and further enhances potency of GalNAc3 conjugated ASOs. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end and the 5 
nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotides.  
These MOE-modified nucleotides confer (1) increased affinity for the target mRNA (Altmann et al. 1996; 
McKay et al. 1999), (2) increased resistance to exonucleases and endonucleases (thereby increasing 
stability in tissue) (Geary et al. 2003), and (3) amelioration of some of the high-dose toxicities, thereby 
resulting in an improved safety profile compared to first-generation antisense drugs containing 
phosphorothioate-modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, the 
central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  This chimeric design is 
called a MOE-Gapmer, and ISIS 681257 employs this chimeric structure to enable use of the ubiquitous 
endonuclease that specifically hydrolyzes the RNA strand in RNA/DNA hybrids (RNase H1)-mechanism 
for antisense activity.  This is because while the 2′-MOE modification confers increased stability and 
affinity, it does not support RNase H1-catalyzed cleavage of RNA hybridized to 2′-MOE-modified 
nucleotides (McKay et al. 1999).  The fourth region is composed of a triantennary cluster of GalNAc3 
sugars that is linked to the 5ʹ end of ISIS 681257 via a phosphodiester linkage.  The GalNAc3 cluster is a 
high affinity ligand for the ASGPR, a receptor expressed primarily on the surface of liver hepatocytes 
(Stockert 1995).  The GalNAc3 cluster enhances delivery of ISIS 681257 to liver hepatocytes over other 
cell types and enhances potency.  After internalization into cells, the GalNAc3 cluster is metabolized to 
release “free ASO” inside the cell (Prakash et al. 2014). 
2.3.3 
Preclinical Experience 
The pharmacology of ISIS 681257 has been examined in apo(a) transgenic (Tg) mice which express the 
entire human apo(a) genomic sequence (Frazer et al. 1995) and nonhuman primates. 
Administration of ISIS 681257, a human apo(a) antisense inhibitor, to mice containing the human apo(a) 
transgene produced dose-dependent reductions in human apo(a) liver mRNA and apo(a) plasma protein 
after 6 weeks of ASO administration at 0.3, 1, 3, and 10 mg/kg/wk. 
When ISIS 681257 was administered to normal chow fed cynomolgus monkeys for 4 weeks at the dose of 
12 mg/kg/wk, it significantly reduced hepatic apo(a) mRNA by 90% relative to the cohort administered 
phosphate buffered saline (PBS).  As there is an 80% sequence conservation between apo(a) and 
plasminogen nucleotide sequences, plasminogen mRNA levels were also measured, and no change 
compared to the PBS cohort was observed. 
Findings from the chronic studies with ISIS 681257 (the 26-week mice and 39-week monkey studies) 
were similar to those observed in the 4- and 6-week studies and were not considered adverse.  The plasma 
and tissue concentrations observed for ISIS 681257 in mice and monkeys were generally similar to those 
observed for other unconjugated 20-mer 2ʹ-MOE ASOs in this chemical class with and without GalNAc3-
conjugation.  However, the proportion of drug in hepatocytes compare to nonparenchymal liver cells was 
greater for ISIS 681257, compared to the parent drug ISIS 494372 (without GalNAc3-conjugation), which 
is the basis for increased potency of ISIS 681257 (unpublished results; Geary et al. 2003; Yu et al. 2007; 
Prakash et al. 2016). 

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The most noteworthy safety finding in the chronic monkey study was a marked platelet reduction that, 
occurred in 2 male monkeys in the high-dose group (20 mg/kg/wk) and 1 animal (1 female) in the mid-
dose (10 mg/kg/wk) group beginning on Days 44-135, which led to the subsequent early termination (ET) 
of these 3 animals.  An additional male monkey in the 10 mg/kg/wk dose group had a moderate decrease 
in platelets that was successfully treated with steroid, and was terminated at the scheduled 6-month 
interim sacrifice.  There were no platelet reductions or other toxicologically significant findings in 
monkeys treated with 2 mg/kg/wk for up to 39 weeks.  There were no marked platelet reductions in mice 
at doses up to 70 mg/kg/wk for 26 weeks.  However, mice exposed to ISIS 681257 at doses of ≥ 
10 mg/kg/wk for up to 26 weeks showed evidence of hepatobiliary effects in both sexes as indicated by 
increases in ALT (up to + 10.3x), AST (up to + 10.4x), and/or ALP (+ 2.5x).  
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 681257 can be found in the 
Investigator’s Brochure.  A summary of the study that has been conducted with ISIS 681257 is included 
below. 
ISIS 681257-CS1 was a Phase 1 double-blind, placebo-controlled, dose-escalation study designed to 
assess the safety, tolerability, PK, and pharmacodynamics (PD) of single and multiple doses of ISIS 
681257 administered subcutaneously (SC) to 45 healthy subjects with Lp(a) ≥ the upper limit of normal 
(ULN) (30 mg/dL).  Twenty one (21) subjects received 10 to 120 mg SC (10, 20, 40, 80, and 120 mg) as a 
single-dose, and 24 subjects received 10, 20, and 40 mg as multiple doses (6 doses in 21 days:  3 loading 
doses during the first week on alternate days (Days 1, 3, and 5), and then once a week for the next 3 
weeks (Days 8, 15, and 22). 
There were no serious adverse events (SAEs), or clinically-relevant changes in laboratory assessments 
and all subjects completed the treatment and post-treatment follow-up periods. 
Constitutional symptoms such as fever, chills, increase in body temperature and arthralgias have been 
observed following parenteral administration of ASOs, primarily during the initial dosing period.  
Following SC administration of ISIS 681257 constitutional symptoms were observed in 4 of the 
6 subjects who received a single-dose of 120 mg.  The symptoms were mild in severity and resolved 
spontaneously with or without treatment with acetaminophen. 
Fluctuations in platelet counts to below the lower limit of normal were observed in 5 study subjects on 
active drug and across doses.  These changes were not considered adverse or clinically-significant by the 
Investigator and did not appear to be dose related. 
Two (2) mild AEs of redness at the site of injection occurred 48 to 72 hours after administration in 1 
subject who received ISIS 681257 in the 20 mg multiple-dose cohort.  Both AEs resolved by the time of 
the subject’s next visit. 
Following SC administration, ISIS 681257 was absorbed rapidly into the systemic circulation, with 
median time to maximum plasma concentrations (Tmax) ranging from 1 to 4 hours.  Similar Tmax values 
were observed at all dose levels.  Maximum observed plasma concentrations (Cmax) and AUC0-24hr were 
dose-dependent over the studied SC dose range.  The mean peak (Cmax) and total exposure (AUC0-24hr) 

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increased proportionally with dose at dose levels ranging from 10 to 40 mg, and greater than dose 
proportionally at dose levels ranging from 40 to 120 mg. 
After reaching Cmax, mean plasma concentrations of ISIS 681257 declined in a biphasic fashion over time, 
with an initial, relatively fast distribution phase that dominated the plasma clearance followed by a slower 
elimination phase.  Characterization of the terminal elimination phase yielded an apparent terminal 
elimination half-life of approximately 3 to 4 weeks over a dose range of 10 to 120 mg (either single- or 
multiple-dose), and appeared to be independent of dose.  This result is consistent with the slow 
elimination of ISIS 681257 observed from monkey tissues, and the comparatively long elimination half-
lives observed for this chemical class. 
Plasma trough concentrations (168 hours or 7 days from previous dose) monitored during the treatment 
period in the multiple-dose cohorts increased with increasing dose, consistent with expectations (based on 
preclinical assessments and experience with other compounds of this chemical class) that trough plasma 
concentrations reflect exposure in tissues.  Plasma trough concentrations did not increase greatly after the 
loading period (Day 15), suggesting that accumulation in major tissues of distribution had approached 
steady-state after the loading period. 
Overall, the human PK of ISIS 681257 are consistent with the expected PK for compounds within this 
chemical class. 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 681257 doses of 10 mg, 20 mg, and 40 mg given weekly that were 
found to be generally well-tolerated and to induce clinically-relevant reductions in Lp(a). 
The range of dosing proposed for the present study will provide the equivalent drug exposure of 5 mg, 10 
mg, 15 mg, and 20 mg administered weekly, and is predicted (based on modelling of PK/PD data 
obtained in Phase 1 study) to result in mean reductions from baseline in plasma Lp(a) ranging from 
approximately 60% to 85% at steady-state. 
The highest dose selected for this study, 20 mg per week, is predicted to provide an approximately 85% 
reduction in Lp(a) at steady-state that is expected to be sufficient to bring almost all patients with 
hyperlipoproteinemia(a) into the normal range (Lp(a) ≤ 30 mg/dL). 
The present study will also evaluate safety and efficacy at different dosing frequencies:  every 4 weeks, 
every 2 weeks, and weekly.  Patients with hyperlipoproteinemia(a) 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.  Dosing regimens of 20 mg every 2 
weeks and 40 mg every 4 weeks will test if similar monthly exposure, at different frequencies of 
administration, will achieve similar safety and similar level of Lp(a) reduction since the reduction 
achieved by a given dose level is principally driven by total exposure, while individual dose levels and the 
related peak concentration (Cmax) may influence tolerance and safety.  

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3.
EXPERIMENTAL PLAN
3.1 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio (225 ISIS 681257 and 45 placebo) to 
receive ISIS 681257 or placebo.  Study Drug (ISIS 681257 or placebo) will be administered SC every 
week, every 2 weeks (biweekly), 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. 
The primary analysis time point is at Week 25 for patients who received every 4-week dosing (Cohorts A-
C) and at Week 27 for patients who received every 2-week or weekly dosing (Cohorts D and E).  For 
patients continuing treatment beyond the primary analysis time point additional supportive efficacy 
analysis (to evaluate whether the treatment effect is maintained) and safety analysis (for the purpose of 
dose(s) selection) will be repeated at the completion of Study Drug treatment. 
The treatment portion of the study will be complete when the last patient reaches 6 months of exposure.  
All patients will then enter a 16-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. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma Lp(a) levels (≥ 60 mg/dL) and a clinical diagnosis 
of CVD are eligible for enrollment upon meeting the study specific eligibility criteria.  Patients will be on 
standard-of-care preventative therapy for other than elevated Lp(a) 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
•
Evidence of cardiac ischemia on exercise testing, or imaging study
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).  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 5 parallel 
dosing cohorts, with each cohort having a 5:1 ratio to receive ISIS 681257 or matching volume of 
placebo, respectively, by SC injection for up to 52 weeks. 
Following the End-of-Treatment, patients will enter the 16-week post-treatment follow-up period. 
3.2 
Number of Study Centers 
This is a multicenter, multinational study. 

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3.3 
Number of Patients 
Approximately 270 patients will be randomized in this study, with approximately 54 patients assigned to 
each of the 5 treatment cohorts. 
3.4 
Overall Study Duration and Follow-up 
The length of patients’ participation in the study may be up to 18 months (72 weeks), which includes a 4-
week screening period, an up to 52-week treatment period with Study Drug (ISIS 681257 or placebo), and 
a 16-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. 
3.4.2 
Treatment 
For each patient, minimum treatment duration is 6 months and maximum is 52 weeks.  
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 5 treatment 
cohorts.  On completion of the 6 months, patients may 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.  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 E), 2 weeks post last dose for every 2-week dosing (Cohort 
D), and 4 weeks post last dose for every 4-week dosing (Cohort A-C).  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 16-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 681257 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 16-week post-treatment follow-up period and will return to 
the Study Center for 3 follow-up visits 4, 10, and 16 weeks after the treatment period as per  
Appendix A (Follow-up). 
The final study visit for each patient will be 16 weeks after the treatment period. 

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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 681257 during this study.  The DSMB will be 
constituted to include expertise in medical specialties relevant to the safety of antisense drugs 
(nephrology, hepatology, hematology and cardiology).  Specialist members of the DSMB will be 
informed and consulted on all treatment-related SAEs relevant to their expertise and all changes of 
relevant laboratory parameters that trigger stopping rules (Section 8.6), within 24 hours of receipt of 
such results.  In addition, all accrued safety data relevant to each of medical area specialist will be 
forwarded monthly for review.  
The full DSMB review of all accumulated data will be performed quarterly.  Based on its ongoing 
assessment of the safety and tolerability of ISIS 681257, 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). 
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 1:1:1:1:1 
ratio to 1 of the 5 parallel-dose cohorts (Cohorts A, B, C, D, or E).  Within each dose cohort, patients will 
be randomized in a 5:1 ratio to receive ISIS 681257 or matching volume of placebo, respectively. 

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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 a 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). 
5.
PATIENT ELIGIBILITY
To be eligible to participate in this study candidates must meet the following eligibility criteria at within 4 
weeks of Study Day 1or 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.
Clinical diagnosis of CVD defined as documented coronary artery disease (CAD), stroke, or
peripheral artery disease
4.
Lp(a) plasma level ≥ 60 mg/dL
5.
Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors
6.
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, proprotein convertase subtilisin/kexin
type 9 [PCSK9s] 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
7.
Females:  must be non-pregnant and non-lactating and either:

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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 16 weeks after the last dose of Study Drug (ISIS 681257 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
8.
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 16 weeks after the last dose of 
ISIS 681257
5.2 
Exclusion Criteria 
1.
Within 6 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 New York Heart Association (NYHA) class 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 with a history of major bleed or high-risk of bleeding diathesis
11. Recent history of, or current drug or alcohol abuse
12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions

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13. Hypersensitivity to the active substance or to any of the excipients
14. Clinically-significant abnormalities in screening laboratory values that would render a patient
unsuitable for inclusion, including the following:
a.
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR above this
threshold, eligibility may be confirmed by a quantitative total urine protein measurement of ˂
300 mg/24-hr
b.
Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR above this
threshold, eligibility may be confirmed by a quantitative total urine albumin measurement of
˂ 150 mg/24-hr
c.
Estimated GFR ˂ 60 mL/min (as determined by the Chronic Kidney Disease-Epidemiological
Collaboration (CKD-EPI) Equation for creatinine clearance
d.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN
e.
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in which
case total bilirubin must be ≤ 3 mg/dL
f.
Alkaline phosphatase (ALP) > ULN
g.
Platelet count ˂ LLN
15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors
16. Treatment with another investigational drug, biological agent, or device within 1 month of
Screening, or 5 half-lives of investigational agent, whichever is longer
17. Treatment with any 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
18. BMI > 40 kg/m2
19. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 8 weeks of
Screening
20. Unwillingness to comply with study procedures, including follow-up, as specified by this
protocol, or unwillingness to cooperate fully with the Investigator
21. 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
6.
STUDY PROCEDURES
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, and C. 

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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.  A 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.  
On confirmation of eligibility and prior to randomization, patients will also undergo a 24 hr urine 
collection for creatinine, albumin, and protein as a baseline assessment. 
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 20 mg doses of Study Drug administered by SC injection once every 4 weeks for up to 49 weeks 
in Cohort A, 40 mg doses of Study Drug administered by SC injection once every 4 weeks for up to 49 
weeks in Cohort B, 60 mg doses of Study Drug administered by SC injection once every 4 weeks for up 
to 49 weeks in Cohort C, 20 mg doses of Study Drug administered by SC injection once every 2 weeks 
for up to 51 weeks in Cohort D, or 20 mg doses of Study Drug administered by SC injection once per 
week (weekly) for up to 52 weeks in Cohort E (Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical laboratory 
parameters (Appendix B), ISIS 681257 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 12 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 681257.  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). 
6.1.3 
Post-Treatment Period 
Each patient will be followed for safety assessments for 16 weeks after the treatment period.  During the 
post-treatment follow-up period, patients will return to the Study Center for 3 outpatient visits at Weeks 
4, 10, and 16 after the treatment period for safety and clinical laboratory evaluations and for blood 
sampling for PK (Appendices A and C). 

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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 (excluding 24-hour urine collection) should be taken after 
fasting for at least 10 hours.  Any confirmatory test, or test taken for safety reasons, may be taken at any 
time, irrespective of fasting status.  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.  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 
and sent to the central laboratory for analysis, per Section 8.5.2.  If there are no test results available 
within 14 days of the last set of results for parameters considered critical to patient safety, the Investigator 
will contact the patient to hold dosing until a new test set is obtained and reviewed. 
While on treatment liver function testing will also be collected every 14 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 sent to the central laboratory are received on the next day 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 on the day of 
sample collection, and should be entered as soon as possible into the eCRF to inform the Sponsor and 
CRO study monitoring teams. 
All platelet count results must be reviewed promptly (within 24 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 (Grade 3 or 

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Grade 4) 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 24 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 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, B, and C at Weeks 5, 13, 21, 25, 33, 41, 49, and 53
•
Cohorts D and E at Weeks 5, 13, 21, 27, 33, 41, 49, and 53
In all cohorts, ECGs will be conducted during the post-treatment follow-up period at 4, 10, and 16 weeks 
after the treatment period. 
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. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 681257 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. 

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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 16 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 16 
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
†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. 

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*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 before visits requiring fasted blood sampling. 
7.
STUDY DRUG
7.1 
Study Drug Description 
Study Drug (ISIS 681257 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 681257 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 681257 
ISIS 681257 vials contains 100 mg/mL ISIS 681257 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 681257 vials.  

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Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 681257 
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 681257 or placebo) labeled in 
accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug (ISIS 681257 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 681257 will be administered to patients by Study Center staff as follows: 
Cohort A: 
a single SC dose of 20 mg once every 4 weeks for up to 49 weeks and a maximum of 13 
doses 
Cohort B: 
a single SC dose of 40 mg once every 4 weeks for up to 49 weeks and a maximum of 13 
doses 
Cohort C: 
a single SC dose of 60 mg once every 4 weeks for up to 49 weeks and a maximum of 13 
doses 
Cohort D: 
a single SC dose of 20 mg every 2 weeks for up to 51 weeks and a maximum of 26 
doses 
Cohort E: 
a single SC dose of 20 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, B, and C should receive 1 dose every 4 weeks, patients in Cohort D should receive 
1 dose every 2 weeks and Cohort E 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 

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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 681257 or placebo) preparation and administration. 
Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.2 mL  
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.4 mL  
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.6 mL  
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 
or placebo 
(Every 2 weeks) 
0.2 mL 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 
or placebo 
(Every week) 
0.2 mL 
≤ 52 
≤ 1040 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 
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. 

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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 681257 or 
placebo).  All new specimen collections should take place as soon as possible (ideally within 3 days of the 
initial collection).  
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, patients must not be re-
dosed 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 681257 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 2 weeks for the first 3 months of the study 
treatment, and monthly thereafter during the Treatment Period. 
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. 

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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. 
All results of liver function tests must be reviewed promptly (within 24 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 (within 24 hours of receipt) reviewed by 
the Investigator and Medical Monitors. 
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 2 weeks throughout the 
study.  Upon completion of the study treatment period, urine renal biomarkers should be monitored every 
2 weeks for the first 6 weeks and then at 10 and 16 weeks post treatment period (as per visit schedule). 

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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 urinary red blood cells 
(RBCs), as well as serum creatinine and cystatin-C to estimate glomerular filtration rate (eGFR), which 
will be monitored every 2 weeks.  In addition, biomarkers of acute renal injury will also be measured 
every 2 weeks (Appendix B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than every 2 weeks 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 at the weekly safety review by the 
Medical Monitor. 
All results of renal function tests must be reviewed promptly (within 24 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:  Creatinine clearance (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 an 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. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of the 
above criteria, dosing with the Study Drug should be interrupted and the Study Medical Monitor 
informed.  In addition, the following supplemental renal tests should be immediately obtained:  
Serum creatinine, urine culture, 24-hour urine sample for creatinine clearance, urine albumin and 
urine protein, urine microscopy sample with inspection of sediment. 
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. 
8.5.3 
Safety Monitoring for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study treatment 
period and must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks.  

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Upon completion of the study treatment period, platelets should be monitored every 2 weeks for the first 6 
weeks and then at 10 and 16 weeks post treatment period (as per visit schedule). In addition, platelet 
function will be evaluated by aggregometry, using an approved point-of-care diagnostic device, in all 
patients at each study site visit; additional functional testing may be performed at selected study centers.  
As described in Section 6.2.1, all platelet count results must be reviewed promptly (within 24 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.  
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are < 140,000 
mm3; 2) when platelet count is ≥ 30% decreased from baseline, or 3) when 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 Minor Bleeding Events 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  Minor bleeding events 
are those that do not fulfill the criteria for major bleeding or clinically-relevant, non-major bleeding 
events (which are defined in Section 8.6.3), for example excess bruising, petechiae, or gingival bleeding 
on brushing teeth.  If a minor bleeding event occurs, the Investigator must notify the Sponsor Medical 
Monitor and additional testing of coagulation parameters activated partial thromboplastin time (aPTT), 
prothrombin time (PT), INR, hepatic enzymes, bilirubin and platelet count should be performed. 
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 symptoms 
should be discussed with the Sponsor Medical Monitor or designee to determine whether additional 
monitoring or laboratory tests are required. 
8.6 
Stopping Rules 
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. 

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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 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 of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the following 
criteria, or any change in renal biomarkers deemed by the nephrologist on the DSMB to require further 
evaluation, a serum creatinine, urine culture, 24-hour urine sample for creatinine clearance and protein, 
and urine microscopy sample with inspection of sediment should be immediately obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 681257 or placebo) will be stopped permanently if 24-hour 
urine testing confirms any of the following values in the absence of an alternative explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, 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 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low platelet count are summarized in Table 3 below. 

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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 steroids 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 steroids.  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 0.5-2 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). 
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; Schulman et al. 2005), 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 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. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
•
Fatal bleeding, and/or
•
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular,
retroperitoneal, intraarterial or pericardial, or intramuscular with compartment syndrome, and/or
•
Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 24 hours, or
leading to transfusion of 2 or more units of whole or red cells
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1.
Multiple-source bleeding
2.
Spontaneous hematoma > 25 cm2
3.
Excessive wound hematoma (not injection site related)
4.
Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an intervention)

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5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis  
6. Bleeding after venipuncture for > 5 minutes 
Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, ≥ 140K/mm3 
No action 
Monitor every 2 weeks 
≥100K to <140K/mm3 
No action 
Closer observation 
Monitor every week* 
≥75K to <100K/mm3 
Permanently reduce as follows: 
For Cohort A:  reduce to 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks  
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 weeks 
For Cohort E:  reduce to 10 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 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks 
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 week 
For Cohort E:  reduce to 10 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)/ anticoagulant 
medication 
≥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/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 

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Platelet Count on Rx 
Drug Dose 
Monitoring 
˂ 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 and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
*
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 steroids.  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 0.5-2 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 Section 8.6.3 
and 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 8.6.3
•
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.
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report Form 
(eCRF) and source documentation. 

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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 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 treatment period.  Following this period, if the platelet count is stable (at least 3 consecutive 
values that are stable as determined by the Sponsor Medical Monitor and > 100,000/mm3), platelets 
should be tested 10 and 16 weeks post 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 16-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 16 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). 
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  
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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, PCSK9 inhibitors, niacin, fibrates, fish oil, other 
products containing omega-3 fatty acids (including OTC preparations) 
• 
Anti-platelet therapies 
• 
Testosterone, estrogens, progesterone, growth hormone, or progestins. 
Disallowed Concomitant Therapy 
Use of the following is disallowed: 
• 
Warfarin, 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 
• 
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. 

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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 of platelet 
count, and liver and renal function as described in Section 6.2.1, Sections 8.5.1-8.5.3, and Sections 8.6.1-
8.6.3. 
While on treatment patients will be required to have platelet counts every 2 weeks 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 2 weeks, and must not receive Study Drug if there are no test results 
for parameters considered critical to patient safety available within the prior 2 weeks.  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 (Grade 3 or Grade 4), 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. 
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 
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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 
• 
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 

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•
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.  When the Investigator is reporting by telephone, it is important to speak to someone in person 
versus leaving a message.  An Initial Serious Adverse Event Form should be completed and a copy 
should be emailed or faxed to the Sponsor or designee.  The contact information for reporting SAEs is as 
follows:  
Attention: 
 
Email: 
 
Fax: 
 
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 
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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 681257 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 681257 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
•
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
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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 681257 or placebo) due to the event is characterized by 1 of the 
following. 
•
None:  No changes were made to Study Drug (ISIS 681257 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)
•
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)

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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 24 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 as per 
Sections 9.3.3.1 and 9.4.1). 
All results of liver function tests must be reviewed promptly (within 24 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 24 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: 
•
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
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•
The condition that required the prescheduled or elective procedure or routinely scheduled
treatment was present before and did not worsen or progress in the opinion of the Investigator
between the patient’s consent to participate in the study and the timing of the procedure or
treatment.  The 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 681257 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 681257 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 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 

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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-C) and at Week 27 for patients who received weekly or biweekly dosing (Cohorts D 
and E).  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 endpoint is the percent change in Lp(a) from baseline at the primary analysis time 
point achieved by ISIS 681257 compared to pooled placebo. 
Lp(a) levels will be analyzed from patient blood samples taken at specified time points throughout the 
study. 
10.1.2 
Secondary Endpoints 
The secondary endpoints include the following parameters from baseline at the primary analysis time 
point for ISIS 681257 compared to placebo: 
•
Percent change from baseline in LDL-C
•
Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L)
•
Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL (≤ 75 nmol/L)
•
Percent change from baseline in apoB
•
Percent change from baseline in OxPL-apo(a)
•
Percent change from baseline in OxPL-apoB
10.1.3 
Safety Endpoints 
The safety analysis will be performed using the following parameters: 
•
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• 
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. 
• 
ECGs 
• 
Use of concomitant medications 
10.1.4 
Dose Selection 
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 clinically-meaningful reduction in plasma Lp(a) 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, and renal or hepatic injury.   
10.2 
Sample Size Considerations 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the standard deviation of 
the percent change in Lp(a) is approximately 20%.  With 23 patients in each ISIS 681257 treatment group 
and 23 in placebo group there would be approximately 90% power to detect a 20% difference in percent 
change in Lp(a) levels between the ISIS 681257 treatment groups and placebo group at an alpha level of 
0.05, assuming 30% reduction in the ISIS 681257 patients and 10% reduction in the placebo patients. 
Based upon prior clinical trial experience with Ionis ASOs, assuming the incidence rate of platelet count 
below lower limit of normal (LLN) in placebo treated patients is 1.9%, in the ISIS 681257 treated patients 
is 3.8%, twice the incidence rate observed in placebo, with 45 patients in each ISIS 681257 treatment 
group, there would be approximately 80% power to detect at least 1 event. 
Therefore, approximately 270 patients (54 patients per cohort, including 45 patients per cohort treated 
with ISIS 681257) will be randomized to ensure that both the safety and efficacy of ISIS 681257 will be 
adequately characterized in the study. 
10.3 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized, received at least 1 dose of Study Drug 
(ISIS 681257 or placebo), and have a Baseline Lp(a) 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.   

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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, B, and C or at least 11 biweekly doses for patients 
randomized in Cohort D or at least 22 weekly doses for patients randomized in Cohort E, 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 Study Drug, and have 
sufficient data for the analysis of PK parameters.  This population will be used for analysis of PK data. 
10.4 
Definition of Baseline 
Baseline for Lp(a), LDL-C, apoB, OxPL-apo(a), OxPL-apoB, and other lipid measurements will be 
defined the pre-dose measurement on Day 1 or 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. 
10.6.2 
Safety Analysis 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug (ISIS 681257 or placebo) received will be summarized by 
treatment group.  Patient incidence rates of all AEs will be tabulated by MedDRA system organ class, and 

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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 681257 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 681257 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 analysis of the primary endpoint will be the pairwise comparison of percent change from 
baseline to primary analysis time point in fasting Lp(a) between ISIS 681257 treatment groups and pooled 
placebo group in the FAS.  The data will be analyzed using an analysis of covariance (ANCOVA) model 
with the Baseline Lp(a) 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. 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints 
•
Percent change from baseline at the primary analysis time point in fasting LDL-C will be
compared between each ISIS 681257 treatment groups and pooled placebo group using an
ANCOVA model with baseline as covariate

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• 
Proportion of patients who achieve ≤ 50 mg/dL (≤ 125 nmol/L) in fasting Lp(a) at the primary 
analysis time point will be compared between each ISIS 681257 treatment group and pooled 
placebo group using a logistic regression model with Baseline Lp(a) as a covariate.  Proportion of 
patients who achieve ≤ 30 mg/dL (≤ 75 nmol/L) in fasting Lp(a) at the primary analysis time 
point will be analyzed similarly 
• 
Percent change from baseline at the primary analysis time point in fasting apoB, OxPL-apo(a) 
and OxPL-apoB will be compared between ISIS 681257 treatment groups and pooled placebo 
group using an ANCOVA model with baseline as covariate 
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 681257 in plasma (as total full length 
oligonucleotides, including fully conjugated, partially conjugated, and unconjugated ISIS 681257) will be 
determined and summarized by treatment with stratification by subject immunogenicity status using 
descriptive statistics. 
In addition, non-compartmental PK analysis of ISIS 681257 concentrations will be carried out on each 
individual patient data set in patients who received ISIS 681257 treatment, and the plasma disposition 
half-life (t1/2λz) associated with the apparent terminal elimination phase will be calculated, if appropriate, 
using available data at the End-of-Treatment and the post-treatment follow-up period from the equation, 
t1/2λz = 0.693/λz, where λz is the rate constant associated with the apparent terminal elimination phase. 
For patients in the PK subgroup only, non-compartmental PK analysis of ISIS 681257 will be carried out 
on each individual patient data set in patients who received ISIS 681257 treatment.  The maximum 
observed drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will be obtained directly from 
the concentration-time data.  Following single dosing (Day 1), area under the plasma concentration-time 
curve from time zero (pre-dose) to 24 hours after the dose (AUC0-24hr) will be calculated using the linear 
trapezoidal rule.  Following multiple dosing, AUC0-24hr and area under the plasma concentration-time 
curve during the time of each sampled dosing interval (tau,τ) at steady-state (AUCτ) will be calculated 
using the linear trapezoidal rule. 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist.  Plasma PK parameters will be summarized using descriptive statistics with stratification by 
subject immunogenicity status.  Exposure-response relationships between selected PD [e.g., Lp(a)] and 
PK measures (including but may not be limited to plasma trough concentrations) may be explored 
(including with and without stratification by IM status) in this study, or in a separate population PK 
analysis with all clinical studies combined. 
The immunogenicity (IM) of ISIS 681257 will be assessed before, during, and after treatment with Study 
Drug (ISIS 681257 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 681257 antibody status may be further classified (when applicable) as 

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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. 
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 681257 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. 
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. 

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The Investigator must submit to and, where necessary, obtain approval from the IEC/IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The Investigator 
should 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. 

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The Investigator and Study Center staff are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation in accordance with Section 8 of the ICH 
Guidelines (E6), suitable for inspection at any time by representatives from the Sponsor or designee 
and/or applicable regulatory authorities.  Elements should include: 
• 
Patient files containing completed 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, 

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omissions, and any apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data management review process, 
data queries and/or Study Center notifications will be sent to the Study Center for completion and return 
to Sponsor or designee. 
The Principal Investigator will sign and date the indicated places on the 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 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bennett CF. Pharmacological properties of 2ʹ-O-methoxyethyl-modified oligonucleotides. In: Crooke ST, editor. 
Antisense Drug Technology: Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis 
Group 2008; 365-400. 
Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized 
phospholipids in human plasma. J Lipid Res 2008; 49: 2230-2239. 
Bertoia ML, Pai JK, Lee J-H, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll 
Cardiol 2013; 61(21): 2169-2179. 
Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) 
lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528. 
Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin 
kexin type 9, significantly reduces lipoprotein (a) in hypercholesterolemic patients receiving statin therapy: an 
analysis from the LAPLACE-TIMI 57 Trial. Circ 2013; 128: 962-969. 
Dubé JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a): more interesting than ever after 50 years. Curr 
Opin Lipidol 2012; 23(2): 133-140. 
Erqou S, Kaptoge S, Perry PL, et al; Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk 
of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4): 412-423. 
Erqou S, Thompson A, Di Angelantonio E, et al. Apoliporotein(a) isoforms and the risk of vascular disease. JACC 
2010; 55(19): 2160-2167. 
Frazer KA, Narla G, Zhang JL, Rubin E. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase 
inducers in YAC transgenic mice. Nat Gen 1995; 9: 424-431. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma 
lipoprotein (a) levels in humans. J Lipid Research 2016; 57: 340-351. 
Guyton JR. Niacin in cardiovascular prevention: mechanisms, efficacy, and safety. Curr Opin Lipidol 2007; 18: 
415-420. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292(2): 468-479. 
Jaeger BR, Richter Y, Nagel D, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to 
reduce high lipoprotein(a) levels and major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009; 6(3): 
229-239. 
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and 
increased risk of myocardial infarction. JAMA 2009; 301(22): 2331-2339. 

ISIS 681257-CS6 
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Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 
activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb 
Vasc Biol 2007; 27: 1788-1795. 
Koschinsky ML and Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into 
lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 2004; 15(2): 167-174. 
Kronenberg F and Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013; 273: 6-30. 
Leebmann J, Roeseler E, Julius U, et al; Pro(a)LiFe Study Group. Lipoprotein apheresis in patients with maximally 
tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: 
Prospective observational multicenter study. Circ 2013; 128: 2567-2576. 
Leibundgut G, Scipione C, Yin H, et al. Determinants of binding of oxidized phospholipids on apolipoprotein(a) and 
lipoprotein(a). J Lipid Res 2013; 54: 2815-2830. 
Li Y, Luke MM, Shiffman D, Devlin JJ. Genetic variants in the apolipoprotein(a) gene and coronary heart disease.  
Circ Cardiovasc Genet 2011; 4(5): 565-573. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Merki E, Graham M, Taleb A, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) in 
transgenic mice. JACC 2011; 57(15): 1611-1621. 
Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as 
a cardiovascular risk factor: current status. Euro Heart J 2010; 31: 2844-2853. 
Parker K, Brunton L, Goodman LS, et al. Goodman & Gilman's the pharmacological basis of therapeutics. New 
York, NY. McGraw-Hill. 2006; ISBN 0-07-142280-142283. 
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; 42: 8796-8807. 
Prakash TP, Yu J, Migawa MT, et al. Comprehensive structure-activity relationship of triantennary N-Acetyl 
galactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J Med Chem 2016 
Mar 24; 59(6): 2718-2733. 
Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolucomab in homozygous familial 
hypercholesterolemia (TESLA Part B): a randomized, double blind, placebo controlled trial. Lancet 2015; 385: 
341-350. 
Rand ML, Sangrar W, Hancock MA, et al. Apoliprotein(a) enhances platelet responses to the thrombin receptor – 
activating peptide SFLLRN. Arterio Thromb Vasc Biol 1998; 18: 1393-1399. 
Rosada A, Kassner U, Vogt A, et al. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) 
levels reduce the incidence of cardiovascular events? Artif Organs 2014; 38: 135-141. 
Safarova M. Specific lipoprotein(a) apheresis reduces atherosclerosis progression. 80th Congress of the European 
Atherosclerosis Society, Milan, Italy 28 May 2012. 
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. 

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Schulman S and Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Spence JD and Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity. Arterioscler Thromb Vasc Biol 2012; 
32: 1550-1551. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Thanassoulis G, Campbell CY, Owens DS, et al; CHARGE Extracoronary Calcium Working Group. Genetic 
associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368(6): 503-512. 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circ 2012; 126: 
2020-2035. 
Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal 
coronary events. J Am Coll Cardiol 2010; 56: 946-955. 
Tsimikas S, Willeit P, Willeit J, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke 
outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60: 2218-2229. 
Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary 
artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 
2014; 63: 1724-1734. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second-
generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.  Drug Metab Dispos 
2007; 35: 460-468.  
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 
 
 
 

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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 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27p 
29 
33 
37 
41 
45 
49 
53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 29 
57 
85 
113 141 
169 
183 184a 185a 197 225 253 281 309 337 
365 
*Post Treatment 
Period 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-Hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
X 
X 
X 
Genetic Testing (optional) 
 
X 
 
Chemistry Panel j,k 
X 
EVERY 14 DAYS f 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh  
Xh  
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 X1 
X 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 

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Appendix A 
Schedule of Procedures – Weekly and Every 2-Week Dosing Continued 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27p 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 
169 
183 184a 185a 197 225 253 281 309 337 
365 
*Post Treatment
Period 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
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 
Archived Serum & Plasma 
Samples j, n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD Panel j 
X 
X 
X 
X 
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 
Lp(a) Characterization 
X 
Study Drug:  SC Injection 
WEEKLY SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 through Week 52/Day 358)o
EVERY 2-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 through Week 51/Day 351)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 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks post treatment 
period, then at Week 10 and Week 16 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. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
25 January 2018 
78 
Appendix A 
Schedule of Procedures – Weekly and Every 2 Week Dosing Continued 
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 24 hours of receipt) by the 
Investigator as per Section 6.2.1.  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 16-week post-treatment follow-up period. 
p     For the last patient to reach 6 months of exposure ONLY, the Week 27 visit will count as the End of Treatment Visit, therefore all Week 53/ET assessments 
will be included in this visit. No dose will be administered at this visit. 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8 hours post SC injection 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
79 
Appendix A 
Schedule of Procedures – Every 4-Week Dosing 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25p 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Treatment 
Period 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
X 
X 
X 
Genetic Testing (optional) 
 
X 
 
 
Chemistry Panel j, k 
X 
EVERY 14 DAYS f 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh 
Xh 
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 
X1 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
25 January 2018 
80 
Appendix A 
Schedule of Procedures – Every 4-Week Dosing Continued 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25p 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Treatment
Period 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
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 
Archived Serum & Plasma 
Samples j, n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PD Panel j 
X 
X 
X 
X 
X 
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 
X 
Lp(a) Characterization 
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 
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 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks post treatment 
period, then at Week 10 and Week 16 Follow-up visits. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
25 January 2018 
81 
Appendix A 
Schedule of Procedures – Every 4-Week Dosing Continued 
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 24 hours of receipt) by the 
Investigator as per Section 6.2.1.  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 16-week post-treatment follow-up period. 
p    For the last patient to reach 6 months of exposure ONLY, the Week 25 visit will count as the End of Treatment Visit, therefore all Week 53/ET assessments will 
be included in this visit. No dose will be administered at this visit. 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8, hrs post SC injection 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
82 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
83 
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 681257 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 
• Free T3 
 
Coagulation 
• aPTT 
• PT 
• INR 
• Fibrinogen 
• Plasminogen 
 
PD Panel 
• Lp(a) 
• OxPL-apoB 
• OxPL-apo(a) 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL 
Lp(a) Characterization 
• Apo(a) isoforms 
 
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 681257 (total full 
length ASO) levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 681257 
antibodies 
 
Genetic Testing 
• LPA SNPs associated with 
elevated Lp(a)  
 
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 
Biomarkers2 
• NGAL  
• NAG 
• KIM-1 
• Cys-C 
 
24 Hour Urine Test3 
• Creatinine clearance 
• Protein 
• Albumin 
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 681257 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.   
3 
To be performed during Screening upon confirmation of eligibility 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
84 
 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 
Sampling Schedule for Weekly and Every 2-Week Dosing Cohorts 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
85 
Appendix C 
PK Sampling Schedule  
Blood samples for the determination of plasma ISIS 681257 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 681257 with plasma constituents.  Extensive PK samples 
will be collected in PK subgroup only (12 subjects 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 
27 
29 
37 
53/ET 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
183 
184 
185 
197 
253 
365 
*Post Treatment Period 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 48-hr3 Pre-
dose 
Pre-
dose 
 
Anytime 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
86 
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 
25 
26 
27 
29 
37 
53/ET 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
170 
171 
176 
183 
197 
253 
365 
*Post Treatment Period  
All 
Patients 
Pre-
dose NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
NA 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
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 
Pre-
dose, 
1, 2, 
4, and 
8-hr1 
24-hr2 48-hr3 Anytime Anytime Pre-
dose 
Pre-
dose 
 
Anytime 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
87 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
88 
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 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
89 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
90 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities Continued 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
91 
 
 
 
 
 
 
 
Appendix E 
Additional Laboratory Tests for Patients with 
Platelet Count ˂ 100,000/mm3 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 6 
Protocol  
 
25 January 2018 
 
92 
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 
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 
Platelet Antibody Bead Array (PABA) 
 

 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
IONIS PHARMACEUTICALS, INC. 
 
ISIS 681257-CS6 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
 
Protocol Amendment 5 – 30 May 2017 
 
 
EudraCT No:  2016-003373-18 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 
Study of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment: 
Amendment 5 
Date: 
30 May 2017 
 
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 681257 
Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD),” dated 30 May 2017, and agree to conduct the study as described 
herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENTS ................................................................................................... 9 
PROTOCOL SUMMARY OF CHANGES .............................................................................. 10 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 18 
STUDY GLOSSARY .................................................................................................................. 19 
1. 
OBJECTIVES ................................................................................................................. 23 
1.1 
Primary Objective ..........................................................................................................23 
1.2 
Secondary Objective(s) ..................................................................................................23 
2. 
BACKGROUND AND RATIONALE .......................................................................... 23 
2.1 
Overview of Disease ......................................................................................................23 
2.1.1 
Lipoprotein (a) ........................................................................................................23 
2.1.2 
Pathophysiology .....................................................................................................25 
2.1.3 
Current Treatment Options .....................................................................................25 
2.2 
Therapeutic Rationale ....................................................................................................26 
2.3 
ISIS 681257 ...................................................................................................................26 
2.3.1 
Mechanism of Action .............................................................................................26 
2.3.2 
Chemistry ...............................................................................................................27 
2.3.3 
Preclinical Experience ............................................................................................27 
2.3.4 
Clinical Experience ................................................................................................28 
2.4 
Rationale for Dose and Schedule of Administration .....................................................29 
3. 
EXPERIMENTAL PLAN .............................................................................................. 30 
3.1 
Study Design ..................................................................................................................30 
3.2 
Number of Study Centers ..............................................................................................31 
3.3 
Number of Patients ........................................................................................................31 
3.4 
Overall Study Duration and Follow-up .........................................................................31 
3.4.1 
Screening ................................................................................................................31 
3.4.2 
Treatment ................................................................................................................31 
3.4.3 
Post-Treatment .......................................................................................................31 
3.5 
End-of-Study ..................................................................................................................31 
3.6 
Data and Safety Monitoring Board ................................................................................32 
4. 
PATIENT ENROLLMENT ........................................................................................... 32 
4.1 
Screening .......................................................................................................................32 
4.2 
Randomization ...............................................................................................................32 
4.3 
Replacement of Patients .................................................................................................33 
4.4 
Unblinding of Treatment Assignment ...........................................................................33 
5. 
PATIENT ELIGIBILITY .............................................................................................. 33 
5.1 
Inclusion Criteria ...........................................................................................................33 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
6 
5.2 
Exclusion Criteria ..........................................................................................................34 
6. 
STUDY PROCEDURES ................................................................................................ 35 
6.1 
Study Schedule ..............................................................................................................35 
6.1.1 
Screening ................................................................................................................36 
6.1.2 
Treatment Period ....................................................................................................36 
6.1.3 
Post-Treatment Period ............................................................................................36 
6.2 
Additional Study Assessments .......................................................................................37 
6.2.1 
Laboratory Assessments .........................................................................................37 
6.2.2 
Physical Exams and Vital Signs .............................................................................38 
6.2.3 
Electrocardiography ...............................................................................................38 
6.2.4 
PK Sampling ...........................................................................................................38 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................39 
6.3.1 
Contraception Requirements ..................................................................................39 
6.3.2 
Other Requirements ................................................................................................40 
7. 
STUDY DRUG ................................................................................................................ 40 
7.1 
Study Drug Description .................................................................................................40 
7.1.1 
ISIS 681257 ............................................................................................................40 
7.1.2 
Placebo ...................................................................................................................40 
7.2 
Packaging and Labeling .................................................................................................40 
7.3 
Study Drug Accountability ............................................................................................40 
8. 
TREATMENT OF PATIENTS ..................................................................................... 41 
8.1 
Study Drug Administration ............................................................................................41 
8.2 
Other Protocol-Required Drugs .....................................................................................42 
8.3 
Other Protocol-Required Treatment Procedures ............................................................42 
8.4 
Treatment Precautions ...................................................................................................42 
8.5 
Safety Monitoring Rules ................................................................................................42 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................43 
8.5.2 
Safety Monitoring for Renal Function ...................................................................44 
8.5.3 
Safety Monitoring for Platelet Count Results ........................................................45 
8.5.4 
Safety Monitoring for Minor Bleeding Events .......................................................46 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................46 
8.6 
Stopping Rules ...............................................................................................................46 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................46 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................47 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................47 
8.7 
Adjustment of Dose .......................................................................................................50 
8.8 
Discontinuation of Study Drug ......................................................................................50 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................50 
8.9 
Withdrawal of Patients from the Study ..........................................................................50 

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8.10 
Concomitant Therapy and Procedures ...........................................................................51 
8.10.1 
Concomitant Therapy .............................................................................................51 
8.10.2 
Concomitant Procedures .........................................................................................52 
8.11 
Treatment Compliance ...................................................................................................52 
8.12 
Safety Monitoring Compliance ......................................................................................52 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 53 
9.1 
Sponsor Review of Safety Information .........................................................................53 
9.2 
Regulatory Requirements ..............................................................................................53 
9.3 
Definitions .....................................................................................................................53 
9.3.1 
Adverse Event ........................................................................................................53 
9.3.2 
Adverse Reaction and Unexpected Adverse Reaction ...........................................54 
9.3.3 
Serious Adverse Event (SAE) ................................................................................54 
9.3.3.1 
Adverse Events of Special Interest ..................................................................54 
9.4 
Monitoring and Recording Adverse Events ...................................................................54 
9.4.1 
Serious Adverse Events/Adverse Events of Special Interest .................................55 
9.4.2 
Non-Serious Adverse Events ..................................................................................55 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................55 
9.4.3.1 
Relationship to the Study Drug ........................................................................55 
9.4.3.2 
Severity ............................................................................................................56 
9.4.3.3 
Action Taken with Study Drug ........................................................................56 
9.4.3.4 
Treatment Given for Adverse Event ................................................................56 
9.4.3.5 
Outcome of the Adverse Event ........................................................................56 
9.5 
Procedures for Handling Special Situations ..................................................................57 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................57 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............58 
9.5.3 
Dosing Errors .........................................................................................................58 
9.5.4 
Contraception and Pregnancy .................................................................................58 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 59 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................59 
10.1.1 
Primary Endpoint(s) ...............................................................................................59 
10.1.2 
Secondary Endpoints ..............................................................................................60 
10.1.3 
Safety Endpoints .....................................................................................................60 
10.1.4 
Dose Selection ........................................................................................................60 
10.2 
Sample Size Considerations ...........................................................................................61 
10.3 
Analysis Populations ......................................................................................................61 
10.4 
Definition of Baseline ....................................................................................................61 
10.5 
Interim Analysis .............................................................................................................61 
10.6 
Planned Methods of Analysis ........................................................................................62 
10.6.1 
Demographic and Baseline Characteristics ............................................................62 
10.6.2 
Safety Analysis .......................................................................................................62 

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10.6.2.1 
Adverse Events ................................................................................................62 
10.6.2.2 
Clinical Laboratory Data..................................................................................62 
10.6.2.3 
Vital Signs and Examinations ..........................................................................62 
10.6.3 
Efficacy Analysis ...................................................................................................63 
10.6.3.1 
Analysis of Primary Efficacy Endpoint ...........................................................63 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints......................................................63 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................63 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 64 
11.1 
Informed Consent ..........................................................................................................64 
11.2 
Ethical Conduct of the Study .........................................................................................65 
11.3 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) .....................65 
11.4 
Patient Confidentiality ...................................................................................................65 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 66 
12.1 
Protocol Amendments ....................................................................................................66 
12.2 
Study Termination .........................................................................................................66 
12.3 
Study Documentation and Storage ................................................................................66 
12.4 
Study Monitoring ...........................................................................................................67 
12.5 
Language ........................................................................................................................67 
12.6 
Compensation for Injury ................................................................................................67 
13. 
REFERENCES ................................................................................................................ 68 
14. 
APPENDICES ................................................................................................................. 71 
Appendix A 
Schedule of Procedures ....................................................................................72 
Appendix B 
List of Laboratory Analytes .............................................................................79 
Appendix C 
PK Sampling Schedule ....................................................................................81 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......84 
Appendix E 
Additional Laboratory Tests for Patients with Platelet Count  
˂ 100,000/mm3 .................................................................................................88 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ................................................................................... 40 
Table 2 
Study Drug Dosing Information ........................................................................... 42 
Table 3 
Actions in Patients with Low Platelet Count ........................................................ 49 
 
TABLE OF FIGURES 
Page 
Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of 
apo(a) Covalently Bound to apoB..........................................................................24 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
9 
PROTOCOL AMENDMENTS 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
Amendment Number: 
5 
Amendment Date: 
30 May 2017 
 
The following table summarizes the history and nature of amendments to the protocol 
ISIS 681257-CS6. 
None of the antecedent versions of the study protocol has been enacted clinically and therefore 
no patients have been enrolled prior to issuance of Amendment 5. 
Protocol Version 
Date 
Rationale for Amendments 
Original Protocol  
15 August 2016 
 
Amendment 1 
6 October 2016 
Regulatory advice on inclusion of more 
detailed description of processes for 
platelet monitoring, and more frequent 
monitoring of liver function. 
Amendment 2 
29 November 2016 
Regulatory advice on inclusion of 
biomarkers of renal damage and increased 
frequency of renal monitoring.  Addition of a 
DSMB. 
Amendment 3 
30 December 2016 
Adjustment of the frequency, and alert and 
intervention limits, for renal safety and 
adjustment of the frequency of liver safety 
testing.   
Amendment 4 
5 January 2017 
The study population was increased to 
270 patients (54 per cohort) to support a 
statistical assessment of risk of platelet 
reduction in this population.  In addition, the 
10 mg weekly treatment cohort has been 
modified to 20 mg every 2 weeks 
(biweekly). 
Amendment 5 
30 May 2017 
Regulatory advice on addition of exclusion 
criteria, reduced permitted timeframe for 
identifying critical laboratory results by the 
investigator and replacement of the AE 
definition.  In addition, Section 8.6.2 was 
edited for consistency. 
 
 

ISIS 681257-CS6 
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Amendment 5 
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30 May 2017 
 
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PROTOCOL SUMMARY OF CHANGES 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
Amendment Number: 
5 
Amendment Date: 
30 May 2017 
 
The following modifications to Protocol ISIS 681257-CS6 Amendment 4 have been made. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design.  
The following table provides a summary list of major changes to the Amendment 4 of the 
protocol: 
Protocol Section 
Description of Change 
Rationale 
Protocol Synopsis 
(Exclusion Criteria), 
5.2 
Exclusion Criteria 
Addition of new exclusion 
criteria, placed at Exclusion 
Number 12 and 13, and shifting 
subsequent exclusion criteria to 
sequentially increased number.   
Adding exclusion criteria to exclude 
patients with known allergic or 
pseudo allergic drug reactions and 
those with hypersensitivity to the 
active drug substance. 
Protocol Synopsis 
(Efficacy Evaluations), 
10.1.2 
Secondary Endpoints, 
10.6.3.2 
Analysis of Secondary Efficacy 
Endpoints 
Provided Lp(a) values in 
additional alternate unit of 
measure 
Laboratories will measure and report 
Lp(a) values in either mg/dL or 
nmol/L, so both units will be 
provided in protocol for clarity.  
Efficacy data will be provided only in 
nmol/L. 
6.2.1 
Laboratory Assessments 
8.5.1 
Safety Monitoring Rules for Liver 
Chemistry Tests, 
8.5.2 
Safety Monitoring for Renal Function, 
8.5.3 
Safety Monitoring for Platelet Count 
Results 
Revision of window allowed for 
review of key safety laboratory 
results to within 24 hours by 
Investigator or designee. 
To ensure more timely review of key 
safety laboratory results while 
patients are on Study Drug. 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
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Protocol Section 
Description of Change 
Rationale 
6.2.1 
Laboratory Assessments, 
9.3.3.1 
Adverse Events of Special Interest 
Adding additional AE of special 
interest – when patient meets 
renal stopping rules. 
To enhance importance of strict 
monitoring of renal function. 
6.3.1 
Contraception Requirements 
To clarify acceptable use of 
contraception methods. 
Clarification. 
8.5.2 
Safety Monitoring for Renal Function, 
8.5.3 
Safety Monitoring for Platelet Count 
Results, 
8.8.1 
Follow-up Visits for Early Termination 
from Treatment Period or from 
Post-Treatment Follow-up Period 
Addition of text to clarify 
frequency and timing of 
assessments and platelet 
monitoring and urine renal 
biomarkers in post Treatment 
Follow-up period to be consistent 
with the landmark study visits 
after Study Drug dosing has 
ended. 
Clarification of time points for 
platelet monitoring post last Study 
Drug dose. 
8.6.2 
Stopping Rules for Renal Function Test 
Results 
Addition of urine culture and 
urine microscopic sample 
inspection to follow-up testing for 
renal stopping rules 
Additional laboratory tests added for 
analysis of renal function to match 
follow-up testing for renal monitoring 
and stopping rules. 
8.8.1 
Follow-up Visits for Early Termination 
from Treatment Period or from 
Post-Treatment Follow-up Period 
Clarification for timing of final 
visit assessment for treatment 
period and final visit for follow-up 
period for patients who 
discontinue early from treatment 
or during the post-treatment 
follow-up period. 
Clarification. 
9.3.2 
Adverse Reaction and Unexpected 
Adverse Reaction 
Correction of definition of 
Adverse Drug Reaction and 
adding definition of Unexpected 
Adverse Reaction. 
Clarification of definition to be 
consistent with ICH. 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
12 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of 
ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and 
Established Cardiovascular Disease (CVD)  
Study Phase 
2 
Indication 
Patients with hyperlipoproteinemia(a) and established CVD. 
Investigational Drug 
ISIS 681257 is a second generation 2ʹ-MOE modified, GalNAc3–conjugated antisense 
oligonucleotide inhibitor of apolipoprotein (a) [apo(a)]. 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of 
different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels 
in patients with hyperlipoproteinemia(a) and established CVD. 
Secondary Objective(s) To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein 
cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on 
apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose 
regimens in patients with hyperlipoproteinemia(a) and established CVD. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio to receive ISIS 681257 or 
placebo.  This number was chosen to provide statistical power for both efficacy and 
safety assessments.  Study Drug (ISIS 681257 or placebo) will be administered SC 
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 enrolled patient 
reaches 6 months of exposure.  All patients will then enter a 16-week post-treatment 
follow-up period. 
The primary efficacy and safety analysis time point is at Week 25 for patients who 
received every 4-week dosing (Cohorts A-C) and at Week 27 for patients who received 
every 2-week or weekly dosing (Cohorts D and E, 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 (as needed) data collected on ISIS 681257 during this 
study, both individual events and aggregate data.   
Number of Subjects 
Approximately 270 
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. 
Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, 
or peripheral artery disease 
4. 
Lp(a) plasma level ≥ 60 mg/dL 
5. 
Must be on standard-of-care preventative therapy for other than elevated Lp(a) 
CVD risk factors 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
13 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Inclusion Criteria 
6. 
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 
7. 
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 16 weeks after the last dose of Study 
Drug (ISIS 681257 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 
8. 
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 16 weeks after the last dose of ISIS 681257 
Exclusion Criteria 
1. 
Within 6 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 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 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
14 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria 
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 with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse  
12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions  
13. Hypersensitivity to the active substance or to any of the excipients 
14. Clinically-significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion, including the following: 
a. 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
protein measurement of ˂ 300 mg/24-hr 
b. 
Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
albumin measurement of ˂ 150 mg/24-hr 
c. 
Estimated GFR ˂ 60 mL/min as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
d. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)  
> 2.0 x ULN 
e. 
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > ULN  
g. 
Platelet count ˂ LLN 
15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
16. Treatment with another investigational drug, biological agent, or device within 
1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 
17. Treatment with any 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 
18. BMI > 40 kg/m2  
19. Blood donation of 50-499 mL within 30 days of screening or of > 499 mL within 
8 weeks of Screening 
20. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator 
21. 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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
15 
PROTOCOL SYNOPSIS Continued 
Treatment Groups 
Patients will be randomized to 5 parallel cohorts: 
Cohort A (n = 54): Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort B (n = 54):  Patients will be randomized 5:1 to receive 40 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort C (n = 54):  Patients will be randomized 5:1 to receive 60 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort D (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every 2 weeks for up to 26 doses. 
Cohort E (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every week for up to 52 doses. 
Cohort 
Treatment 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 or placebo  
(Every 4 weeks) 
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 or placebo 
(Every 2 weeks) 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 or placebo 
(Every week) 
≤ 52 
≤ 1040 mg 
Study Drug Dosage 
and Administration 
The Sponsor will provide ISIS 681257 in a concentration of 100 mg/mL and matching 
volume placebo: 
Cohort A:  20 mg every 4 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort B:  40 mg every 4 weeks ISIS 681257 or placebo (0.4 mL) 
Cohort C:  60 mg every 4 weeks ISIS 681257 or placebo (0.6 mL) 
Cohort D:  20 mg every 2 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort E:  20 mg every week ISIS 681257 or placebo (0.2 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 681257 doses of 10 mg, 20 mg, and 40 mg given 
weekly that were found to be generally well-tolerated and to induce clinically-relevant 
reductions in Lp(a).  The range of dosing proposed for the present study will provide the 
equivalent drug exposure of 5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and 
is predicted (based on modelling of PK/PD data obtained in Phase 1 study) to result in 
mean reductions from baseline in plasma Lp(a) ranging from approximately 60% to 85% 
at steady-state.  
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to 
bring almost all patients with hyperlipoproteinemia(a) into the normal range 
(Lp(a) ≤ 30 mg/dL). 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
16 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and 
Schedule Selection 
Continued 
The present study will also evaluate safety and efficacy at different dosing 
frequencies:  every 4 weeks, every 2 weeks, and weekly.  Patients with 
hyperlipoproteinemia(a) 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.  Dosing regimens of 
20 mg every 2 weeks and 40 mg every 4 weeks will test if similar monthly exposure, at 
different frequencies of administration, will achieve similar safety and similar level of 
Lp(a) reduction since the reduction achieved by a given dose level is principally driven 
by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety. 
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 are outlined in Section 6, 
Appendices A and C. 
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may continue treatment 
within the same randomized cohort until the last enrolled patient reaches 6 months of 
exposure (for continuing safety assessments), with a maximal exposure period of 
12 months.  
The study for an individual patient will generally consist of the following periods:  
• 
An up to 4-week screening period 
• 
An up to 52-week treatment period during which Study Drug will be 
administered per assigned cohort by SC injection 
• 
A 16-week post-treatment follow-up period 
Patients in Cohorts A through C will receive up to 13 SC doses of ISIS 681257 or 
placebo every 4 weeks.  Patients in Cohort D will receive up to 26 SC doses of 
ISIS 681257 or placebo every 2 weeks and patients in Cohort E will receive up to 52 SC 
doses of ISIS 681257 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).  
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 and use of concomitant 
medications.  Safety and tolerability results in patients dosed with ISIS 681257 will be 
compared with those dosed with placebo. 
Efficacy Evaluations 
The primary analysis time point is at Week 25 for patients who received every 4-week 
dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly 
dosing (Cohorts D and E). 
The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary 
analysis time point for ISIS 681257 treatment groups compared to placebo. 
The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at 
the primary analysis time point on the following: 
• 
Percent change from baseline in LDL-C 
• 
Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L) 
• 
Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL (≤ 75 nmol/L) 
• 
Percent change from baseline in apoB 
• 
Percent change from baseline in OxPL-apo(a) 
• 
Percent change from baseline in OxPL-apoB 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
17 
PROTOCOL SYNOPSIS Continued 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all patients for the measurement of ISIS 681257 
plasma trough levels throughout treatment and during the post-treatment follow-up 
period.  In addition, in a subset of patients (approximately 12 patients per cohort), more 
frequent plasma samples will be taken following the first and Day 169 (for Cohorts A, B, 
and C) or Day 183 (for Cohorts D and E) dose to determine PK parameters.  Plasma 
sample collection time points are detailed in Appendices A and C. 
The plasma ISIS 681257 levels over time will be descriptively summarized by treatment 
with stratification by subject immunogenicity status.  Apparent terminal elimination 
half-life will be calculated in patients who received ISIS 681257 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 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 Lp(a) between 
ISIS 681257 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the baseline Lp(a) 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 plasma Lp(a) 
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. 
Sample Size Considerations: 
Efficacy: 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the 
standard deviation of the percent change in Lp(a) is approximately 20%.  With 
23 patients in each ISIS 681257 treatment group and 23 in placebo group there would 
be approximately 90% power to detect a 20% difference in percent change in Lp(a) 
levels between the ISIS 681257 treatment groups and placebo group at an alpha level of 
0.05, assuming 30% reduction in the ISIS 681257 patients and 10% reduction in the 
placebo patients. 
Safety: 
Based upon prior clinical trial experience with ISIS ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in 
the ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, 
with 45 patients in each ISIS 681257 treatment group, there would be approximately 
80% power to detect at least 1 event. 
A total of approximately 270 patients (54 patients per cohort, including 45 patients per 
cohort treated with ISIS 681257) will be randomized to ensure that both the safety and 
efficacy of ISIS 681257 will be adequately characterized in the study. 
Sponsor/Collaborator 
Ionis Pharmaceuticals/Akcea Therapeutics 
 
 

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STUDY DESIGN AND TREATMENT SCHEMA 
 
SCREENING PERIOD 
Weeks -4 to -1 
TREATMENT PERIOD 
Weeks 1 to 52* 
Dosing per assigned cohort: 
Cohorts A, B, and C:  Every 4 weeks SC 
administration of 20, 40, or 60 mg ISIS 681257 or 
placebo 
Cohort D:  Every 2 weeks SC administration of 
20 mg ISIS 681257 or placebo 
Cohort E:  Every week SC administration of 20 mg 
ISIS 681257 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 enrolled patient reaches 6 months of 
exposure. 
POST-TREATMENT 
EVALUATIONS 
Weeks 4, 10, and 16 after last dose of 
Study Drug 
3 clinical visits for safety, efficacy,  
PK and PD assessments 
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 (16 Weeks 
after last dose of Study Drug) 

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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 
apo(a) 
apolipoprotein(a) 
apoB 
apolipoprotein B 
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 
CVD 
cardiovascular disease 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
Cys C 
Cystatin C 
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 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 681257 
antisense inhibitor of apolipoprotein (a) 
IV 
intravenous(ly) 
IXRS 
interactive voice/internet response system 
KIM-1 
kidney injury molecule 1 
kg 
kilogram 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
L 
liter 
m2 
square meter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
MI 
myocardial infarction 
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 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OxPL 
oxidized phospholipids 
PAD 
peripheral arterial disease 
PBS 
phosphate buffered saline 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLA2 
Lp(a)-associated Lp-phospholipase A2 
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 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
SC 
subcutaneous(ly) 
Study Drug 
ISIS 681257 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
Tg 
transgenic 
Tmax 
time to maximal concentration 
UACR 
urine albumin -creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein- creatinine ratio 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 

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1. 
OBJECTIVES 
1.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of 
different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels in 
patients with hyperlipoproteinemia(a) and established cardiovascular disease (CVD). 
1.2 
Secondary Objective(s) 
To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol 
(LDL-C), apolipoprotein B (apoB), oxidized phospholipids (OxPL) on apolipoprotein (a) 
[apo(a)] [OxPL-apo(a)] and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in 
in patients with hyperlipoproteinemia(a) and established CVD. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
2.1.1 
Lipoprotein (a) 
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein (Figure 1, Koschinsky and Marcovina 2004) 
in which the apoB component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], 
the distinct protein component of Lp(a) that is mainly responsible for its signature structural and 
functional properties (Dubé et al. 2012; Kronenberg and Utermann 2013).  Lp(a) is now 
recognized as an independent, genetic, causal risk factor for coronary artery disease (CAD), 
stroke, peripheral arterial disease (PAD), and calcific aortic stenosis (Erquo et al. 2009; 
Nordestgaard et al. 2010; Thanassoulis et al. 2013). 
 

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Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of apo(a) 
Covalently Bound to apoB 
Apo(a) contains 10 unique units of kringle IV repeats, of which KIV2 are present in variable copies (1 to > 40) 
conferring structural heterogeneity to Lp(a).  Apo(a) also contains kringle V and an inactive protease-like (P) 
domain.  In this model, 4 KIV2 repeats are shown.  Lp(a) also contains OxPL in the lipid phase of apoB as 
well as covalently bound to apo(a). 
 
Plasma levels of Lp(a) vary substantially among individuals, and most of this variation reflects 
the effects of genetic variation in the LPA gene which encodes the apo(a) protein. 
A second contributor to plasma-level variability are LPA single nucleotide polymorphisms 
(SNPs) that can be associated with either higher or lower Lp(a) levels (Clarke et al. 2009; 
Li et al. 2011).  Significant associations exist between 2 particular LPA variants, rs10455872 and 
rs3798220, increased Lp(a) levels, CVD, and aortic stenosis, with the CVD risk primarily 
mediated by Lp(a) plasma levels rather than an independent effect of the SNPs (Clarke et al. 
2009; Li et al. 2011). 
Lp(a) plasma levels are generally inversely associated with apo(a) size, and can vary by 
> 1,000-fold (0.1 to > 250 mg/dL or ˂ 0.25 to > 625 nmol/L) between individuals 
(Merki et al. 2011).  Despite this inter-individual variation, intra-individual Lp(a) levels are 
thought to be generally stable over time along a pre-set genetically determined levels without 
significant impact from dietary or environmental factors, mediating CVD risk throughout the 
patient’s lifetime. 

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2.1.2 
Pathophysiology 
Lp(a) adheres to plaque sites and is retained in the artery wall and has proatherogenic and 
pro-inflammatory properties due to its LDL and apo(a) components  
(Spence and Koschinsky 2012).  In addition, Lp(a) may be prothrombotic by inhibiting 
fibrinolysis because of its structural similarity to plasminogen and its enhancement of platelet 
aggregation (Rand et al. 1998).  In vitro studies have provided evidence for both of these 
pathogenic mechanisms, but in vivo data are not definitive (Dubé et al. 2012).  In humans, Lp(a) 
is the main lipoprotein carrier of OxPL, which may drive the risk associated with Lp(a) 
(Bergmark et al. 2008; Leibundgut et al. 2013; Tsimikas et al. 2014).  In fact, OxPL measured on 
apoB (OxPL-apoB), which largely reflect the OxPL on Lp(a), have been shown to be a 
prognostic indicator for future CV events (Tsimikas et al. 2010; Tsimikas et al. 2012; 
Tsimikas et al. 2014).  OxPL associated with Lp(a) can be subjected to degradation by the 
Lp(a)-associated Lp-phospholipase A2 (PLA2), implicating Lp(a) in novel proinflammatory and 
atherogenic pathways (Kiechl et al. 2007). 
Hyperlipoproteinemia(a) in humans is associated with increased risk of cardiac death, 
myocardial infarction (MI), stroke, aortic stenosis, and peripheral arterial disease (PAD), 
particularly in subjects with small apo(a) isoforms (Bennett 2008; Erqou et al. 2009; 
Erqou et al. 2010; Bertoia et al. 2013; Thanassoulis et al. 2013).  Although prospective, 
randomized, controlled outcomes studies have not been conducted, epidemiological, genome-
wide association and Mendelian randomized controlled study data to date provide supporting 
evidence for a role of Lp(a) as a risk factor for CVD (Kamstrup et al. 2009).  For example, in the 
Copenhagen City Heart Studies of 42,000 subjects with a 15-year follow-up 
(Kamstrup et al. 2009) using a Mendelian randomization approach, higher Lp(a) levels were 
related to risk of MI. 
2.1.3 
Current Treatment Options 
In 2010, the European Atherosclerosis Society (EAS) Consensus Panel recommended screening 
for elevated Lp(a) in people at moderate to high risk of CVD to reach a treatment goal of 
˂ 50 mg/dL (125 nmol/L), after therapeutic management of LDL-C (Nordestgaard et al. 2010).  
Approximately 20% of people are estimated to have plasma Lp(a) levels over 50 mg/dL 
(125 nmol/L) and approximately 0.3% to have levels over 175 mg/dL (438 nmol/L).  There are 
no gender differences in Lp(a) concentrations but racial differences have been observed, with 
whites and Asians having lower levels while blacks and Hispanics generally have somewhat 
higher levels (Nordestgaard et al. 2010). 
Lifestyle and diet are thought to have little impact on an individual’s Lp(a) level.  Current 
treatment recommendations from the EAS Consensus Panel are limited to the use of 1 to 3 g of 
niacin (nicotinic acid) daily which could result in an up to 30% reduction in Lp(a).  However, 
niacin is associated with side effects (e.g., flushing) that reduce patient tolerability and 
compliance (Parker et al. 2006; Guyton 2007). 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are neither indicated nor 
formally recommended for treatment of hyperlipoproteinemia(a) but have been reported to 
reduce Lp(a) levels by ~20%-35% in patients with hypercholesterolemia (Desai et al. 2013; 
Raal et al. 2015). 

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The other current option for patients with significantly elevated Lp(a) levels (≥ 60 mg/dL) is 
lipoprotein apheresis, either general lipoprotein apheresis (Jaeger et al. 2009; 
Leebmann et al. 2013; Rosada et al. 2014) or Lp(a)-specific apheresis (Safarova 2012).  While 
very effective at acutely lowering Lp(a) (acute and interval Lp(a) reductions of > 60% and 
> 30% respectively), this treatment option is expensive, burdensome for patients, and 
unavailable/not reimbursed in many countries and regions. 
2.2 
Therapeutic Rationale 
Therapeutic modalities to reduce Lp(a) levels in humans are few, and there are no drugs 
currently available that specifically target Lp(a) alone.  Antisense oligonucleotides (ASOs) are 
emerging as viable therapeutic agents to treat disorders where overexpression of proteins is 
associated with a disease process.  Apo(a) is synthesized primarily in the liver, a target organ for 
ASOs, where it is subsequently covalently linked to the apoB-100 component of LDL to form 
the Lp(a) lipoprotein.  The goal of treatment with ISIS 681257 is to reduce the production of 
apo(a) in the liver and thus, the level of Lp(a) lipoprotein by using an ASO directed against the 
messenger ribonucleic acid (mRNA) of apo(a).  It has been hypothesized that a pharmacologic 
reduction in Lp(a) could slow down or reverse CVD by reducing thrombotic, atherogenic, or 
inflammatory events in patients with elevated Lp(a) levels (Nordestgaard et al. 2010). 
Importantly, there is no evidence that lowering Lp(a) will result in adverse consequences in 
individuals, and there are no reports linking very low Lp(a) to any deleterious effects. 
2.3 
ISIS 681257 
Please refer to the ISIS 681257 Investigator’s Brochure for more details on ISIS 681257 
mechanism of action, chemistry, pre-clinical and clinical experience.  The summary is provided 
below. 
2.3.1 
Mechanism of Action 
ISIS 681257 is a second-generation ASO drug targeted to apo(a) that has been covalently bonded 
to triantennary N-acetyl galactosamine (GalNAc3), a high-affinity ligand for the 
hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc3 conjugate.  
This GalNAc3-conjugate approach results in enhanced ASO delivery to hepatocytes versus 
non-parenchymal cells and has increased ASO potency by approximately 10-fold compared to 
unconjugated ASOs in mice (Prakash et al. 2014). 
The ASO portion of ISIS 681257 is complementary to a region spanning the Exon 24-25 splice 
site at position 3901 of apo(a) transcript sequence (NM_005577.2) and binds to the mRNA by 
Watson and Crick base pairing.  The hybridization (binding) of ISIS 681257 to the cognate 
mRNA results in the Ribonuclease H1 (a non-specific endonuclease that catalyzes the cleavage 
of RNA via hydrolytic mechanism RNase H1-mediated degradation of the apo(a) mRNA, thus 
preventing production of the apo(a) protein).  Maximal antisense-mediated reduction of target 
mRNA levels is typically greater than 90% of control levels in sensitive tissues 
(Zhang et al. 2010).  Furthermore, reduction in target mRNA levels using this approach 
correlates directly with a subsequent reduction in target protein levels.  
ISIS 681257 does not have any complementary homology to plasminogen mRNA 
(Graham et al. 2016). 

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2.3.2 
Chemistry 
Chemically, ISIS 681257 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone 
design).  The mixed backbone design reduces the total number of phosphorothioate linkages, 
which reduces non-specific interactions with proteins and further enhances potency of GalNAc3 
conjugated ASOs. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity for the target 
mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of 
some of the high-dose toxicities, thereby resulting in an improved safety profile compared to 
first-generation antisense drugs containing phosphorothioate-modified oligodeoxynucleotides 
(DNA) (Henry et al. 2000).  The third region, the central portion of the oligonucleotide, is 
composed of 10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and 
ISIS 681257 employs this chimeric structure to enable use of the ubiquitous endonuclease that 
specifically hydrolyzes the RNA strand in RNA/DNA hybrids (RNase H1)-mechanism for 
antisense activity.  This is because while the 2′-MOE modification confers increased stability and 
affinity, it does not support RNase H1-catalyzed cleavage of RNA hybridized to 
2′-MOE-modified nucleotides (McKay et al. 1999).  The fourth region is composed of a 
triantennary cluster of GalNAc3 sugars that is linked to the 5ʹ end of ISIS 681257 via a 
phosphodiester linkage.  The GalNAc3 cluster is a high affinity ligand for the ASGPR, a receptor 
expressed primarily on the surface of liver hepatocytes (Stockert 1995).  The GalNAc3 cluster 
enhances delivery of ISIS 681257 to liver hepatocytes over other cell types and enhances 
potency.  After internalization into cells, the GalNAc3 cluster is metabolized to release “free 
ASO” inside the cell (Prakash et al. 2014). 
2.3.3 
Preclinical Experience 
The pharmacology of ISIS 681257 has been examined in apo(a) transgenic (Tg) mice which 
express the entire human apo(a) genomic sequence (Frazer et al. 1995) and nonhuman primates. 
Administration of ISIS 681257, a human apo(a) antisense inhibitor, to mice containing the 
human apo(a) transgene produced dose-dependent reductions in human apo(a) liver mRNA and 
apo(a) plasma protein after 6 weeks of ASO administration at 0.3, 1, 3, and 10 mg/kg/wk. 
When ISIS 681257 was administered to normal chow fed cynomolgus monkeys for 4 weeks at 
the dose of 12 mg/kg/wk, it significantly reduced hepatic apo(a) mRNA by 90% relative to the 
cohort administered phosphate buffered saline (PBS).  As there is an 80% sequence conservation 
between apo(a) and plasminogen nucleotide sequences, plasminogen mRNA levels were also 
measured, and no change compared to the PBS cohort was observed. 
Findings from the chronic studies with ISIS 681257 (the 26-week mice and 39-week monkey 
studies) were similar to those observed in the 4- and 6-week studies and were not considered 
adverse.  The plasma and tissue concentrations observed for ISIS 681257 in mice and monkeys 
were generally similar to those observed for other unconjugated 20-mer 2ʹ-MOE ASOs in this 
chemical class with and without GalNAc3-conjugation.  However, the proportion of drug in 

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hepatocytes compare to nonparenchymal liver cells was greater for ISIS 681257, compared to the 
parent drug ISIS 494372 (without GalNAc3-conjugation), which is the basis for increased 
potency of ISIS 681257 (unpublished results; Geary et al. 2003; Yu et al. 2007; 
Prakash et al. 2016). 
The most noteworthy safety finding in the chronic monkey study was a marked platelet reduction 
that, occurred in 2 male monkeys in the high-dose group (20 mg/kg/wk) and 1 animal (1 female) 
in the mid-dose (10 mg/kg/wk) group beginning on Days 44-135, which led to the subsequent 
early termination (ET) of these 3 animals.  An additional male monkey in the 10 mg/kg/wk dose 
group had a moderate decrease in platelets that was successfully treated with steroid, and was 
terminated at the scheduled 6-month interim sacrifice.  There were no platelet reductions or other 
toxicologically significant findings in monkeys treated with 2 mg/kg/wk for up to 39 weeks.  
There were no marked platelet reductions in mice at doses up to 70 mg/kg/wk for 26 weeks.  
However, mice exposed to ISIS 681257 at doses of ≥ 10 mg/kg/wk for up to 26 weeks showed 
evidence of hepatobiliary effects in both sexes as indicated by increases in ALT (up to + 10.3x), 
AST (up to + 10.4x), and/or ALP (+ 2.5x).  
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 681257 can be found in 
the Investigator’s Brochure.  A summary of the study that has been conducted with ISIS 681257 
is included below. 
ISIS 681257-CS1 was a Phase 1 double-blind, placebo-controlled, dose-escalation study 
designed to assess the safety, tolerability, PK, and pharmacodynamics (PD) of single and 
multiple doses of ISIS 681257 administered subcutaneously (SC) to 45 healthy subjects with 
Lp(a) ≥ the upper limit of normal (ULN) (30 mg/dL).  Twenty one (21) subjects received 10 to 
120 mg SC (10, 20, 40, 80, and 120 mg) as a single-dose, and 24 subjects received 10, 20, and 
40 mg as multiple doses (6 doses in 21 days:  3 loading doses during the first week on alternate 
days (Days 1, 3, and 5), and then once a week for the next 3 weeks (Days 8, 15, and 22). 
There were no serious adverse events (SAEs), or clinically-relevant changes in laboratory 
assessments and all subjects completed the treatment and post-treatment follow-up periods. 
Constitutional symptoms such as fever, chills, increase in body temperature and arthralgias have 
been observed following parenteral administration of ASOs, primarily during the initial dosing 
period.  Following SC administration of ISIS 681257 constitutional symptoms were observed in 
4 of the 6 subjects who received a single-dose of 120 mg.  The symptoms were mild in severity 
and resolved spontaneously with or without treatment with acetaminophen. 
Fluctuations in platelet counts to below the lower limit of normal were observed in 5 study 
subjects on active drug and across doses.  These changes were not considered adverse or 
clinically-significant by the Investigator and did not appear to be dose related. 
Two (2) mild AEs of redness at the site of injection occurred 48 to 72 hours after administration 
in 1 subject who received ISIS 681257 in the 20 mg multiple-dose cohort.  Both AEs resolved by 
the time of the subject’s next visit. 

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Following SC administration, ISIS 681257 was absorbed rapidly into the systemic circulation, 
with median time to maximum plasma concentrations (Tmax) ranging from 1 to 4 hours.  Similar 
Tmax values were observed at all dose levels.  Maximum observed plasma concentrations (Cmax) 
and AUC0-24hr were dose-dependent over the studied SC dose range.  The mean peak (Cmax) and 
total exposure (AUC0-24hr) increased proportionally with dose at dose levels ranging from 10 to 
40 mg, and greater than dose proportionally at dose levels ranging from 40 to 120 mg. 
After reaching Cmax, mean plasma concentrations of ISIS 681257 declined in a biphasic fashion 
over time, with an initial, relatively fast distribution phase that dominated the plasma clearance 
followed by a slower elimination phase.  Characterization of the terminal elimination phase 
yielded an apparent terminal elimination half-life of approximately 3 to 4 weeks over a dose 
range of 10 to 120 mg (either single- or multiple-dose), and appeared to be independent of dose.  
This result is consistent with the slow elimination of ISIS 681257 observed from monkey tissues, 
and the comparatively long elimination half-lives observed for this chemical class. 
Plasma trough concentrations (168 hours or 7 days from previous dose) monitored during the 
treatment period in the multiple-dose cohorts increased with increasing dose, consistent with 
expectations (based on preclinical assessments and experience with other compounds of this 
chemical class) that trough plasma concentrations reflect exposure in tissues.  Plasma trough 
concentrations did not increase greatly after the loading period (Day 15), suggesting that 
accumulation in major tissues of distribution had approached steady-state after the loading 
period. 
Overall, the human PK of ISIS 681257 are consistent with the expected PK for compounds 
within this chemical class. 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 681257 doses of 10 mg, 20 mg, and 40 mg given weekly 
that were found to be generally well-tolerated and to induce clinically-relevant reductions in 
Lp(a). 
The range of dosing proposed for the present study will provide the equivalent drug exposure of 
5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and is predicted (based on modelling of 
PK/PD data obtained in Phase 1 study) to result in mean reductions from baseline in plasma 
Lp(a) ranging from approximately 60% to 85% at steady-state. 
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to bring 
almost all patients with hyperlipoproteinemia(a) into the normal range (Lp(a) ≤ 30 mg/dL). 
The present study will also evaluate safety and efficacy at different dosing frequencies:  every 
4 weeks, every 2 weeks, and weekly.  Patients with hyperlipoproteinemia(a) 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.  Dosing regimens of 20 mg every 2 weeks and 40 mg every 4 weeks will test if similar 
monthly exposure, at different frequencies of administration, will achieve similar safety and 
similar level of Lp(a) reduction since the reduction achieved by a given dose level is principally 

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driven by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio (225 ISIS 681257 and 45 placebo) 
to receive ISIS 681257 or placebo.  Study Drug (ISIS 681257 or placebo) will be administered 
SC every week, every 2 weeks (biweekly), 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. 
The primary analysis time point is at Week 25 for patients who received every 4-week dosing 
(Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly dosing 
(Cohorts D and E).  For patients continuing treatment beyond the primary analysis time point 
additional supportive efficacy analysis (to evaluate whether the treatment effect is maintained) 
and safety analysis (for the purpose of dose(s) selection) will be repeated at the completion of 
Study Drug treatment. 
The treatment portion of the study will be complete when the last enrolled patient reaches 
6 months of exposure.  All patients will then enter a 16-week post-treatment follow-up period. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma Lp(a) levels (≥ 60 mg/dL) and a clinical 
diagnosis of CVD are eligible for enrollment upon meeting the study specific eligibility criteria.  
Patients will be on standard-of-care preventative therapy for other than elevated Lp(a) 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 
• Evidence of cardiac ischemia on exercise testing, or imaging study 
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).  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 5 parallel dosing cohorts, with each cohort having a 5:1 ratio to 
receive ISIS 681257 or matching volume of placebo, respectively, by SC injection for up to 
52 weeks. 
Following the End-of-Treatment, patients will enter the 16-week post-treatment follow-up 
period. 

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3.2 
Number of Study Centers 
This is a multicenter, multinational study. 
3.3 
Number of Patients 
Approximately 270 patients will be randomized in this study, with approximately 54 patients 
assigned to each of the 5 treatment cohorts. 
3.4 
Overall Study Duration and Follow-up 
The length of patients’ participation in the study may be up to 18 months (72 weeks), which 
includes a 4-week screening period, an up to 52-week treatment period with Study Drug 
(ISIS 681257 or placebo), and a 16-week post-treatment follow-up period.  The treatment portion 
of the study will be complete when the last enrolled 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. 
3.4.2 
Treatment 
For each patient minimum treatment duration is 6 months and maximum of 52 weeks.  
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may continue treatment within the 
same randomized cohort until the last enrolled patient reaches 6 months of exposure (for 
continuing safety assessments), with a maximal exposure period of 12 months.  When this 
milestone is met, all patients will then enter a 16-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 681257 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 16-week post-treatment follow-up period and will 
return to the Study Center for 3 follow-up visits 4, 10, and 16 weeks after their last injection of 
Study Drug as per Appendix A (Follow-up). 
The final study visit for each patient will be 16 weeks after the last dose of Study Drug. 
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. 

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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 681257 during this study.  The 
DSMB will be constituted to include expertise in medical specialties relevant to the safety of 
antisense drugs (nephrology, hepatology, hematology and cardiology).  Specialist members of 
the DSMB will be informed and consulted on all treatment-related SAEs relevant to their 
expertise and all changes of relevant laboratory parameters that trigger stopping rules 
(Section 8.6), within 24 hours of receipt of such results.  In addition, all accrued safety data 
relevant to each of medical area specialist will be forwarded monthly for review.  
The full DSMB review of all accumulated data will be performed quarterly.  Based on its 
ongoing assessment of the safety and tolerability of ISIS 681257, 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). 
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 
1:1:1:1:1 ratio to 1 of the 5 parallel-dose cohorts (Cohorts A, B, C, D, or E).  Within each dose 
cohort, patients will be randomized in a 5:1 ratio to receive ISIS 681257 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. 

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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 a 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). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria at 
within 4 weeks of Study Day 1or 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. Clinical diagnosis of CVD defined as documented coronary artery disease (CAD), stroke, 
or peripheral artery disease 
4. Lp(a) plasma level ≥ 60 mg/dL  
5. Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk 
factors  
6. 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, proprotein convertase subtilisin/kexin 
type 9 [PCSK9s] 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 
7. Females:  must be non-pregnant and non-lactating and either: 
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) 
 
 

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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 16 weeks after the last dose of Study Drug 
(ISIS 681257 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 
8. 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 16 weeks 
after the last dose of ISIS 681257 
5.2 
Exclusion Criteria 
1. Within 6 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 New York Heart Association (NYHA) class 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 with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse 
12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions  
13. Hypersensitivity to the active substance or to any of the excipients 

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14. Clinically-significant abnormalities in screening laboratory values that would render a 
patient unsuitable for inclusion, including the following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR above 
this threshold, eligibility may be confirmed by a quantitative total urine protein 
measurement of ˂ 300 mg/24-hr 
b. Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR above 
this threshold, eligibility may be confirmed by a quantitative total urine albumin 
measurement of ˂ 150 mg/24-hr 
c. Estimated GFR ˂ 60 mL/min (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN 
e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
f. Alkaline phosphatase (ALP) > ULN 
g. Platelet count ˂ LLN 
15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
16. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
17. Treatment with any 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 
18. BMI > 40 kg/m2  
19. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
20. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
21. 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 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, and C. 

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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.  A 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.  
On confirmation of eligibility and prior to randomization, patients will also undergo a 24 hr urine 
collection for creatinine, albumin, and protein as a baseline assessment. 
6.1.2 
Treatment Period 
During the treatment period, patients will report to the study center for clinic visits.  Patients will 
receive 20 mg doses of Study Drug administered by SC injection once every 4 weeks for up to 
52 weeks in Cohort A, 40 mg doses of Study Drug administered by SC injection once every 
4 weeks for up to 52 weeks in Cohort B, 60 mg doses of Study Drug administered by SC 
injection once every 4 weeks for up to 52 weeks in Cohort C, 20 mg doses of Study Drug 
administered by SC injection once every 2 weeks for up to 52 weeks in Cohort D, or 20 mg 
doses of Study Drug administered by SC injection once per week (weekly) for up to 52 weeks in 
Cohort E (Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 681257 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 12 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 681257.  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). 
6.1.3 
Post-Treatment Period 
Each patient will be followed for safety assessments for 16 weeks after the last dose of 
Study Drug.  During the post-treatment follow-up period, patients will return to the Study Center 
for 3 outpatient visits at Weeks 4, 10, and 16 after the last dose of Study Drug for safety and 
clinical laboratory evaluations and for blood sampling for PK (Appendices A and C). 

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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 (excluding 24-hour urine collection) should be taken 
after fasting for at least 10 hours.  Any confirmatory test, or test taken for safety reasons, may be 
taken at any time, irrespective of fasting status.  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.  Each time a 
hematology lab is drawn and sent to the central laboratory for analysis, an additional sample 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 and sent to the central laboratory for analysis, per Section 8.5.2.  If there are no 
test results available within 14 days of the last set of results for parameters considered critical to 
patient safety, the Investigator will contact the patient to hold dosing until a new test set is 
obtained and reviewed. 
While on treatment liver function testing will also be collected every 14 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 sent to the central laboratory are received on the next day 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 on the day of sample collection, and should be entered as soon as 
possible into the eCRF to inform the Sponsor and CRO study monitoring teams. 
All platelet count results must be reviewed promptly (within 24 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 

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reduction to levels below 50,000/mm3 (Grade 3 or Grade 4) 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 24 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 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, B, and C at Weeks 5, 13, 21, 25, 33, 41, 49, and 53  
• Cohorts D and E at Weeks 5, 13, 21, 27, 33, 41, 49, and 53 
In all cohorts, ECGs will be conducted during the post-treatment follow-up period at 4, 10, and 
16 weeks after the last dose of Study Drug. 
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. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 681257 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. 

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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 16 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 16 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 
†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. 

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*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 before visits requiring fasted blood 
sampling. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 681257 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 681257 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 681257 
ISIS 681257 vials contains 100 mg/mL ISIS 681257 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 681257 vials.  
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 681257 
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 681257 or placebo) 
labeled in accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 681257 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 

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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 681257 will be administered to patients by Study Center staff as follows: 
Cohort A: a single SC dose of 20 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort B: a single SC dose of 40 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort C: a single SC dose of 60 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort D: a single SC dose of 20 mg every 2 weeks for up to 52 weeks and a maximum of 
26 doses 
Cohort E: a single SC dose of 20 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, B, and C should receive 1 dose every 4 weeks, patients in Cohort D 
should receive 1 dose every 2 weeks and Cohort E 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 681257 or placebo) preparation and administration. 
 
 

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Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.2 mL  
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.4 mL  
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.6 mL  
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 
or placebo 
(Every 2 weeks) 
0.2 mL 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 
or placebo 
(Every week) 
0.2 mL 
≤ 52 
≤ 1040 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 
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 

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Study Drug (ISIS 681257 or placebo).  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  
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, patients must 
not be re-dosed 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 681257 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 2 weeks for the first 3 months of the 
study treatment, and monthly thereafter during the Treatment Period. 
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 24 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 (within 24 hours of receipt) 
reviewed by the Investigator and Medical Monitors. 
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 2 weeks 
throughout the study.  Upon completion of the study treatment period, urine renal biomarkers 
should be monitored every 2 weeks for the first 6 weeks and then at 10 and 16 weeks post last 
dose (as per visit schedule). 
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 to estimate glomerular 
filtration rate (eGFR), which will be monitored every 2 weeks.  In addition, biomarkers of acute 
renal injury will also be measured every 2 weeks (Appendix B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than every 
2 weeks 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 at the weekly safety review 
by the Medical Monitor. 
All results of renal function tests must be reviewed promptly (within 24 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:  Creatinine clearance (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 an 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. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of 
the above criteria, dosing with the Study Drug should be interrupted and the Study Medical 
Monitor informed.  In addition, the following supplemental renal tests should be immediately 
obtained:  
Serum creatinine, urine culture, 24-hour urine sample for creatinine clearance, urine 
albumin and urine protein, urine microscopy sample with inspection of sediment. 
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. 
8.5.3 
Safety Monitoring for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study 
treatment period and must not receive Study Drug without an interpretable platelet count result in 
the prior 2 weeks.  Upon completion of the study treatment period, platelets should be monitored 
every 2 weeks for the first 6 weeks and then at 10 and 16 weeks post last dose (as per visit 
schedule). In addition, platelet function will be evaluated by aggregometry, using an approved 
point-of-care diagnostic device, in all patients at each study site visit; additional functional 
testing may be performed at selected study centers.  

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As described in Section 6.2.1, all platelet count results must be reviewed promptly (within 
24 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.  
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are 
< 140,000 mm3; 2) when platelet count is ≥ 30% decreased from baseline, or 3) when 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 D, 
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 Minor Bleeding Events 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  Minor 
bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, 
petechiae, or gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR, hepatic 
enzymes, bilirubin and platelet count should be performed. 
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 symptoms should be discussed with the Sponsor Medical Monitor or 
designee to determine whether additional monitoring or laboratory tests are required. 
8.6 
Stopping Rules  
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 

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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 
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 of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the 
following criteria, or any change in renal biomarkers deemed by the nephrologist on the DSMB 
to require further evaluation, a serum creatinine, urine culture, 24-hour urine sample for 
creatinine clearance and protein, and urine microscopy sample with inspection of sediment 
should be immediately obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 681257 or placebo) will be stopped permanently if 
24-hour urine testing confirms any of the following values in the absence of an alternative 
explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, 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 
Stopping Rules 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 steroids 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 

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steroids.  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 
0.5-2 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). 
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; Schulman et al. 2005), 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 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 
irrespective of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis  
6. Bleeding after venipuncture for > 5 minutes 
 

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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every week* 
75K-100K/mm3 
Permanently reduce as follows: 
For Cohort A:  reduce to 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks  
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 weeks 
For Cohort E:  reduce to 10 mg every week 
Closer observation 
Monitor every week* 
50K-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 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks 
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 week 
For Cohort E:  reduce to 10 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)/ anticoagulant 
medication 
25K-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/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
˂ 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 and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  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 0.5-2 mg/kg/d for 2-4 weeks then taper; or Methylprednisolone 
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8.7 
Adjustment of Dose  
Dose frequency adjustments for platelet count reduction must be made in accordance with 
Section 8.6.3 and 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 8.6.3 
• 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. 
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 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 after discontinuing Study Drug.  Following this period, if the platelet count is 
stable (at least 3 consecutive values that are stable as determined by the Sponsor Medical 
Monitor and > 100,000/mm3), platelets should be tested 10 and 16 weeks post last dose (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 16-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 16 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: 

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• 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). 
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, PCSK9 inhibitors, niacin, fibrates, fish oil, other 
products containing omega-3 fatty acids (including OTC preparations) 
• Anti-platelet therapies 
• Testosterone, estrogens, progesterone, growth hormone, or progestins. 

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Disallowed Concomitant Therapy 
Use of the following is disallowed: 
• Warfarin, 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 
• 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 of 
platelet count, and liver and renal function as described in Section 6.2.1, Sections 8.5.1-8.5.3, 
and Sections 8.6.1-8.6.3. 
While on treatment patients will be required to have platelet counts every 2 weeks 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 2 weeks, and must not receive Study Drug if there are no test 
results for parameters considered critical to patient safety available within the prior 2 weeks.  In 

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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 (Grade 3 or Grade 4), 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. 
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. 

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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 
• 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. 

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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.  When the Investigator is reporting by telephone, it is 
important to speak to someone in person versus leaving a message.  An Initial Serious Adverse 
Event Form should be completed and a copy should be emailed or faxed to the Sponsor or 
designee.  The contact information for reporting SAEs is as follows:  
Attention:  
 
Email: 
 
 
Fax: 
 
 
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 681257 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 
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• 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 
• 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 681257 or placebo) due to the event is characterized by 1 of 
the following. 
• None:  No changes were made to Study Drug (ISIS 681257 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 

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• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious eCRF (the 
SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
9.5 
Procedures for Handling Special Situations 
9.5.1 
Abnormalities of Laboratory Tests 
Clinically-significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs.  
Clinically-significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor 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 24 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 as per Sections 9.3.3.1 and 9.4.1). 

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All results of liver function tests must be reviewed promptly (within 24 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 24 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: 
• 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 681257 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 681257 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 

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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 
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-C) and at Week 27 for patients who received weekly or 
biweekly dosing (Cohorts D and E).  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 endpoint is the percent change in Lp(a) from baseline at the primary 
analysis time point achieved by ISIS 681257 compared to pooled placebo. 

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Lp(a) levels will be analyzed from patient blood samples taken at specified time points 
throughout the study. 
10.1.2 
Secondary Endpoints 
The secondary endpoints include the following parameters from baseline at the primary analysis 
time point for ISIS 681257 compared to placebo: 
• Percent change from baseline in LDL-C  
• Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L) 
• Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL (≤ 75 nmol/L) 
• Percent change from baseline in apoB 
• Percent change from baseline in OxPL-apo(a) 
• Percent change from baseline in OxPL-apoB 
10.1.3 
Safety Endpoints 
The safety analysis will be performed using the following parameters: 
• 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. 
• ECGs 
• Use of concomitant medications 
10.1.4 
Dose Selection 
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 clinically-meaningful reduction in plasma Lp(a) 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, and renal or hepatic 
injury.   

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10.2 
Sample Size Considerations 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the standard 
deviation of the percent change in Lp(a) is approximately 20%.  With 23 patients in each 
ISIS 681257 treatment group and 23 in placebo group there would be approximately 90% power 
to detect a 20% difference in percent change in Lp(a) levels between the ISIS 681257 treatment 
groups and placebo group at an alpha level of 0.05, assuming 30% reduction in the ISIS 681257 
patients and 10% reduction in the placebo patients. 
Based upon prior clinical trial experience with Ionis ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in the 
ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, with 
45 patients in each ISIS 681257 treatment group, there would be approximately 80% power to 
detect at least 1 event. 
Therefore, approximately 270 patients (54 patients per cohort, including 45 patients per cohort 
treated with ISIS 681257) will be randomized to ensure that both the safety and efficacy of 
ISIS 681257 will be adequately characterized in the study. 
10.3 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized, received at least 1 dose of Study 
Drug (ISIS 681257 or placebo), and have a Baseline Lp(a) 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, B, and C or at least 20 weekly doses 
for patients randomized in Cohorts D and E, 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 Study Drug, and 
have sufficient data for the analysis of PK parameters.  This population will be used for analysis 
of PK data. 
10.4 
Definition of Baseline 
Baseline for Lp(a), LDL-C, apoB, OxPL-apo(a), OxPL-apoB, and other lipid measurements will 
be defined the pre-dose measurement on Day 1 or 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. 

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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. 
10.6.2 
Safety Analysis 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug (ISIS 681257 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 681257 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 681257 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.   

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10.6.3 
Efficacy Analysis 
10.6.3.1 
Analysis of Primary Efficacy Endpoint 
The primary analysis of the primary endpoint will be the pairwise comparison of percent change 
from baseline to primary analysis time point in fasting Lp(a) between ISIS 681257 treatment 
groups and pooled placebo group in the FAS.  The data will be analyzed using an analysis of 
covariance (ANCOVA) model with the Baseline Lp(a) 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. 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints 
• Percent change from baseline at the primary analysis time point in fasting LDL-C will be 
compared between each ISIS 681257 treatment groups and pooled placebo group using 
an ANCOVA model with baseline as covariate 
• Proportion of patients who achieve ≤ 50 mg/dL (≤ 125 nmol/L) in fasting Lp(a) at the 
primary analysis time point will be compared between each ISIS 681257 treatment group 
and pooled placebo group using a logistic regression model with Baseline Lp(a) as a 
covariate.  Proportion of patients who achieve ≤ 30 mg/dL (≤ 75 nmol/L) in fasting Lp(a) 
at the primary analysis time point will be analyzed similarly 
• Percent change from baseline at the primary analysis time point in fasting apoB, 
OxPL-apo(a) and OxPL-apoB will be compared between ISIS 681257 treatment groups 
and pooled placebo group using an ANCOVA model with baseline as covariate 
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 681257 in plasma (as total full 
length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 681257) will be determined and summarized by treatment with stratification by subject 
immunogenicity status using descriptive statistics. 
In addition, non-compartmental PK analysis of ISIS 681257 concentrations will be carried out on 
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disposition half-life (t1/2λz) associated with the apparent terminal elimination phase will be 
calculated, if appropriate, using available data at the End-of-Treatment and the post-treatment 
follow-up period from the equation, t1/2λz = 0.693/λz, where λz is the rate constant associated with 
the apparent terminal elimination phase. 
For patients in the PK subgroup only, non-compartmental PK analysis of ISIS 681257 will be 
carried out on each individual patient data set in patients who received ISIS 681257 treatment.  
The maximum observed drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will 
be obtained directly from the concentration-time data.  Following single dosing (Day 1), area 
under the plasma concentration-time curve from time zero (pre-dose) to 24 hours after the dose 
(AUC0-24hr) will be calculated using the linear trapezoidal rule.  Following multiple dosing, 
AUC0-24hr and area under the plasma concentration-time curve during the time of each sampled 
dosing interval (tau,τ) at steady-state (AUCτ) will be calculated using the linear trapezoidal rule. 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist.  Plasma PK parameters will be summarized using descriptive statistics with 
stratification by subject immunogenicity status.  Exposure-response relationships between 
selected PD [e.g., Lp(a)] and PK measures (including but may not be limited to plasma trough 
concentrations) may be explored (including with and without stratification by IM status) in this 
study, or in a separate population PK analysis with all clinical studies combined. 
The immunogenicity (IM) of ISIS 681257 will be assessed before, during, and after treatment 
with Study Drug (ISIS 681257 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 681257 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. 
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 681257 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.  

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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. 
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 
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. 

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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 
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. 

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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 
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. 

ISIS 681257-CS6 
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68 
13. 
REFERENCES 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bennett CF. Pharmacological properties of 2ʹ-O-methoxyethyl-modified oligonucleotides. In: Crooke ST, editor. 
Antisense Drug Technology: Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis 
Group 2008; 365-400. 
Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized 
phospholipids in human plasma. J Lipid Res 2008; 49: 2230-2239. 
Bertoia ML, Pai JK, Lee J-H, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll 
Cardiol 2013; 61(21): 2169-2179. 
Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) 
lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528. 
Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin 
kexin type 9, significantly reduces lipoprotein (a) in hypercholesterolemic patients receiving statin therapy: an 
analysis from the LAPLACE-TIMI 57 Trial. Circ 2013; 128: 962-969. 
Dubé JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a): more interesting than ever after 50 years. Curr 
Opin Lipidol 2012; 23(2): 133-140. 
Erqou S, Kaptoge S, Perry PL, et al; Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk 
of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4): 412-423. 
Erqou S, Thompson A, Di Angelantonio E, et al. Apoliporotein(a) isoforms and the risk of vascular disease. JACC 
2010; 55(19): 2160-2167. 
Frazer KA, Narla G, Zhang JL, Rubin E. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase 
inducers in YAC transgenic mice. Nat Gen 1995; 9: 424-431. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma 
lipoprotein (a) levels in humans. J Lipid Research 2016; 57: 340-351. 
Guyton JR. Niacin in cardiovascular prevention: mechanisms, efficacy, and safety. Curr Opin Lipidol 2007; 18: 
415-420. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292(2): 468-479. 
Jaeger BR, Richter Y, Nagel D, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to 
reduce high lipoprotein(a) levels and major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009; 6(3): 
229-239. 
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and 
increased risk of myocardial infarction. JAMA 2009; 301(22): 2331-2339. 
Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 
activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb 
Vasc Biol 2007; 27: 1788-1795. 
Koschinsky ML and Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into 
lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 2004; 15(2): 167-174. 
Kronenberg F and Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013; 273: 6-30. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol 
 
30 May 2017 
 
69 
Leebmann J, Roeseler E, Julius U, et al; Pro(a)LiFe Study Group. Lipoprotein apheresis in patients with maximally 
tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: 
Prospective observational multicenter study. Circ 2013; 128: 2567-2576. 
Leibundgut G, Scipione C, Yin H, et al. Determinants of binding of oxidized phospholipids on apolipoprotein(a) and 
lipoprotein(a). J Lipid Res 2013; 54: 2815-2830. 
Li Y, Luke MM, Shiffman D, Devlin JJ. Genetic variants in the apolipoprotein(a) gene and coronary heart disease.  
Circ Cardiovasc Genet 2011; 4(5): 565-573. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Merki E, Graham M, Taleb A, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) in 
transgenic mice. JACC 2011; 57(15): 1611-1621. 
Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as 
a cardiovascular risk factor: current status. Euro Heart J 2010; 31: 2844-2853. 
Parker K, Brunton L, Goodman LS, et al. Goodman & Gilman's the pharmacological basis of therapeutics. New 
York, NY. McGraw-Hill. 2006; ISBN 0-07-142280-142283. 
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; 42: 8796-8807. 
Prakash TP, Yu J, Migawa MT, et al. Comprehensive structure-activity relationship of triantennary N-Acetyl 
galactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J Med Chem 2016 
Mar 24; 59(6): 2718-2733. 
Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolucomab in homozygous familial 
hypercholesterolemia (TESLA Part B): a randomized, double blind, placebo controlled trial. Lancet 2015; 385: 
341-350. 
Rand ML, Sangrar W, Hancock MA, et al. Apoliprotein(a) enhances platelet responses to the thrombin receptor – 
activating peptide SFLLRN. Arterio Thromb Vasc Biol 1998; 18: 1393-1399. 
Rosada A, Kassner U, Vogt A, et al. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) 
levels reduce the incidence of cardiovascular events? Artif Organs 2014; 38: 135-141. 
Safarova M. Specific lipoprotein(a) apheresis reduces atherosclerosis progression. 80th Congress of the European 
Atherosclerosis Society, Milan, Italy 28 May 2012. 
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. 
Schulman S and Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Spence JD and Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity. Arterioscler Thromb Vasc Biol 2012; 
32: 1550-1551. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Thanassoulis G, Campbell CY, Owens DS, et al; CHARGE Extracoronary Calcium Working Group. Genetic 
associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368(6): 503-512. 

ISIS 681257-CS6 
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70 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circ 2012; 126: 
2020-2035. 
Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal 
coronary events. J Am Coll Cardiol 2010; 56: 946-955. 
Tsimikas S, Willeit P, Willeit J, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke 
outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60: 2218-2229. 
Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary 
artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 
2014; 63: 1724-1734. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second-
generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.  Drug Metab Dispos 
2007; 35: 460-468.  
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 
 
 
 

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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 
 

ISIS 681257-CS6 
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Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27 
29 
33 
37 
41 
45 
49 
53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 29 
57 
85 
113 141 
169 183 184a 185a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-Hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
X 
X 
X 
Genetic Testing 
 
X 
 
Chemistry Panel j,k 
X 
EVERY 14 DAYS f 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh  
Xh  
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 X1 
X 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 

ISIS 681257-CS6 
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Amendment 5 
Protocol  
 
30 May 2017 
 
74 
Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 
169 
183 184a 185a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
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 
Archived Serum & Plasma 
Samples j, n 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
PD Panel j 
X 
X 
 
X 
X 
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 
Lp(a) Characterization 
 
X 
 
 
Study Drug:  SC Injection 
 
WEEKLY AND EVERY 2-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG  
(Week 1 through Week 53/Day 365)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 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then at Week 10 and Week 16 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. 
 
 

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Appendix A Schedule of Procedures – Weekly and Every 2 Week Dosing Continued 
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 24 hours of receipt) by the 
Investigator as per Section 6.2.1.  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 enrolled reaches 6 months of exposure.  When this milestone is met, all 
patients still on treatment will then enter a 16-week post-treatment follow-up period. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8 hours post SC injection 
 
 

ISIS 681257-CS6 
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Amendment 5 
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76 
Appendix A Schedule of Procedures – Every 4-Week Dosing 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
X 
X 
X 
Genetic Testing 
 
X 
 
 
Chemistry Panel j, k 
X 
EVERY 14 DAYS f 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh 
Xh 
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 
X1 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 5 
Protocol  
 
30 May 2017 
 
77 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit and Testing Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
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 
Archived Serum & Plasma 
Samples j, n 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PD Panel j 
X 
X 
 
X 
X 
X 
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 
X 
Lp(a) Characterization 
 
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 
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 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then at Week 10 and Week 16 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. 
 

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Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
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 24 hours of receipt) by the 
Investigator as per Section 6.2.1.  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 enrolled reaches 6 months of exposure.  When this milestone is met, all 
patients still on treatment will then enter a 16-week post-treatment follow-up period. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8, hrs post SC injection 

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Appendix B 
List of Laboratory Analytes 
 
 

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Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 681257 or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• 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 
• Free T3 
 
Coagulation 
• aPTT 
• PT 
• INR 
• Fibrinogen 
• Plasminogen 
 
PD Panel 
• Lp(a) 
• OxPL-apoB 
• OxPL-apo(a) 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL 
Lp(a) Characterization 
• Apo(a) isoforms 
 
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 681257 (total full 
length ASO) levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 681257 
antibodies 
 
Genetic Testing 
• LPA SNPs associated with 
elevated Lp(a)  
 
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 
Biomarkers2 
• NGAL  
• NAG 
• KIM-1 
• Cys-C 
 
24 Hour Urine Test3 
• Creatinine clearance 
• Protein 
• Albumin 
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 681257 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.   
3 
To be performed during Screening upon confirmation of eligibility 
 

ISIS 681257-CS6 
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Appendix C 
PK Sampling Schedule 
 
Sampling Schedule for Weekly and Every 2-Week Dosing Cohorts 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
 

ISIS 681257-CS6 
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Amendment 5 
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82 
Appendix C PK Sampling Schedule  
Blood samples for the determination of plasma ISIS 681257 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 681257 
with plasma constituents.  Extensive PK samples will be collected in PK subgroup only (10 subjects 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 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
183 
184 
185 
197 
253 
365 
*Post Last Dose 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 48-hr3 Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
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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 
25 
26 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
170 
171 
176 
183 
197 
253 
365 
*Post Last Dose  
All 
Patients 
Pre-
dose NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
NA 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
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 
Pre-
dose, 
1, 2, 4, 
and 
8-hr1 
24-hr2 48-hr3 Anytime Anytime Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

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Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 

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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. 
 
 
 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 

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Amendment 5 
Protocol  
 
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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 

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Appendix E 
Additional Laboratory Tests for Patients with 
Platelet Count ˂ 100,000/mm3 
 
 
 

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Appendix E Laboratory Tests to Be Performed in the Event of a Platelet Count 
˂ 100,000/mm3 
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 
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 
Platelet Antibody Bead Array (PABA) 
 

 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
IONIS PHARMACEUTICALS, INC. 
 
ISIS 681257-CS6 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
 
Protocol Amendment 4 – 5 January 2017 
 
 
EudraCT No:  2016-003373-18 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol 
 
5 January 2017 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 
Study of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment: 
Amendment 4 
Date: 
5 January 2017 
 
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 681257 
Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD),” dated 5 January 2017, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol 
 
5 January 2017 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENTS ................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 16 
STUDY GLOSSARY .................................................................................................................. 17 
1. 
OBJECTIVES ................................................................................................................. 21 
1.1 
Primary Objective ..........................................................................................................21 
1.2 
Secondary Objective(s) ..................................................................................................21 
2. 
BACKGROUND AND RATIONALE .......................................................................... 21 
2.1 
Overview of Disease ......................................................................................................21 
2.1.1 
Lipoprotein (a) ........................................................................................................21 
2.1.2 
Pathophysiology .....................................................................................................23 
2.1.3 
Current Treatment Options .....................................................................................23 
2.2 
Therapeutic Rationale ....................................................................................................24 
2.3 
ISIS 681257 ...................................................................................................................24 
2.3.1 
Mechanism of Action .............................................................................................24 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................25 
2.3.4 
Clinical Experience ................................................................................................26 
2.4 
Rationale for Dose and Schedule of Administration .....................................................27 
3. 
EXPERIMENTAL PLAN .............................................................................................. 28 
3.1 
Study Design ..................................................................................................................28 
3.2 
Number of Study Centers ..............................................................................................29 
3.3 
Number of Patients ........................................................................................................29 
3.4 
Overall Study Duration and Follow-up .........................................................................29 
3.4.1 
Screening ................................................................................................................29 
3.4.2 
Treatment ................................................................................................................29 
3.4.3 
Post-Treatment .......................................................................................................29 
3.5 
End-of-Study ..................................................................................................................29 
3.6 
Data and Safety Monitoring Board ................................................................................30 
4. 
PATIENT ENROLLMENT ........................................................................................... 30 
4.1 
Screening .......................................................................................................................30 
4.2 
Randomization ...............................................................................................................30 
4.3 
Replacement of Patients .................................................................................................31 
4.4 
Unblinding of Treatment Assignment ...........................................................................31 
5. 
PATIENT ELIGIBILITY .............................................................................................. 31 
5.1 
Inclusion Criteria ...........................................................................................................31 
5.2 
Exclusion Criteria ..........................................................................................................32 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol 
 
5 January 2017 
 
6 
6. 
STUDY PROCEDURES ................................................................................................ 34 
6.1 
Study Schedule ..............................................................................................................34 
6.1.1 
Screening ................................................................................................................34 
6.1.2 
Treatment Period ....................................................................................................34 
6.1.3 
Post-Treatment Period ............................................................................................34 
6.2 
Additional Study Assessments .......................................................................................35 
6.2.1 
Laboratory Assessments .........................................................................................35 
6.2.2 
Physical Exams and Vital Signs .............................................................................36 
6.2.3 
Electrocardiography ...............................................................................................36 
6.2.4 
PK Sampling ...........................................................................................................36 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................37 
6.3.1 
Contraception Requirements ..................................................................................37 
6.3.2 
Other Requirements ................................................................................................38 
7. 
STUDY DRUG ................................................................................................................ 38 
7.1 
Study Drug Description .................................................................................................38 
7.1.1 
ISIS 681257 ............................................................................................................38 
7.1.2 
Placebo ...................................................................................................................38 
7.2 
Packaging and Labeling .................................................................................................38 
7.3 
Study Drug Accountability ............................................................................................38 
8. 
TREATMENT OF PATIENTS ..................................................................................... 39 
8.1 
Study Drug Administration ............................................................................................39 
8.2 
Other Protocol-Required Drugs .....................................................................................40 
8.3 
Other Protocol-Required Treatment Procedures ............................................................40 
8.4 
Treatment Precautions ...................................................................................................40 
8.5 
Safety Monitoring Rules ................................................................................................40 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................41 
8.5.2 
Safety Monitoring for Renal Function ...................................................................42 
8.5.3 
Safety Monitoring for Platelet Count Results ........................................................43 
8.5.4 
Safety Monitoring for Minor Bleeding Events .......................................................44 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................44 
8.6 
Stopping Rules ...............................................................................................................44 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................44 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................45 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................45 
8.7 
Adjustment of Dose .......................................................................................................48 
8.8 
Discontinuation of Study Drug ......................................................................................48 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................48 
8.9 
Withdrawal of Patients from the Study ..........................................................................49 
8.10 
Concomitant Therapy and Procedures ...........................................................................49 

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Amendment 4 
Protocol 
 
5 January 2017 
 
7 
8.10.1 
Concomitant Therapy .............................................................................................49 
8.10.2 
Concomitant Procedures .........................................................................................50 
8.11 
Treatment Compliance ...................................................................................................50 
8.12 
Safety Monitoring Compliance ......................................................................................50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 51 
9.1 
Sponsor Review of Safety Information .........................................................................51 
9.2 
Regulatory Requirements ..............................................................................................51 
9.3 
Definitions .....................................................................................................................52 
9.3.1 
Adverse Event ........................................................................................................52 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................52 
9.3.3 
Serious Adverse Event (SAE) ................................................................................52 
9.3.3.1 
Adverse Events of Special Interest ..................................................................53 
9.4 
Monitoring and Recording Adverse Events ...................................................................53 
9.4.1 
Serious Adverse Events/Adverse Events of Special Interest .................................53 
9.4.2 
Non-Serious Adverse Events ..................................................................................53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................53 
9.4.3.1 
Relationship to the Study Drug ........................................................................54 
9.4.3.2 
Severity ............................................................................................................54 
9.4.3.3 
Action Taken with Study Drug ........................................................................54 
9.4.3.4 
Treatment Given for Adverse Event ................................................................55 
9.4.3.5 
Outcome of the Adverse Event ........................................................................55 
9.5 
Procedures for Handling Special Situations ..................................................................55 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................55 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............56 
9.5.3 
Dosing Errors .........................................................................................................56 
9.5.4 
Contraception and Pregnancy .................................................................................57 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 57 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................57 
10.1.1 
Primary Endpoint(s) ...............................................................................................58 
10.1.2 
Secondary Endpoints ..............................................................................................58 
10.1.3 
Safety Endpoints .....................................................................................................58 
10.1.4 
Dose Selection ........................................................................................................59 
10.2 
Sample Size Considerations ...........................................................................................59 
10.3 
Analysis Populations ......................................................................................................59 
10.4 
Definition of Baseline ....................................................................................................60 
10.5 
Interim Analysis .............................................................................................................60 
10.6 
Planned Methods of Analysis ........................................................................................60 
10.6.1 
Demographic and Baseline Characteristics ............................................................60 
10.6.2 
Safety Analysis .......................................................................................................60 
10.6.2.1 
Adverse Events ................................................................................................60 

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Amendment 4 
Protocol 
 
5 January 2017 
 
8 
10.6.2.2 
Clinical Laboratory Data..................................................................................60 
10.6.2.3 
Vital Signs and Examinations ..........................................................................61 
10.6.3 
Efficacy Analysis ...................................................................................................61 
10.6.3.1 
Analysis of Primary Efficacy Endpoint ...........................................................61 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints......................................................61 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................62 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 62 
11.1 
Informed Consent ..........................................................................................................62 
11.2 
Ethical Conduct of the Study .........................................................................................63 
11.3 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) .....................63 
11.4 
Patient Confidentiality ...................................................................................................63 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 64 
12.1 
Protocol Amendments ....................................................................................................64 
12.2 
Study Termination .........................................................................................................64 
12.3 
Study Documentation and Storage ................................................................................64 
12.4 
Study Monitoring ...........................................................................................................65 
12.5 
Language ........................................................................................................................66 
12.6 
Compensation for Injury ................................................................................................66 
13. 
REFERENCES ................................................................................................................ 67 
14. 
APPENDICES ................................................................................................................. 70 
Appendix A 
Schedule of Procedures .....................................................................................71 
Appendix B 
List of Laboratory Analytes ..............................................................................78 
Appendix C 
PK Sampling Schedule ......................................................................................80 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities .......83 
Appendix E 
Additional Laboratory Tests for Patients with Platelet Count ˂ 100,000/mm3.87 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ................................................................................... 38 
Table 2 
Study Drug Dosing Information ........................................................................... 40 
Table 3 
Actions in Patients with Low Platelet Count ........................................................ 47 
 
TABLE OF FIGURES 
Page 
Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of 
apo(a) Covalently Bound to apoB..........................................................................22 
 
 

ISIS 681257-CS6 
CONFIDENTIAL
Amendment 4
Protocol 
5 January 2017
 
9 
PROTOCOL AMENDMENTS 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
Amendment Number: 
4 
Amendment Date: 
5 January 2017 
 
The following table summarizes the history and nature of amendments to the protocol of Study 
ISIS 681257-CS6.   
None of the antecedent versions of the study protocol has been enacted clinically and therefore 
no patients have been enrolled prior to issuance of Amendment 4. 
Protocol Version 
Date 
Rationale for Amendments 
Original Protocol  
15 August 2016 
 
Amendment 1 
6 October 2016 
Regulatory advice on inclusion of more 
detailed description of processes for 
platelet monitoring, and more frequent 
monitoring of liver function. 
Amendment 2 
29 November 2016 
Regulatory advice on inclusion of 
biomarkers of renal damage and increased 
frequency of renal monitoring.  Addition of a 
DSMB. 
Amendment 3 
30 December 2016 
Adjustment of the frequency, and alert and 
intervention limits, for renal safety and 
adjustment of the frequency of liver safety 
testing.   
Amendment 4 
5 January 2017 
The study population was increased to 
270 patients (54 per cohort) to support a 
statistical assessment of risk of platelet 
reduction in this population.  In addition, the 
10 mg weekly treatment cohort has been 
modified to 20 mg every 2 weeks 
(biweekly). 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol 
 
5 January 2017 
 
10 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of 
ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and 
Established Cardiovascular Disease (CVD)  
Study Phase 
2 
Indication 
Patients with hyperlipoproteinemia(a) and established CVD. 
Investigational Drug 
ISIS 681257 is a second generation 2ʹ-MOE modified, GalNAc3–conjugated antisense 
oligonucleotide inhibitor of apolipoprotein (a) [apo(a)]. 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of 
different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels 
in patients with hyperlipoproteinemia(a) and established CVD. 
Secondary Objective(s) To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein 
cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on 
apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose 
regimens in patients with hyperlipoproteinemia(a) and established CVD. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio to receive ISIS 681257 or 
placebo.  This number was chosen to provide statistical power for both efficacy and 
safety assessments.  Study Drug (ISIS 681257 or placebo) will be administered SC 
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 enrolled patient 
reaches 6 months of exposure.  All patients will then enter a 16-week post-treatment 
follow-up period. 
The primary efficacy and safety analysis time point is at Week 25 for patients who 
received every 4-week dosing (Cohorts A-C) and at Week 27 for patients who received 
every 2-week or weekly dosing (Cohorts D and E, 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 (as needed) data collected on ISIS 681257 during this 
study, both individual events and aggregate data.   
Number of Subjects 
Approximately 270 
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. 
Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, 
or peripheral artery disease 
4. 
Lp(a) plasma level ≥ 60 mg/dL 
5. 
Must be on standard-of-care preventative therapy for other than elevated Lp(a) 
CVD risk factors 
 
 

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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Inclusion Criteria 
6. 
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 
7. 
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 16 weeks after the last dose of Study 
Drug (ISIS 681257 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 
8. 
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 16 weeks after the last dose of ISIS 681257 
Exclusion Criteria 
1. 
Within 6 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 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  

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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria 
10. Patients with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse 
12. Clinically-significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion, including the following: 
a. 
Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
protein measurement of ˂ 300 mg/24-hr 
b. 
Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR 
above this threshold, eligibility may be confirmed by a quantitative total urine 
albumin measurement of ˂ 150 mg/24-hr 
c. 
Estimated GFR ˂ 60 mL/min as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
d. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)  
> 2.0 x ULN 
e. 
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > ULN  
g. 
Platelet count ˂ LLN 
13. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
14. Treatment with another investigational drug, biological agent, or device within 
1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 
15. Treatment with any 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 
16. BMI > 40 kg/m2  
17. Blood donation of 50-499 mL within 30 days of screening or of > 499 mL within 
8 weeks of Screening 
18. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator 
19. 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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PROTOCOL SYNOPSIS Continued 
Treatment Groups 
Patients will be randomized to 5 parallel cohorts: 
Cohort A (n = 54): Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort B (n = 54):  Patients will be randomized 5:1 to receive 40 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort C (n = 54):  Patients will be randomized 5:1 to receive 60 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort D (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every 2 weeks for up to 26 doses. 
Cohort E (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every week for up to 52 doses. 
Cohort 
Treatment 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 or placebo  
(Every 4 weeks) 
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 or placebo 
(Every 2 weeks) 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 or placebo 
(Every week) 
≤ 52 
≤ 1040 mg 
Study Drug Dosage 
and Administration 
The Sponsor will provide ISIS 681257 in a concentration of 100 mg/mL and matching 
volume placebo: 
Cohort A:  20 mg every 4 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort B:  40 mg every 4 weeks ISIS 681257 or placebo (0.4 mL) 
Cohort C:  60 mg every 4 weeks ISIS 681257 or placebo (0.6 mL) 
Cohort D:  20 mg every 2 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort E:  20 mg every week ISIS 681257 or placebo (0.2 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 681257 doses of 10 mg, 20 mg, and 40 mg given 
weekly that were found to be generally well-tolerated and to induce clinically-relevant 
reductions in Lp(a).  The range of dosing proposed for the present study will provide the 
equivalent drug exposure of 5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and 
is predicted (based on modelling of PK/PD data obtained in Phase 1 study) to result in 
mean reductions from baseline in plasma Lp(a) ranging from approximately 60% to 85% 
at steady-state.  
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to 
bring almost all patients with hyperlipoproteinemia(a) into the normal range 
(Lp(a) ≤ 30 mg/dL). 
 
 

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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and 
Schedule Selection 
Continued 
The present study will also evaluate safety and efficacy at different dosing 
frequencies:  every 4 weeks, every 2 weeks, and weekly.  Patients with 
hyperlipoproteinemia(a) 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.  Dosing regimens of 
20 mg every 2 weeks and 40 mg every 4 weeks will test if similar monthly exposure, at 
different frequencies of administration, will achieve similar safety and similar level of 
Lp(a) reduction since the reduction achieved by a given dose level is principally driven 
by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety. 
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 are outlined in Section 6, 
Appendices A and C. 
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may continue treatment 
within the same randomized cohort until the last enrolled patient reaches 6 months of 
exposure (for continuing safety assessments), with a maximal exposure period of 
12 months.  
The study for an individual patient will generally consist of the following periods:  
• 
An up to 4-week screening period 
• 
An up to 52-week treatment period during which Study Drug will be 
administered per assigned cohort by SC injection 
• 
A 16-week post-treatment follow-up period 
Patients in Cohorts A through C will receive up to 13 SC doses of ISIS 681257 or 
placebo every 4 weeks.  Patients in Cohort D will receive up to 26 SC doses of 
ISIS 681257 or placebo every 2 weeks and patients in Cohort E will receive up to 52 SC 
doses of ISIS 681257 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).  
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 and use of concomitant 
medications.  Safety and tolerability results in patients dosed with ISIS 681257 will be 
compared with those dosed with placebo. 
Efficacy Evaluations 
The primary analysis time point is at Week 25 for patients who received every 4-week 
dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly 
dosing (Cohorts D and E). 
The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary 
analysis time point for ISIS 681257 treatment groups compared to placebo. 
The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at 
the primary analysis time point on the following: 
• 
Percent change from baseline in LDL-C 
• 
Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL 
• 
Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL 
• 
Percent change from baseline in apoB 
• 
Percent change from baseline in OxPL-apo(a) 
• 
Percent change from baseline in OxPL-apoB 

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PROTOCOL SYNOPSIS Continued 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all patients for the measurement of ISIS 681257 
plasma trough levels throughout treatment and during the post-treatment follow-up 
period.  In addition, in a subset of patients (approximately 12 patients per cohort), more 
frequent plasma samples will be taken following the first and Day 169 (for Cohorts A, B, 
and C) or Day 183 (for Cohorts D and E) dose to determine PK parameters.  Plasma 
sample collection time points are detailed in Appendices A and C. 
The plasma ISIS 681257 levels over time will be descriptively summarized by treatment 
with stratification by subject immunogenicity status.  Apparent terminal elimination half-
life will be calculated in patients who received ISIS 681257 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 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 Lp(a) between 
ISIS 681257 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the baseline Lp(a) 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 plasma Lp(a) 
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. 
Sample Size Considerations: 
Efficacy: 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the 
standard deviation of the percent change in Lp(a) is approximately 20%.  With 
23 patients in each ISIS 681257 treatment group and 23 in placebo group there would 
be approximately 90% power to detect a 20% difference in percent change in Lp(a) 
levels between the ISIS 681257 treatment groups and placebo group at an alpha level of 
0.05, assuming 30% reduction in the ISIS 681257 patients and 10% reduction in the 
placebo patients. 
Safety: 
Based upon prior clinical trial experience with ISIS ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in 
the ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, 
with 45 patients in each ISIS 681257 treatment group, there would be approximately 
80% power to detect at least 1 event. 
A total of approximately 270 patients (54 patients per cohort, including 45 patients per 
cohort treated with ISIS 681257) will be randomized to ensure that both the safety and 
efficacy of ISIS 681257 will be adequately characterized in the study. 
Sponsor/Collaborator 
Ionis Pharmaceuticals/Akcea Therapeutics 
 
 
 

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STUDY DESIGN AND TREATMENT SCHEMA 
 
SCREENING PERIOD 
Weeks -4 to -1 
TREATMENT PERIOD 
Weeks 1 to 52* 
Dosing per assigned cohort: 
Cohorts A, B, and C:  Every 4 weeks SC 
administration of 20, 40, or 60 mg ISIS 681257 or 
placebo 
Cohort D:  Every 2 weeks SC administration of 
20 mg ISIS 681257 or placebo 
Cohort E:  Every week SC administration of 20 mg 
ISIS 681257 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 enrolled patient reaches 6 months of 
exposure. 
POST-TREATMENT 
EVALUATIONS 
Weeks 4, 10, and 16 after last dose of 
Study Drug 
3 clinical visits for safety, efficacy,  
PK and PD assessments 
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 (16 Weeks 
after last dose of Study Drug) 

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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 
apo(a) 
apolipoprotein(a) 
apoB 
apolipoprotein B 
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 
CVD 
cardiovascular disease 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
Cys C 
Cystatin C 
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 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 681257 
antisense inhibitor of apolipoprotein (a) 
IV 
intravenous(ly) 
IXRS 
interactive voice/internet response system 
KIM-1 
kidney injury molecule 1 
kg 
kilogram 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
L 
liter 
m2 
square meter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
MI 
myocardial infarction 
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 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OxPL 
oxidized phospholipids 
PAD 
peripheral arterial disease 
PBS 
phosphate buffered saline 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLA2 
Lp(a)-associated Lp-phospholipase A2 
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 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
SC 
subcutaneous(ly) 
Study Drug 
ISIS 681257 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
Tg 
transgenic 
Tmax 
time to maximal concentration 
UACR 
urine albumin -creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein- creatinine ratio 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 

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1. 
OBJECTIVES 
1.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of 
different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels in 
patients with hyperlipoproteinemia(a) and established cardiovascular disease (CVD). 
1.2 
Secondary Objective(s) 
To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol 
(LDL-C), apolipoprotein B (apoB), oxidized phospholipids (OxPL) on apolipoprotein (a) 
[apo(a)] [OxPL-apo(a)] and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in 
in patients with hyperlipoproteinemia(a) and established CVD. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
2.1.1 
Lipoprotein (a) 
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein (Figure 1, Koschinsky and Marcovina 2004) 
in which the apoB component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], 
the distinct protein component of Lp(a) that is mainly responsible for its signature structural and 
functional properties (Dubé et al. 2012; Kronenberg and Utermann 2013).  Lp(a) is now 
recognized as an independent, genetic, causal risk factor for coronary artery disease (CAD), 
stroke, peripheral arterial disease (PAD), and calcific aortic stenosis (Erquo et al. 2009; 
Nordestgaard et al. 2010; Thanassoulis et al. 2013). 
 

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Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of apo(a) 
Covalently Bound to apoB 
Apo(a) contains 10 unique units of kringle IV repeats, of which KIV2 are present in variable copies (1 to > 40) 
conferring structural heterogeneity to Lp(a).  Apo(a) also contains kringle V and an inactive protease-like (P) 
domain.  In this model, 4 KIV2 repeats are shown.  Lp(a) also contains OxPL in the lipid phase of apoB as 
well as covalently bound to apo(a). 
 
Plasma levels of Lp(a) vary substantially among individuals, and most of this variation reflects 
the effects of genetic variation in the LPA gene which encodes the apo(a) protein. 
A second contributor to plasma-level variability are LPA single nucleotide polymorphisms 
(SNPs) that can be associated with either higher or lower Lp(a) levels (Clarke et al. 2009; 
Li et al. 2011).  Significant associations exist between 2 particular LPA variants, rs10455872 and 
rs3798220, increased Lp(a) levels, CVD, and aortic stenosis, with the CVD risk primarily 
mediated by Lp(a) plasma levels rather than an independent effect of the SNPs (Clarke et al. 
2009; Li et al. 2011). 
Lp(a) plasma levels are generally inversely associated with apo(a) size, and can vary by 
> 1,000-fold (0.1 to > 250 mg/dL or ˂ 0.25 to > 625 nmol/L) between individuals (Merki et al. 
2011).  Despite this inter-individual variation, intra-individual Lp(a) levels are thought to be 
generally stable over time along a pre-set genetically determined levels without significant 
impact from dietary or environmental factors, mediating CVD risk throughout the patient’s 
lifetime. 

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2.1.2 
Pathophysiology 
Lp(a) adheres to plaque sites and is retained in the artery wall and has proatherogenic and 
pro-inflammatory properties due to its LDL and apo(a) components (Spence and Koschinsky 
2012).  In addition, Lp(a) may be prothrombotic by inhibiting fibrinolysis because of its 
structural similarity to plasminogen and its enhancement of platelet aggregation (Rand et al. 
1998).  In vitro studies have provided evidence for both of these pathogenic mechanisms, but 
in vivo data are not definitive (Dubé et al. 2012).  In humans, Lp(a) is the main lipoprotein 
carrier of OxPL, which may drive the risk associated with Lp(a) (Bergmark et al. 2008; 
Leibundgut et al. 2013; Tsimikas et al. 2014).  In fact, OxPL measured on apoB (OxPL-apoB), 
which largely reflect the OxPL on Lp(a), have been shown to be a prognostic indicator for future 
CV events (Tsimikas et al. 2010; Tsimikas et al. 2012; Tsimikas et al. 2014).  OxPL associated 
with Lp(a) can be subjected to degradation by the Lp(a)-associated Lp-phospholipase A2 (PLA2), 
implicating Lp(a) in novel proinflammatory and atherogenic pathways (Kiechl et al. 2007). 
Hyperlipoproteinemia(a) in humans is associated with increased risk of cardiac death, 
myocardial infarction (MI), stroke, aortic stenosis, and peripheral arterial disease (PAD), 
particularly in subjects with small apo(a) isoforms (Bennett 2008; Erqou et al. 2009; Erqou et al. 
2010; Bertoia et al. 2013; Thanassoulis et al. 2013).  Although prospective, randomized, 
controlled outcomes studies have not been conducted, epidemiological, genome-wide association 
and Mendelian randomized controlled study data to date provide supporting evidence for a role 
of Lp(a) as a risk factor for CVD (Kamstrup et al. 2009).  For example, in the Copenhagen City 
Heart Studies of 42,000 subjects with a 15-year follow-up (Kamstrup et al. 2009) using a 
Mendelian randomization approach, higher Lp(a) levels were related to risk of MI. 
2.1.3 
Current Treatment Options 
In 2010, the European Atherosclerosis Society (EAS) Consensus Panel recommended screening 
for elevated Lp(a) in people at moderate to high risk of CVD to reach a treatment goal of 
˂ 50 mg/dL (125 nmol/L), after therapeutic management of LDL-C (Nordestgaard et al. 2010).  
Approximately 20% of people are estimated to have plasma Lp(a) levels over 50 mg/dL 
(125 nmol/L) and approximately 0.3% to have levels over 175 mg/dL (438 nmol/L).  There are 
no gender differences in Lp(a) concentrations but racial differences have been observed, with 
whites and Asians having lower levels while blacks and Hispanics generally have somewhat 
higher levels (Nordestgaard et al. 2010). 
Lifestyle and diet are thought to have little impact on an individual’s Lp(a) level.  Current 
treatment recommendations from the EAS Consensus Panel are limited to the use of 1 to 3 g of 
niacin (nicotinic acid) daily which could result in an up to 30% reduction in Lp(a).  However, 
niacin is associated with side effects (e.g., flushing) that reduce patient tolerability and 
compliance (Parker et al. 2006; Guyton 2007). 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are neither indicated nor 
formally recommended for treatment of hyperlipoproteinemia(a) but have been reported to 
reduce Lp(a) levels by ~20%-35% in patients with hypercholesterolemia (Desai et al. 2013; 
Raal et al. 2015). 
The other current option for patients with significantly elevated Lp(a) levels (≥ 60 mg/dL) is 
lipoprotein apheresis, either general lipoprotein apheresis (Jaeger et al. 2009;  

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Leebmann et al. 2013; Rosada et al. 2014) or Lp(a)-specific apheresis (Safarova 2012).  While 
very effective at acutely lowering Lp(a) (acute and interval Lp(a) reductions of > 60% and 
> 30% respectively), this treatment option is expensive, burdensome for patients, and 
unavailable/not reimbursed in many countries and regions. 
2.2 
Therapeutic Rationale 
Therapeutic modalities to reduce Lp(a) levels in humans are few, and there are no drugs 
currently available that specifically target Lp(a) alone.  Antisense oligonucleotides (ASOs) are 
emerging as viable therapeutic agents to treat disorders where overexpression of proteins is 
associated with a disease process.  Apo(a) is synthesized primarily in the liver, a target organ for 
ASOs, where it is subsequently covalently linked to the apoB-100 component of LDL to form 
the Lp(a) lipoprotein.  The goal of treatment with ISIS 681257 is to reduce the production of 
apo(a) in the liver and thus, the level of Lp(a) lipoprotein by using an ASO directed against the 
messenger ribonucleic acid (mRNA) of apo(a).  It has been hypothesized that a pharmacologic 
reduction in Lp(a) could slow down or reverse CVD by reducing thrombotic, atherogenic, or 
inflammatory events in patients with elevated Lp(a) levels (Nordestgaard et al. 2010). 
Importantly, there is no evidence that lowering Lp(a) will result in adverse consequences in 
individuals, and there are no reports linking very low Lp(a) to any deleterious effects. 
2.3 
ISIS 681257 
Please refer to the ISIS 681257 Investigator’s Brochure for more details on ISIS 681257 
mechanism of action, chemistry, pre-clinical and clinical experience.  The summary is provided 
below. 
2.3.1 
Mechanism of Action 
ISIS 681257 is a second-generation ASO drug targeted to apo(a) that has been covalently bonded 
to triantennary N-acetyl galactosamine (GalNAc3), a high-affinity ligand for the hepatocyte-
specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc3 conjugate.  This 
GalNAc3-conjugate approach results in enhanced ASO delivery to hepatocytes versus 
non-parenchymal cells and has increased ASO potency by approximately 10-fold compared to 
unconjugated ASOs in mice (Prakash et al. 2014). 
The ASO portion of ISIS 681257 is complementary to a region spanning the Exon 24-25 splice 
site at position 3901 of apo(a) transcript sequence (NM_005577.2) and binds to the mRNA by 
Watson and Crick base pairing.  The hybridization (binding) of ISIS 681257 to the cognate 
mRNA results in the Ribonuclease H1 (a non-specific endonuclease that catalyzes the cleavage 
of RNA via hydrolytic mechanism RNase H1-mediated degradation of the apo(a) mRNA, thus 
preventing production of the apo(a) protein).  Maximal antisense-mediated reduction of target 
mRNA levels is typically greater than 90% of control levels in sensitive tissues (Zhang et al. 
2010).  Furthermore, reduction in target mRNA levels using this approach correlates directly 
with a subsequent reduction in target protein levels.  
ISIS 681257 does not have any complementary homology to plasminogen mRNA (Graham et al. 
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2.3.2 
Chemistry 
Chemically, ISIS 681257 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone 
design).  The mixed backbone design reduces the total number of phosphorothioate linkages, 
which reduces non-specific interactions with proteins and further enhances potency of GalNAc3 
conjugated ASOs. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity for the target 
mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of 
some of the high-dose toxicities, thereby resulting in an improved safety profile compared to 
first-generation antisense drugs containing phosphorothioate-modified oligodeoxynucleotides 
(DNA) (Henry et al. 2000).  The third region, the central portion of the oligonucleotide, is 
composed of 10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and 
ISIS 681257 employs this chimeric structure to enable use of the ubiquitous endonuclease that 
specifically hydrolyzes the RNA strand in RNA/DNA hybrids (RNase H1)-mechanism for 
antisense activity.  This is because while the 2′-MOE modification confers increased stability and 
affinity, it does not support RNase H1-catalyzed cleavage of RNA hybridized to 2′-MOE-
modified nucleotides (McKay et al. 1999).  The fourth region is composed of a triantennary 
cluster of GalNAc3 sugars that is linked to the 5ʹ end of ISIS 681257 via a phosphodiester 
linkage.  The GalNAc3 cluster is a high affinity ligand for the ASGPR, a receptor expressed 
primarily on the surface of liver hepatocytes (Stockert 1995).  The GalNAc3 cluster enhances 
delivery of ISIS 681257 to liver hepatocytes over other cell types and enhances potency.  After 
internalization into cells, the GalNAc3 cluster is metabolized to release “free ASO” inside the 
cell (Prakash et al. 2014). 
2.3.3 
Preclinical Experience 
The pharmacology of ISIS 681257 has been examined in apo(a) transgenic (Tg) mice which 
express the entire human apo(a) genomic sequence (Frazer et al. 1995) and nonhuman primates. 
Administration of ISIS 681257, a human apo(a) antisense inhibitor, to mice containing the 
human apo(a) transgene produced dose-dependent reductions in human apo(a) liver mRNA and 
apo(a) plasma protein after 6 weeks of ASO administration at 0.3, 1, 3, and 10 mg/kg/wk. 
When ISIS 681257 was administered to normal chow fed cynomolgus monkeys for 4 weeks at 
the dose of 12 mg/kg/wk, it significantly reduced hepatic apo(a) mRNA by 90% relative to the 
cohort administered phosphate buffered saline (PBS).  As there is an 80% sequence conservation 
between apo(a) and plasminogen nucleotide sequences, plasminogen mRNA levels were also 
measured, and no change compared to the PBS cohort was observed. 
Findings from the chronic studies with ISIS 681257 (the 26-week mice and 39-week monkey 
studies) were similar to those observed in the 4- and 6-week studies and were not considered 
adverse.  The plasma and tissue concentrations observed for ISIS 681257 in mice and monkeys 
were generally similar to those observed for other unconjugated 20-mer 2ʹ-MOE ASOs in this 
chemical class with and without GalNAc3-conjugation.  However, the proportion of drug in 

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hepatocytes compare to nonparenchymal liver cells was greater for ISIS 681257, compared to the 
parent drug ISIS 494372 (without GalNAc3-conjugation), which is the basis for increased 
potency of ISIS 681257 (unpublished results; Geary et al. 2003; Yu et al. 2007; Prakash et al. 
2016). 
The most noteworthy safety finding in the chronic monkey study was a marked platelet reduction 
that, occurred in 2 male monkeys in the high-dose group (20 mg/kg/wk) and 1 animal (1 female) 
in the mid-dose (10 mg/kg/wk) group beginning on Days 44-135, which led to the subsequent 
early termination (ET) of these 3 animals.  An additional male monkey in the 10 mg/kg/wk dose 
group had a moderate decrease in platelets that was successfully treated with steroid, and was 
terminated at the scheduled 6-month interim sacrifice.  There were no platelet reductions or other 
toxicologically significant findings in monkeys treated with 2 mg/kg/wk for up to 39 weeks.  
There were no marked platelet reductions in mice at doses up to 70 mg/kg/wk for 26 weeks.  
However, mice exposed to ISIS 681257 at doses of ≥ 10 mg/kg/wk for up to 26 weeks showed 
evidence of hepatobiliary effects in both sexes as indicated by increases in ALT (up to + 10.3x), 
AST (up to + 10.4x), and/or ALP (+ 2.5x).  
2.3.4 
Clinical Experience 
Detailed information concerning the clinical studies conducted with ISIS 681257 can be found in 
the Investigator’s Brochure.  A summary of the study that has been conducted with ISIS 681257 
is included below. 
ISIS 681257-CS1 was a Phase 1 double-blind, placebo-controlled, dose-escalation study 
designed to assess the safety, tolerability, PK, and pharmacodynamics (PD) of single and 
multiple doses of ISIS 681257 administered subcutaneously (SC) to 45 healthy subjects with 
Lp(a) ≥ the upper limit of normal (ULN) (30 mg/dL).  Twenty one (21) subjects received 10 to 
120 mg SC (10, 20, 40, 80, and 120 mg) as a single-dose, and 24 subjects received 10, 20, and 
40 mg as multiple doses (6 doses in 21 days:  3 loading doses during the first week on alternate 
days (Days 1, 3, and 5), and then once a week for the next 3 weeks (Days 8, 15, and 22). 
There were no serious adverse events (SAEs), or clinically-relevant changes in laboratory 
assessments and all subjects completed the treatment and post-treatment follow-up periods. 
Constitutional symptoms such as fever, chills, increase in body temperature and arthralgias have 
been observed following parenteral administration of ASOs, primarily during the initial dosing 
period.  Following SC administration of ISIS 681257 constitutional symptoms were observed in 
4 of the 6 subjects who received a single-dose of 120 mg.  The symptoms were mild in severity 
and resolved spontaneously with or without treatment with acetaminophen. 
Fluctuations in platelet counts to below the lower limit of normal were observed in 5 study 
subjects on active drug and across doses.  These changes were not considered adverse or 
clinically-significant by the Investigator and did not appear to be dose related. 
Two (2) mild AEs of redness at the site of injection occurred 48 to 72 hours after administration 
in 1 subject who received ISIS 681257 in the 20 mg multiple-dose cohort.  Both AEs resolved by 
the time of the subject’s next visit. 

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Following SC administration, ISIS 681257 was absorbed rapidly into the systemic circulation, 
with median time to maximum plasma concentrations (Tmax) ranging from 1 to 4 hours.  Similar 
Tmax values were observed at all dose levels.  Maximum observed plasma concentrations (Cmax) 
and AUC0-24hr were dose-dependent over the studied SC dose range.  The mean peak (Cmax) and 
total exposure (AUC0-24hr) increased proportionally with dose at dose levels ranging from 10 to 
40 mg, and greater than dose proportionally at dose levels ranging from 40 to 120 mg. 
After reaching Cmax, mean plasma concentrations of ISIS 681257 declined in a biphasic fashion 
over time, with an initial, relatively fast distribution phase that dominated the plasma clearance 
followed by a slower elimination phase.  Characterization of the terminal elimination phase 
yielded an apparent terminal elimination half-life of approximately 3 to 4 weeks over a dose 
range of 10 to 120 mg (either single- or multiple-dose), and appeared to be independent of dose.  
This result is consistent with the slow elimination of ISIS 681257 observed from monkey tissues, 
and the comparatively long elimination half-lives observed for this chemical class. 
Plasma trough concentrations (168 hours or 7 days from previous dose) monitored during the 
treatment period in the multiple-dose cohorts increased with increasing dose, consistent with 
expectations (based on preclinical assessments and experience with other compounds of this 
chemical class) that trough plasma concentrations reflect exposure in tissues.  Plasma trough 
concentrations did not increase greatly after the loading period (Day 15), suggesting that 
accumulation in major tissues of distribution had approached steady-state after the loading 
period. 
Overall, the human PK of ISIS 681257 are consistent with the expected PK for compounds 
within this chemical class. 
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 program evaluated ISIS 681257 doses of 10 mg, 20 mg, and 40 mg given weekly 
that were found to be generally well-tolerated and to induce clinically-relevant reductions in 
Lp(a). 
The range of dosing proposed for the present study will provide the equivalent drug exposure of 
5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and is predicted (based on modelling of 
PK/PD data obtained in Phase 1 study) to result in mean reductions from baseline in plasma 
Lp(a) ranging from approximately 60% to 85% at steady-state. 
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to bring 
almost all patients with hyperlipoproteinemia(a) into the normal range (Lp(a) ≤ 30 mg/dL). 
The present study will also evaluate safety and efficacy at different dosing frequencies:  every 
4 weeks, every 2 weeks, and weekly.  Patients with hyperlipoproteinemia(a) 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.  Dosing regimens of 20 mg every 2 weeks and 40 mg every 4 weeks will test if similar 
monthly exposure, at different frequencies of administration, will achieve similar safety and 
similar level of Lp(a) reduction since the reduction achieved by a given dose level is principally 

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driven by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio (225 ISIS 681257 and 45 placebo) 
to receive ISIS 681257 or placebo.  Study Drug (ISIS 681257 or placebo) will be administered 
SC every week, every 2 weeks (biweekly), 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. 
The primary analysis time point is at Week 25 for patients who received every 4-week dosing 
(Cohorts A-C) and at Week 27 for patients who received 2-week or weekly dosing (Cohorts D 
and E).  For patients continuing treatment beyond the primary analysis time point additional 
supportive efficacy analysis (to evaluate whether the treatment effect is maintained) and safety 
analysis (for the purpose of dose(s) selection) will be repeated at the completion of Study Drug 
treatment. 
The treatment portion of the study will be complete when the last enrolled patient reaches 
6 months of exposure.  All patients will then enter a 16-week post-treatment follow-up period. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma Lp(a) levels (≥ 60 mg/dL ) and a clinical 
diagnosis of CVD are eligible for enrollment upon meeting the study specific eligibility criteria.  
Patients will be on standard-of-care preventative therapy for other than elevated Lp(a) 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 
• Evidence of cardiac ischemia on exercise testing, or imaging study 
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).  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 5 parallel dosing cohorts, with each cohort having a 5:1 ratio to 
receive ISIS 681257 or matching volume of placebo, respectively, by SC injection for up to 
52 weeks. 
Following the End-of-Treatment, patients will enter the 16-week post-treatment follow-up 
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3.2 
Number of Study Centers 
This is a multicenter, multinational study. 
3.3 
Number of Patients 
Approximately 270 patients will be randomized in this study, with approximately 54 patients 
assigned to each of the 5 treatment cohorts. 
3.4 
Overall Study Duration and Follow-up 
The length of patients’ participation in the study may be up to 18 months (72 weeks), which 
includes a 4-week screening period, an up to 52-week treatment period with Study Drug 
(ISIS 681257 or placebo), and a 16-week post-treatment follow-up period.  The treatment portion 
of the study will be complete when the last enrolled 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. 
3.4.2 
Treatment 
For each patient minimum treatment duration is 6 months and maximum of 52 weeks.  
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may continue treatment within the 
same randomized cohort until the last enrolled patient reaches 6 months of exposure (for 
continuing safety assessments), with a maximal exposure period of 12 months.  When this 
milestone is met, all patients will then enter a 16-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 681257 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 16-week post-treatment follow-up period and will 
return to the Study Center for 3 follow-up visits 4, 10, and 16 weeks after their last injection of 
Study Drug as per Appendix A (Follow-up). 
The final study visit for each patient will be 16 weeks after the last dose of Study Drug. 
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. 

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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 681257 during this study.  The 
DSMB will be constituted to include expertise in medical specialties relevant to the safety of 
antisense drugs (nephrology, hepatology, hematology and cardiology).  Specialist members of 
the DSMB will be informed and consulted on all treatment-related SAEs relevant to their 
expertise and all changes of relevant laboratory parameters that trigger stopping rules 
(Section 8.6), within 48 hours of receipt of such results.  In addition, all accrued safety data 
relevant to each of medical area specialist will be forwarded monthly for review.  
The full DSMB review of all accumulated data will be performed quarterly.  Based on its 
ongoing assessment of the safety and tolerability of ISIS 681257, 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). 
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 
1:1:1:1:1 ratio to 1 of the 5 parallel-dose cohorts (Cohorts A, B, C, D, or E).  Within each dose 
cohort, patients will be randomized in a 5:1 ratio to receive ISIS 681257 or matching volume of 
placebo, respectively. 
A permuted block schedule will be used.  The randomization schedule will be generated and held 
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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 a 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). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria at 
within 4 weeks of Study Day 1or 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. Clinical diagnosis of CVD defined as documented coronary artery disease (CAD), stroke, 
or peripheral artery disease 
4. Lp(a) plasma level ≥ 60 mg/dL  
5. Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk 
factors  
6. 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, proprotein convertase subtilisin/kexin type 9 
[PCSK9s] 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 
 
 

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7. 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 16 weeks after the last dose of Study Drug 
(ISIS 681257 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 
8. 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 16 weeks 
after the last dose of ISIS 681257 
5.2 
Exclusion Criteria 
1. Within 6 months of Screening:  acute coronary syndrome, major cardiac surgery, or 
stroke/transient ischemic attach 
2. Within 3 months of Screening:  coronary or peripheral arterial revascularization, major 
non-cardiac surgery, or lipoprotein apheresis  
3. Heart failure New York Heart Association (NYHA) class 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  

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10. Patients with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse 
12. Clinically-significant abnormalities in screening laboratory values that would render a 
patient unsuitable for inclusion, including the following: 
a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg.  In the event of a UPCR above 
this threshold, eligibility may be confirmed by a quantitative total urine protein 
measurement of ˂ 300 mg/24-hr 
b. Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g.  In the event of a UACR above 
this threshold, eligibility may be confirmed by a quantitative total urine albumin 
measurement of ˂ 150 mg/24-hr 
c. Estimated GFR ˂ 60 mL/min (as determined by the Chronic Kidney Disease-
Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance 
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN 
e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
f. Alkaline phosphatase (ALP) > ULN 
g. Platelet count ˂ LLN 
13. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
14. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
15. Treatment with any 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 
16. BMI > 40 kg/m2  
17. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
18. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
19. 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 
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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.  A 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.  
On confirmation of eligibility and prior to randomization, patients will also undergo a 24 hr urine 
collection for creatinine, albumin, and protein as a baseline assessment. 
6.1.2 
Treatment Period 
During the treatment period, patients will report to the study center for clinic visits.  Patients will 
receive 20 mg doses of Study Drug administered by SC injection once every 4 weeks for up to 
52 weeks in Cohort A, 40 mg doses of Study Drug administered by SC injection once every 
4 weeks for up to 52 weeks in Cohort B, 60 mg doses of Study Drug administered by SC 
injection once every 4 weeks for up to 52 weeks in Cohort C, 20 mg doses of Study Drug 
administered by SC injection once every 2 weeks for up to 52 weeks in Cohort D, or 20 mg 
doses of Study Drug administered by SC injection once per week (weekly) for up to 52 weeks in 
Cohort E (Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 681257 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 12 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 681257.  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). 
6.1.3 
Post-Treatment Period 
Each patient will be followed for safety assessments for 16 weeks after the last dose of 
Study Drug.  During the post-treatment follow-up period, patients will return to the Study Center 

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for 3 outpatient visits at Weeks 4, 10, and 16 after the last dose of Study Drug 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.  A list of these analytes is 
contained in Appendix B. 
Routine blood chemistry and urine samples (excluding 24-hour urine collection) should be taken 
after fasting for at least 10 hours.  Any confirmatory test, or test taken for safety reasons, may be 
taken at any time, irrespective of fasting status.  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). 
Hematology samples will be collected every 14 days.  Each time a hematology lab is drawn and 
sent to the central laboratory for analysis, an additional sample must 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. 
Blood and urine samples for renal function testing will also be collected every 14 days and sent 
to the central laboratory for analysis, per Section 8.5.2.  If there are no test results available 
within 14 days of the last set of results for parameters considered critical to patient safety, the 
Investigator will contact the patient to hold dosing until a new test set is obtained and reviewed. 
Liver function testing will also be collected every 14 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 sent to the central laboratory are received on the next day 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 on the day of sample collection, and should be entered as soon as 
possible into the eCRF to inform the Sponsor and CRO study monitoring teams. 
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 

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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 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. 
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 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, B, and C at Weeks 5, 13, 21, 25, 33, 41, 49, and 53  
• Cohorts D and E at Weeks 5, 13, 21, 27, 33, 41, 49, and 53 
In all cohorts, ECGs will be conducted during the post-treatment follow-up period at 4, 10, and 
16 weeks after the last dose of Study Drug. 
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. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 681257 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. 

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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 16 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 16 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 1 or more 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 
†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. 

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*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 before visits requiring fasted blood 
sampling. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 681257 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 681257 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 681257 
ISIS 681257 vials contains 100 mg/mL ISIS 681257 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 681257 vials.  
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 681257 
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 681257 or placebo) 
labeled in accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 681257 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 

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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 681257 will be administered to patients by Study Center staff as follows: 
Cohort A: a single SC dose of 20 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort B: a single SC dose of 40 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort C: a single SC dose of 60 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort D: a single SC dose of 20 mg every 2 weeks for up to 52 weeks and a maximum of 
26 doses 
Cohort E: a single SC dose of 20 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, B, and C should receive 1 dose every 4 weeks, patients in Cohort D 
should receive 1 dose every 2 weeks and Cohort E 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 681257 or placebo) preparation and administration. 
 
 

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Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.2 mL  
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.4 mL  
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.6 mL  
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 
or placebo 
(Every 2 weeks) 
0.2 mL 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 
or placebo 
(Every week) 
0.2 mL 
≤ 52 
≤ 1040 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 
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 

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Study Drug (ISIS 681257 or placebo).  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  
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, patients must 
not be re-dosed 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 681257 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 2 weeks for the first 3 months of the 
study treatment, and monthly thereafter during the Treatment Period. 
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 (within 48 hours of receipt) 
reviewed by the Investigator and Medical Monitors. 
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 
All patients will have renal function tests monitored every 2 weeks throughout the study.  
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. 
During the course of the study, urinary surveillance will include urinalysis to include urine 
albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red blood 
cells (RBCs), as well as serum creatinine and cystatin-C to estimate glomerular filtration rate 

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(eGFR), which will be monitored every 2 weeks.  In addition, biomarkers of acute renal injury 
will also be measured every 2 weeks (Appendix B).  
The assessment of serum creatinine, cystatin-C, and urinalysis more frequently than every 
2 weeks 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 at the weekly safety review 
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:  Creatinine clearance (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 an 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. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of 
the above criteria, dosing with the Study Drug should be interrupted and the Study Medical 
Monitor informed.  In addition, the following supplemental renal tests should be immediately 
obtained:  
Serum creatinine, urine culture, 24-hour urine sample for creatinine clearance, urine 
albumin and urine protein, urine microscopy sample with inspection of sediment. 
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. 
8.5.3 
Safety Monitoring for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study and 
must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks.  
In addition, platelet function will be evaluated by aggregometry, using an approved point-of-care 
diagnostic device, in all patients at each study site visit, with additional functional testing being 
performed at selected study centers.  
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 

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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.  
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are 
< 140,000 mm3; 2) when platelet count is ≥ 30% decreased from baseline, or 3) when 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 D, 
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 Minor Bleeding Events 
Patients will be instructed to promptly report any signs or symptoms of bleeding.  Minor 
bleeding events are those that do not fulfill the criteria for major bleeding or clinically-relevant, 
non-major bleeding events (which are defined in Section 8.6.3), for example excess bruising, 
petechiae, or gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR, hepatic 
enzymes, bilirubin and platelet count should be performed. 
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 symptoms should be discussed with the Sponsor Medical Monitor or 
designee to determine whether additional monitoring or laboratory tests are required. 
8.6 
Stopping Rules  
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 

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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 
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 of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the 
following criteria, or any change in renal biomarkers deemed by the nephrologist on the DSMB 
to require further evaluation, a serum creatinine and 24-hour urine sample for creatinine 
clearance and protein should be obtained: 
1. CKD-EPI decrease of > 40% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 681257 or placebo) will be stopped permanently if 
24-hour urine testing confirms any of the following values in the absence of an alternative 
explanation: 
1. Urine protein is > 1.0 g 
2. Creatinine clearance decrease of > 40% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, 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 
Stopping Rules 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 steroids 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 

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steroids.  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 
0.5-2 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). 
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; Schulman et al. 2005), 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 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 
irrespective of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 
Definition of Major Bleeding Events (Schulman et al. 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 
Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman et al. 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis  
6. Bleeding after venipuncture for > 5 minutes 
 

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Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every week* 
75K-100K/mm3 
Permanently reduce as follows: 
For Cohort A:  reduce to 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks  
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 weeks 
For Cohort E:  reduce to 10 mg every week 
Closer observation 
Monitor every week* 
50K-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 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks 
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 week 
For Cohort E:  reduce to 10 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)/ anticoagulant 
medication 
25K-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/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
˂ 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 and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  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 0.5-2 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). 

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8.7 
Adjustment of Dose  
Dose frequency adjustments for platelet count reduction must be made in accordance with 
Section 8.6.3 and 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 8.6.3 
• 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. 
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 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 after discontinuing Study Drug.  Following this period, if the platelet count is 
stable (at least 3 consecutive values that are stable as determined by the Sponsor Medical 
Monitor and > 100,000/mm3), the next platelet count should be taken within at least 6 weeks so 
that patients are monitored for at least 12 weeks after discontinuing Study Drug. 
Following 6 weeks of Study Drug discontinuation, patients should be strongly encouraged to 
attend planned Study Center visits (including End-of-Treatment Week 53 visit and final 
Post-Treatment Follow-up visit 16 weeks after their last dose of Study Drug) to collect the study 
assessments in accordance with the Schedule of Procedures in Appendix A. 
If the patient declines or is unable to participate in the above, an ET visit (Week 53 visit 
assessments) should be performed at the time of withdrawal, at a minimum, and ideally within 
2 weeks from the last dose of Study Drug. 

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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 permanently discontinues Study Drug (see Section 8.8)   
• 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 study procedures and observations at the time of withdrawal 
(Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the ET study procedures and observations at the time of withdrawal (see 
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:  

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• Lipid lowering drugs (statins, ezetimibe, PCSK9 inhibitors, niacin, fibrates, fish oil, other 
products containing omega-3 fatty acids (including OTC preparations) 
• Anti-platelet therapies 
• Testosterone, estrogens, progesterone, growth hormone, or progestins. 
Disallowed Concomitant Therapy 
Use of the following is disallowed: 
• Warfarin, 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 
• 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 of 
platelet count, and liver and renal function as described in Section 6.2.1, Sections 8.5.1-8.5.3, 
and Sections 8.6.1-8.6.3. 
Patients will be required to have platelet counts every 2 weeks for the duration of the study and 
must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks, in 

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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. 
Patients will also be required to have renal function testing and assessment of biomarkers of 
renal damage every 2 weeks, and must not receive Study Drug if there are no test results for 
parameters considered critical to patient safety available within the prior 2 weeks.  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 (Grade 3 or Grade 4) is 
considered an adverse event of special interest and should be reported in an expedited fashion to 
the Sponsor. 
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.   

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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the Study Drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening, that is, poses an immediate risk of death at the time of the event 
• An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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 

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9.3.3.1 
Adverse Events of Special Interest 
For the purpose of this study severe reductions in platelet count < 50,000 mm3 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.  When the Investigator is reporting by telephone, it is 
important to speak to someone in person versus leaving a message.  An Initial Serious Adverse 
Event Form should be completed and a copy should be emailed or faxed to the Sponsor or 
designee.  The contact information for reporting SAEs is as follows:  
Attention:  
 
Email: 
 
 
Fax: 
 
 
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: 

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9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 681257 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 681257 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 
• 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 681257 or placebo) due to the event is characterized by 1 of 
the following. 
• None:  No changes were made to Study Drug (ISIS 681257 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 

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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) 
• 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. 

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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 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. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment.  The 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 681257 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 681257 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. 

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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 
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 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-C) and at Week 27 for patients who received weekly or 
biweekly dosing (Cohorts D and E).  For patients continuing treatment beyond the primary 

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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 endpoint is the percent change in Lp(a) from baseline at the primary 
analysis time point achieved by ISIS 681257 compared to pooled placebo. 
Lp(a) levels will be analyzed from patient blood samples taken at specified time points 
throughout the study. 
10.1.2 
Secondary Endpoints 
The secondary endpoints include the following parameters from baseline at the primary analysis 
time point for ISIS 681257 compared to placebo: 
• Percent change from baseline in LDL-C  
• Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL 
• Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL 
• Percent change from baseline in apoB 
• Percent change from baseline in OxPL-apo(a) 
• Percent change from baseline in OxPL-apoB 
10.1.3 
Safety Endpoints 
The safety analysis will be performed using the following parameters: 
• 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 events by severity, number of patients meeting renal 
stopping rules, and change in renal function tests by severity. 
• ECGs 
• Use of concomitant medications 

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10.1.4 
Dose Selection 
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 clinically-meaningful reduction in plasma Lp(a) 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, and renal or hepatic 
injury.   
10.2 
Sample Size Considerations 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the standard 
deviation of the percent change in Lp(a) is approximately 20%.  With 23 patients in each 
ISIS 681257 treatment group and 23 in placebo group there would be approximately 90% power 
to detect a 20% difference in percent change in Lp(a) levels between the ISIS 681257 treatment 
groups and placebo group at an alpha level of 0.05, assuming 30% reduction in the ISIS 681257 
patients and 10% reduction in the placebo patients. 
Based upon prior clinical trial experience with Ionis ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in the 
ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, with 
45 patients in each ISIS 681257 treatment group, there would be approximately 80% power to 
detect at least 1 event. 
Therefore, approximately 270 patients (54 patients per cohort, including 45 patients per cohort 
treated with ISIS 681257) will be randomized to ensure that both the safety and efficacy of 
ISIS 681257 will be adequately characterized in the study. 
10.3 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized, received at least 1 dose of Study 
Drug (ISIS 681257 or placebo), and have a Baseline Lp(a) 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, B, and C or at least 20 weekly doses 
for patients randomized in Cohorts D and E, 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 Study Drug, and 
have sufficient data for the analysis of PK parameters.  This population will be used for analysis 
of PK data. 

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10.4 
Definition of Baseline 
Baseline for Lp(a), LDL-C, apoB, OxPL-apo(a), OxPL-apoB, and other lipid measurements will 
be defined the pre-dose measurement on Day 1 or 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. 
10.6.2 
Safety Analysis 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug (ISIS 681257 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 681257 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 681257 or placebo) administration, as 

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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 analysis of the primary endpoint will be the pairwise comparison of percent change 
from baseline to primary analysis time point in fasting Lp(a) between ISIS 681257 treatment 
groups and pooled placebo group in the FAS.  The data will be analyzed using an analysis of 
covariance (ANCOVA) model with the Baseline Lp(a) 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 at least 50% of randomized patients have completed Week 52 visits, 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. 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints 
• Percent change from baseline at the primary analysis time point in fasting LDL-C will be 
compared between each ISIS 681257 treatment groups  and pooled placebo group using 
an ANCOVA model with baseline as covariate 
• Proportion of patients who achieve ≤ 50 mg/dL in fasting Lp(a) at the primary analysis 
time point will be compared between each ISIS 681257 treatment group and pooled 
placebo group using a logistic regression model with Baseline Lp(a) as a covariate.  
Proportion of patients who achieve ≤ 30 mg/dL in fasting Lp(a) at the primary analysis 
time point will be analyzed similarly 
• Percent change from baseline at the primary analysis time point in fasting apoB, 
OxPL-apo(a) and OxPL-apoB will be compared between ISIS 681257 treatment groups 
and pooled placebo group using an ANCOVA model with baseline as covariate 
All analyses of secondary endpoints will be performed on the FAS as primary and PPS as 
supportive. 

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10.6.4 
Pharmacokinetic and Immunogenicity Analysis 
For all patients, trough and post-treatment concentrations of ISIS 681257 in plasma (as total full 
length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 681257) will be determined and summarized by treatment with stratification by subject 
immunogenicity status using descriptive statistics. 
In addition, non-compartmental PK analysis of ISIS 681257 concentrations will be carried out on 
each individual patient data set in patients who received ISIS 681257 treatment, and the plasma 
disposition half-life (t1/2λz) associated with the apparent terminal elimination phase will be 
calculated, if appropriate, using available data at the End-of-Treatment and the post-treatment 
follow-up period from the equation, t1/2λz = 0.693/λz, where λz is the rate constant associated with 
the apparent terminal elimination phase. 
For patients in the PK subgroup only, non-compartmental PK analysis of ISIS 681257 will be 
carried out on each individual patient data set in patients who received ISIS 681257 treatment.  
The maximum observed drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will 
be obtained directly from the concentration-time data.  Following single dosing (Day 1), area 
under the plasma concentration-time curve from time zero (pre-dose) to 24 hours after the dose 
(AUC0-24hr) will be calculated using the linear trapezoidal rule.  Following multiple dosing, 
AUC0-24hr and area under the plasma concentration-time curve during the time of each sampled 
dosing interval (tau,τ) at steady-state (AUCτ) will be calculated using the linear trapezoidal rule. 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist.  Plasma PK parameters will be summarized using descriptive statistics with 
stratification by subject immunogenicity status.  Exposure-response relationships between 
selected PD [e.g., Lp(a)] and PK measures (including but may not be limited to plasma trough 
concentrations) may be explored (including with and without stratification by IM status) in this 
study, or in a separate population PK analysis with all clinical studies combined. 
The immunogenicity (IM) of ISIS 681257 will be assessed before, during, and after treatment 
with Study Drug (ISIS 681257 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 681257 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. 
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. 

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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 681257 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. 
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 
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.  

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Documents that are not for submission to the Sponsor or designee (e.g., signed informed consent 
forms) should be kept in strict confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IEC/IRB direct access to review the patient’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 
study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator must be obtained for all protocol amendments and amendments 
to the informed consent document.  The regulatory authority and IEC/IRB must be informed of 
all amendments and give approval for any amendments likely to affect the safety of the patients 
or the conduct of the trial.  The Investigator must send a copy of the approval letter from the 
IEC/IRB to the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract.  The 
Investigator/Sponsor or designee should notify the IEC/IRB in writing of the trial’s completion 
or 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 
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 

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• 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 
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. 

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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 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bennett CF. Pharmacological properties of 2ʹ-O-methoxyethyl-modified oligonucleotides. In: Crooke ST, editor. 
Antisense Drug Technology: Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis 
Group 2008; 365-400. 
Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized 
phospholipids in human plasma. J Lipid Res 2008; 49: 2230-2239. 
Bertoia ML, Pai JK, Lee J-H, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll 
Cardiol 2013; 61(21): 2169-2179. 
Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) 
lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528. 
Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin 
kexin type 9, significantly reduces lipoprotein (a) in hypercholesterolemic patients receiving statin therapy: an 
analysis from the LAPLACE-TIMI 57 Trial. Circ 2013; 128: 962-969. 
Dubé JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a): more interesting than ever after 50 years. Curr 
Opin Lipidol 2012; 23(2): 133-140. 
Erqou S, Kaptoge S, Perry PL, et al; Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk 
of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4): 412-423. 
Erqou S, Thompson A, Di Angelantonio E, et al. Apoliporotein(a) isoforms and the risk of vascular disease. JACC 
2010; 55(19): 2160-2167. 
Frazer KA, Narla G, Zhang JL, Rubin E. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase 
inducers in YAC transgenic mice. Nat Gen 1995; 9: 424-431. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma 
lipoprotein (a) levels in humans. J Lipid Research 2016; 57: 340-351. 
Guyton JR. Niacin in cardiovascular prevention: mechanisms, efficacy, and safety. Curr Opin Lipidol 2007; 18: 
415-420. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292(2): 468-479. 
Jaeger BR, Richter Y, Nagel D, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to 
reduce high lipoprotein(a) levels and major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009; 6(3): 
229-239. 
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and 
increased risk of myocardial infarction. JAMA 2009; 301(22): 2331-2339. 
Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 
activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb 
Vasc Biol 2007; 27: 1788-1795. 
Koschinsky ML and Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into 
lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 2004; 15(2): 167-174. 
Kronenberg F and Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013; 273: 6-30. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol 
 
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68 
Leebmann J, Roeseler E, Julius U, et al; Pro(a)LiFe Study Group. Lipoprotein apheresis in patients with maximally 
tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: 
Prospective observational multicenter study. Circ 2013; 128: 2567-2576. 
Leibundgut G, Scipione C, Yin H, et al. Determinants of binding of oxidized phospholipids on apolipoprotein(a) and 
lipoprotein(a). J Lipid Res 2013; 54: 2815-2830. 
Li Y, Luke MM, Shiffman D, Devlin JJ. Genetic variants in the apolipoprotein(a) gene and coronary heart disease.  
Circ Cardiovasc Genet 2011; 4(5): 565-573. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Merki E, Graham M, Taleb A, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) in 
transgenic mice. JACC 2011; 57(15): 1611-1621. 
Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as 
a cardiovascular risk factor: current status. Euro Heart J 2010; 31: 2844-2853. 
Parker K, Brunton L, Goodman LS, et al. Goodman & Gilman's the pharmacological basis of therapeutics. New 
York, NY. McGraw-Hill. 2006; ISBN 0-07-142280-142283. 
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; 42: 8796-8807. 
Prakash TP, Yu J, Migawa MT, et al. Comprehensive structure-activity relationship of triantennary N-Acetyl 
galactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J Med Chem 2016 
Mar 24; 59(6): 2718-2733. 
Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolucomab in homozygous familial 
hypercholesterolemia (TESLA Part B): a randomized, double blind, placebo controlled trial. Lancet 2015; 385: 
341-350. 
Rand ML, Sangrar W, Hancock MA, et al. Apoliprotein(a) enhances platelet responses to the thrombin receptor – 
activating peptide SFLLRN. Arterio Thromb Vasc Biol 1998; 18: 1393-1399. 
Rosada A, Kassner U, Vogt A, et al. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) 
levels reduce the incidence of cardiovascular events? Artif Organs 2014; 38: 135-141. 
Safarova M. Specific lipoprotein(a) apheresis reduces atherosclerosis progression. 80th Congress of the European 
Atherosclerosis Society, Milan, Italy 28 May 2012. 
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. 
Schulman S and Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Spence JD and Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity. Arterioscler Thromb Vasc Biol 2012; 
32: 1550-1551. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Thanassoulis G, Campbell CY, Owens DS, et al; CHARGE Extracoronary Calcium Working Group. Genetic 
associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368(6): 503-512. 

ISIS 681257-CS6 
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Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circ 2012; 126: 
2020-2035. 
Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal 
coronary events. J Am Coll Cardiol 2010; 56: 946-955. 
Tsimikas S, Willeit P, Willeit J, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke 
outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60: 2218-2229. 
Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary 
artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 
2014; 63: 1724-1734. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second-
generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.  Drug Metab Dispos 
2007; 35: 460-468.  
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 
 
 
 

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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 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27 
29 
33 
37 
41 
45 
49 
53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 
169 
183 184a 185a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-Hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
X 
X 
X 
Genetic Testing 
 
X 
 
Chemistry Panel j,k 
X 
EVERY 14 DAYS f 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology  j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh  
Xh  
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 
X1 
X 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
73 
Appendix A Schedule of Procedures – Weekly and Every 2-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 
169 
183 184a 185a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
FSH (women only, if 
applicable) j, m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test m 
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 
PD Panel j 
X 
X 
 
X 
X 
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 
Lp(a) Characterization 
 
X 
 
 
Study Drug:  SC Injection 
 
WEEKLY AND EVERY 2-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG  
(Week 1 through Week 53/Day 365)o 
 
 
 
Adverse Events 
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 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then every 6 weeks.  
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. 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
74 
Appendix A Schedule of Procedures – Weekly and Every 2 Week Dosing Continued 
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 as per Section 6.2.1.  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.) in this or subsequent clinical studies of 
ISIS 681257. 
o 
Patients will continue treatment in the study until the last patient enrolled reaches 6 months of exposure, and 50% of the enrolled patients have received 
Study Drug for 52 weeks.  When both of these milestones are met, all patients will then enter a 16-week post-treatment follow-up period. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8 hours post SC injection 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
75 
Appendix A Schedule of Procedures – Every 4-Week Dosing 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
24-hour Urine for Creatinine 
Clearance and Protein 
X 
 
 
 
 
Extended Urinalysis e 
X 
EXTENDED URINALYSIS PERFORMED EVERY 14 DAYS e, f 
X 
X 
X 
Renal Biomarkers g 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS f, g 
Xh 
Xh 
Xh 
Serum Creatinine and Cys-C i, j 
 
SERUM CREATININE and Cys-C PERFORMED EVERY 14 DAYS f, i 
 
 
 
Genetic Testing 
 
X 
 
 
Chemistry Panel j, k 
X 
EVERY 14 DAYS f 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology j, k 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS f, k 
Xh 
Xh 
Xh 
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation  
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 l 
 
X3 
X1 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
76 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 53/ET 
4* 
10* 
16* 
Study Day 
-28 to -1 
1 
2a 
29 
57 
85 
113 141 169 170a 171a 176a 183a 197 225 253 281 309 337 
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3b 
0 
2 
2 
2 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
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 
Archived Serum & Plasma 
Samples j, n 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PD Panel j 
X 
X 
 
X 
X 
X 
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 
X 
Lp(a) Characterization 
 
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 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
(Section 8.5.2). 
h 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then every 6 weeks. 
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. 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
77 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
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 as per Section 6.2.1.  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.) in this or subsequent clinical studies of 
ISIS 681257. 
o 
Patients will continue treatment in the study until the last patient enrolled reaches 6 months of exposure, and 50% of the enrolled patients have received 
Study Drug for 52 weeks.  When both of these milestones are met, all patients will then enter a 16-week post-treatment follow-up period. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8, hrs post SC injection 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
78 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
79 
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 681257 or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• 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 
• Free T3 
 
Coagulation 
• Fibrinogen 
• Plasminogen 
 
PD Panel 
• Lp(a) 
• OxPL-apoB 
• OxPL-apo(a) 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL 
Lp(a) Characterization 
• Apo(a) isoforms 
 
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 681257 (total full 
length ASO) levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 681257 
antibodies 
 
Genetic Testing 
• LPA SNPs associated with 
elevated Lp(a)  
 
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 
Biomarkers2 
• NGAL  
• NAG 
• KIM-1 
• Cys-C 
 
24 Hour Urine Test3 
• Creatinine clearance 
• Protein 
• Albumin 
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 681257 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.   
3 
To be performed during Screening upon confirmation of eligibility 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
80 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 
Sampling Schedule for Weekly and Every 2-Week Dosing Cohorts 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
81 
Appendix C PK Sampling Schedule  
Blood samples for the determination of plasma ISIS 681257 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 681257 
with plasma constituents.  Extensive PK samples will be collected in PK subgroup only (10 subjects 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 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
183 
184 
185 
197 
253 
365 
*Post Last Dose 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2
48-hr3 Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
82 
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 
25 
26 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
170 
171 
176 
183 
197 
253 
365 
*Post Last Dose  
All 
Patients 
Pre-
dose NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
NA 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
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 
Pre-
dose, 
1, 2, 4, 
and 
8-hr1 
24-hr2 48-hr3 Anytime Anytime Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
83 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
84 
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 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
  
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
86 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
87 
 
 
 
 
 
 
 
Appendix E 
Additional Laboratory Tests for Patients with 
Platelet Count ˂ 100,000/mm3 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 4 
Protocol  
 
5 January 2017 
 
88 
Appendix E Laboratory Tests to Be Performed in the Event of a Platelet Count 
˂ 100,000/mm3 
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 
Fibrinogen 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
von Willebrand factor (vWF) Antigen 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori  
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 
Platelet Antibody Bead Array (PABA) 
 

 
 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Collaborator: 
Akcea Therapeutics 
55 Cambridge Parkway, Suite 100 
Cambridge, MA  02142 
 
IONIS PHARMACEUTICALS, INC. 
 
ISIS 681257-CS6 
 
 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
 
Protocol Amendment 3 – 9 December 2016 
 
 
EudraCT No:  2016-003373-18 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 
Study of ISIS 681257 Administered Subcutaneously to Patients with 
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD) 
Amendment: 
Amendment 3 
Date: 
9 December 2016 
 
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 681257 
Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD),” dated 9 December 2016, and agree to conduct the study as 
described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
5 
TABLE OF CONTENTS 
Page 
PROTOCOL AMENDMENT...................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 16 
STUDY GLOSSARY .................................................................................................................. 17 
1. 
OBJECTIVES ................................................................................................................. 21 
1.1 
Primary Objective ..........................................................................................................21 
1.2 
Secondary Objective(s) ..................................................................................................21 
2. 
BACKGROUND AND RATIONALE .......................................................................... 21 
2.1 
Overview of Disease ......................................................................................................21 
2.1.1 
Lipoprotein (a) ........................................................................................................21 
2.1.2 
Pathophysiology .....................................................................................................23 
2.1.3 
Current Treatment Options .....................................................................................23 
2.2 
Therapeutic Rationale ....................................................................................................24 
2.3 
ISIS 681257 ...................................................................................................................24 
2.3.1 
Mechanism of Action .............................................................................................24 
2.3.2 
Chemistry ...............................................................................................................25 
2.3.3 
Preclinical Experience ............................................................................................25 
2.3.4 
Clinical Experience ................................................................................................26 
2.4 
Rationale for Dose and Schedule of Administration .....................................................27 
3. 
EXPERIMENTAL PLAN .............................................................................................. 28 
3.1 
Study Design ..................................................................................................................28 
3.2 
Number of Study Centers ..............................................................................................29 
3.3 
Number of Patients ........................................................................................................29 
3.4 
Overall Study Duration and Follow-up .........................................................................29 
3.4.1 
Screening ................................................................................................................29 
3.4.2 
Treatment ................................................................................................................29 
3.4.3 
Post-Treatment .......................................................................................................29 
3.5 
End-of-Study ..................................................................................................................29 
3.6 
Data and Safety Monitoring Board ................................................................................30 
4. 
PATIENT ENROLLMENT ........................................................................................... 30 
4.1 
Screening .......................................................................................................................30 
4.2 
Randomization ...............................................................................................................30 
4.3 
Replacement of Patients .................................................................................................31 
4.4 
Unblinding of Treatment Assignment ...........................................................................31 
5. 
PATIENT ELIGIBILITY .............................................................................................. 31 
5.1 
Inclusion Criteria ...........................................................................................................31 
5.2 
Exclusion Criteria ..........................................................................................................32 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
6 
6. 
STUDY PROCEDURES ................................................................................................ 33 
6.1 
Study Schedule ..............................................................................................................33 
6.1.1 
Screening ................................................................................................................33 
6.1.2 
Treatment Period ....................................................................................................34 
6.1.3 
Post-Treatment Period ............................................................................................34 
6.2 
Additional Study Assessments .......................................................................................34 
6.2.1 
Laboratory Assessments .........................................................................................34 
6.2.2 
Physical Exams and Vital Signs .............................................................................36 
6.2.3 
Electrocardiography ...............................................................................................36 
6.2.4 
PK Sampling ...........................................................................................................36 
6.3 
Restriction on the Lifestyle of Patients ..........................................................................36 
6.3.1 
Contraception Requirements ..................................................................................36 
6.3.2 
Other Requirements ................................................................................................37 
7. 
STUDY DRUG ................................................................................................................ 37 
7.1 
Study Drug Description .................................................................................................37 
7.1.1 
ISIS 681257 ............................................................................................................38 
7.1.2 
Placebo ...................................................................................................................38 
7.2 
Packaging and Labeling .................................................................................................38 
7.3 
Study Drug Accountability ............................................................................................38 
8. 
TREATMENT OF PATIENTS ..................................................................................... 38 
8.1 
Study Drug Administration ............................................................................................38 
8.2 
Other Protocol-Required Drugs .....................................................................................39 
8.3 
Other Protocol-Required Treatment Procedures ............................................................39 
8.4 
Treatment Precautions ...................................................................................................40 
8.5 
Safety Monitoring Rules ................................................................................................40 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................40 
8.5.2 
Safety Monitoring for Renal Function ...................................................................42 
8.5.3 
Safety Monitoring for Platelet Count Results ........................................................43 
8.5.4 
Safety Monitoring for Minor Bleeding Events .......................................................43 
8.5.5 
Safety Monitoring for Constitutional Symptoms ...................................................43 
8.6 
Stopping Rules ...............................................................................................................44 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................44 
8.6.2 
Stopping Rules for Renal Function Test Results ....................................................44 
8.6.3 
Stopping Rule for Platelet Count Results ...............................................................45 
8.7 
Adjustment of Dose .......................................................................................................47 
8.8 
Discontinuation of Study Drug ......................................................................................47 
8.8.1 
Follow-up Visits for Early Termination from Treatment Period or from 
Post-Treatment Follow-up Period ..........................................................................48 
8.9 
Withdrawal of Patients from the Study ..........................................................................48 
8.10 
Concomitant Therapy and Procedures ...........................................................................49 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
7 
8.10.1 
Concomitant Therapy .............................................................................................49 
8.10.2 
Concomitant Procedures .........................................................................................50 
8.11 
Treatment Compliance ...................................................................................................50 
8.12 
Safety Monitoring Compliance ......................................................................................50 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 50 
9.1 
Sponsor Review of Safety Information .........................................................................50 
9.2 
Regulatory Requirements ..............................................................................................50 
9.3 
Definitions .....................................................................................................................51 
9.3.1 
Adverse Event ........................................................................................................51 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................51 
9.3.3 
Serious Adverse Event (SAE) ................................................................................51 
9.3.3.1 
Adverse Events of Special Interest ..................................................................52 
9.4 
Monitoring and Recording Adverse Events ...................................................................52 
9.4.1 
Serious Adverse Events/Adverse Events of Special Interest .................................52 
9.4.2 
Non-Serious Adverse Events ..................................................................................53 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................53 
9.4.3.1 
Relationship to the Study Drug ........................................................................53 
9.4.3.2 
Severity ............................................................................................................53 
9.4.3.3 
Action Taken with Study Drug ........................................................................54 
9.4.3.4 
Treatment Given for Adverse Event ................................................................54 
9.4.3.5 
Outcome of the Adverse Event ........................................................................54 
9.5 
Procedures for Handling Special Situations ..................................................................55 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................55 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............55 
9.5.3 
Dosing Errors .........................................................................................................56 
9.5.4 
Contraception and Pregnancy .................................................................................56 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 57 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................57 
10.1.1 
Primary Endpoint(s) ...............................................................................................57 
10.1.2 
Secondary Endpoints ..............................................................................................57 
10.1.3 
Safety Endpoints .....................................................................................................57 
10.1.4 
Dose Selection ........................................................................................................58 
10.2 
Sample Size Considerations ...........................................................................................58 
10.3 
Analysis Populations ......................................................................................................58 
10.4 
Definition of Baseline ....................................................................................................59 
10.5 
Interim Analysis .............................................................................................................59 
10.6 
Planned Methods of Analysis ........................................................................................59 
10.6.1 
Demographic and Baseline Characteristics ............................................................59 
10.6.2 
Safety Analysis .......................................................................................................59 
10.6.2.1 
Adverse Events ................................................................................................59 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
8 
10.6.2.2 
Clinical Laboratory Data..................................................................................60 
10.6.2.3 
Vital Signs and Examinations ..........................................................................60 
10.6.3 
Efficacy Analysis ...................................................................................................60 
10.6.3.1 
Analysis of Primary Efficacy Endpoint ...........................................................60 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints......................................................60 
10.6.4 
Pharmacokinetic and Immunogenicity Analysis ....................................................61 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 62 
11.1 
Informed Consent ..........................................................................................................62 
11.2 
Ethical Conduct of the Study .........................................................................................62 
11.3 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) .....................62 
11.4 
Patient Confidentiality ...................................................................................................63 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 63 
12.1 
Protocol Amendments ....................................................................................................63 
12.2 
Study Termination .........................................................................................................63 
12.3 
Study Documentation and Storage ................................................................................63 
12.4 
Study Monitoring ...........................................................................................................64 
12.5 
Language ........................................................................................................................65 
12.6 
Compensation for Injury ................................................................................................65 
13. 
REFERENCES ................................................................................................................ 66 
14. 
APPENDICES ................................................................................................................. 69 
Appendix A 
Schedule of Procedures ....................................................................................70 
Appendix B 
List of Laboratory Analytes .............................................................................77 
Appendix C 
PK Sampling Schedule ....................................................................................79 
Appendix D 
Grading Scale for Adverse Events Relating to Laboratory Abnormalities......83 
Appendix E 
Additional Laboratory Tests for Patients with Platelet Count ˂ 100,000/mm387 
 
 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ................................................................................... 38 
Table 2 
Study Drug Dosing Information ........................................................................... 39 
Table 3 
Actions in Patients with Low Platelet Count ........................................................ 46 
 
TABLE OF FIGURES 
Page 
Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of 
apo(a) Covalently Bound to apoB..........................................................................22 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 681257-CS6 
Protocol Title: 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging 
Phase 2 Study of ISIS 681257 Administered Subcutaneously to 
Patients with Hyperlipoproteinemia(a) and Established 
Cardiovascular Disease (CVD) 
Amendment Number: 
3 
Amendment Date: 
9 December 2016 
 
The following table summarizes the history of amendments to the protocol of Study 
ISIS 681257-CS6.  None of the antecedent versions of the study protocol has been enacted 
clinically and therefore no patients have been enrolled prior to issuance of Amendment 3. 
Protocol Version 
Date 
Rationale for Amendments 
Original Protocol  
15 August 2016 
 
Amendment 1 
6 October 2016 
Regulatory advice on inclusion of more 
detailed description of processes for 
platelet monitoring, and more frequent 
monitoring of liver function. 
Amendment 2 
29 November 2016 
Regulatory advice on inclusion of 
biomarkers of renal damage and increased 
frequency of renal monitoring. 
Amendment 3 
9 December 2016 
The study population was increased to 
270 patients (54 per cohort) to support a 
statistical assessment of risk of platelet 
reduction in this population.  In addition, the 
treatment cohorts have been modified to 
reflect both potential doses and dose 
regimens. 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
10 
PROTOCOL SYNOPSIS 
Protocol Title 
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of 
ISIS 681257 Administered Subcutaneously to Patients with Hyperlipoproteinemia(a) and 
Established Cardiovascular Disease (CVD)  
Study Phase 
2 
Indication 
Patients with hyperlipoproteinemia(a) and established CVD. 
Investigational Drug 
ISIS 681257 is a second generation 2ʹ-MOE modified, GalNAc3–conjugated antisense 
oligonucleotide inhibitor of apolipoprotein (a) [apo(a)]. 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy 
and safety of different doses and dosing regimens of ISIS 681257 for reduction of 
plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established CVD. 
Secondary Objective(s) To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein 
cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on 
apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose 
regimens in patients with hyperlipoproteinemia(a) and established CVD. 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio to receive ISIS 681257 or 
placebo.  This number was chosen to provide statistical power for both efficacy and 
safety assessments.  Study Drug (ISIS 681257 or placebo) will be administered SC 
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 enrolled patient 
reaches 6 months of exposure.  All patients will then enter a 16-week post-treatment 
follow-up period. 
The primary efficacy and safety analysis time point is at Week 25 for patients who 
received every 4-week dosing (Cohorts A-C) and at Week 27 for patients who received 
every 2-week or weekly dosing (Cohorts D and E, 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 (as needed) data collected on ISIS 681257 during this 
study, both individual events and aggregate data.   
Number of Subjects 
Approximately 270 
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. 
Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, 
or peripheral artery disease 
4. 
Lp(a) plasma level ≥ 60 mg/dL 
5. 
Must be on standard-of-care preventative therapy for other than elevated Lp(a) 
CVD risk factors 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
11 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Inclusion Criteria 
6. 
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 
7. 
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 16 weeks after the last dose of Study 
Drug (ISIS 681257 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 
8. 
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 16 weeks after the last dose of ISIS 681257 
Exclusion Criteria 
1. 
Within 6 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 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  

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
12 
PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria 
10. Patients with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse 
12. Clinically-significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion, including the following: 
a. 
Urine protein/creatinine (P/C) ratio ≥ 0.25 mg/mg.  In the event of a P/C ratio 
above this threshold, eligibility may be confirmed by a quantitative total urine 
protein measurement of ˂ 500 mg/24-hr 
b. 
Positive test (including trace) for blood upon urinalysis.  In the event of a 
positive test, eligibility may be confirmed with a urine microscopy showing 
≤ 5 red blood cells (RBCs) per high power field 
c. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x 
ULN 
d. 
Estimated GFR ˂ 60 mL/min (as determined by the Cockcroft-Gault Equation 
for creatinine clearance) 
e. 
Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s 
syndrome in which case total bilirubin must be ≤ 3 mg/dL 
f. 
Alkaline phosphatase (ALP) > ULN  
g. 
Platelet count ˂ LLN 
13. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
14. Treatment with another investigational drug, biological agent, or device within 
1 month of Screening, or 5 half-lives of investigational agent, whichever is longer 
15. Treatment with any 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 
16. BMI > 40 kg/m2  
17. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
18. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator 
19. 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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL
Amendment 3
Protocol 
9 December 2016
 
13 
PROTOCOL SYNOPSIS Continued 
Treatment Groups 
Patients will be randomized to 5 parallel cohorts: 
Cohort A (n = 54): Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort B (n = 54):  Patients will be randomized 5:1 to receive 40 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort C (n = 54):  Patients will be randomized 5:1 to receive 60 mg ISIS 681257 
or placebo SC once every 4 weeks for up to 13 doses. 
Cohort D (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every 2 weeks for up to 26 doses. 
Cohort E (n = 54):  Patients will be randomized 5:1 to receive 20 mg ISIS 681257 
or placebo SC every week for up to 52 doses. 
Cohort 
Treatment 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 or placebo
(Every 4 weeks) 
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 or placebo 
(Every 4 weeks) 
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 or placebo
(Every 2 weeks) 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 or placebo
(Every week) 
≤ 52 
≤ 1040 mg 
 
Study Drug Dosage 
and Administration 
The Sponsor will provide ISIS 681257 in a concentration of 100 mg/mL and matching 
volume placebo: 
Cohort A:  20 mg every 4 weeks ISIS 681257 or placebo (0.2 mL) 
Cohort B:  40 mg every 4 weeks ISIS 681257 or placebo (0.4 mL) 
Cohort C:  60 mg every 4 weeks ISIS 681257 or placebo (0.6 mL) 
Cohort D:  20 mg every 2 weeks ISIS 681257 or placebo (0.20 mL) 
Cohort E:  20 mg every week ISIS 681257 or placebo (0.20 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 study, ISIS 681257-CS1, evaluated 3 multiple-dose cohorts of 
ISIS 681257, 10 mg, 20 mg, and 40 mg.  Subjects were randomized (8:2 active:placebo) 
to receive ISIS 681257 for a total of 6 doses administered by SC injection:  3 doses 
during the first week and then once a week for the next 3 weeks.  These doses at this 
frequency of administration were found to be generally well-tolerated and to induce 
clinically-relevant reductions in LP(a). 
The range of dosing proposed for the present study will provide the equivalent drug 
exposure of 5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and is predicted 
(based on modelling of PK/PD data obtained in Phase 1 study) to result in mean 
reductions from baseline in plasma Lp(a) ranging from approximately 60% to 85% at 
steady-state.  
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to 
bring almost all patients with hyperlipoproteinemia(a) into the normal range (Lp(a) 
≤ 30 mg/dL). 

ISIS 681257-CS6 
CONFIDENTIAL
Amendment 3
Protocol 
9 December 2016
 
14 
PROTOCOL SYNOPSIS Continued 
Rationale for Dose and 
Schedule Selection 
Continued 
The present study will also evaluate safety and efficacy at different dosing frequencies:  
every 4 weeks, every 2 weeks, and weekly.  Patients with hyperlipoproteinemia(a) 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.  Dosing regimens of 20 mg every 2 weeks and 
40 mg every 4 weeks will test if similar monthly exposure, at different frequencies of 
administration, will achieve similar safety and similar level of Lp(a) reduction since the 
reduction achieved by a given dose level is principally driven by total exposure, while 
individual dose levels and the related peak concentration (Cmax) may influence tolerance 
and safety. 
Adjustment of Dose 
and/or Treatment 
Schedule 
Dose adjustments, including dose interruptions, and/or decreasing the dose 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 are outlined in Section 6, 
Appendices A and C. 
All patients enrolled will be randomized to a minimum of 6 months of treatment in 1 of 
5 treatment cohorts.  On completion of the 6 months, patients may continue treatment 
within the same randomized cohort until the last enrolled patient reaches 6 months of 
exposure (for continuing safety assessments), with a maximal exposure period of 12 
months. 
The study for an individual patient will generally consist of the following periods: 
An up to 4-week screening period 
An up to 52-week treatment period during which Study Drug will be administered per 
assigned cohort by SC injection 
A 16-week post-treatment follow-up period 
Patients in Cohorts A through C will receive up to 13 SC doses of ISIS 681257 or 
placebo every 4 weeks.  Patients in Cohort D will receive up to 26 SC doses of 
ISIS 681257 or placebo every 2 weeks and patients in Cohort E will receive up to 
52 weekly SC doses of ISIS 681257 or placebo.  Patients will return regularly for 
outpatient visits throughout the treatment and post-treatment follow-up periods according 
to the Schedule of Procedures (Appendix A). 
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 and use of concomitant 
medications.  Safety and tolerability results, including results of laboratory tests related 
to the monitoring rules for platelets, liver and renal functions, in patients dosed with 
ISIS 681257 will be compared with those dosed with placebo. 
Efficacy Evaluations 
The primary analysis time point is at Week 25 for patients who received every 4-week 
dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly 
dosing (Cohorts D and E, respectively). 
The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary 
analysis time point for ISIS 681257 treatment groups compared to placebo. 
The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at 
the primary analysis time point on the following: 
• 
Percent change from baseline in LDL-C  
• 
Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL 
• 
Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL, 
• 
Percent change from baseline in apoB 
• 
Percent change from baseline in OxPL-apo(a) 
• 
Percent change from baseline in OxPL-apoB 

ISIS 681257-CS6 
CONFIDENTIAL
Amendment 3
Protocol 
9 December 2016
 
15 
PROTOCOL SYNOPSIS Continued 
Pharmacokinetic 
Evaluations 
Plasma samples will be taken from all patients for the measurement of ISIS 681257 
plasma trough levels throughout treatment and during the post-treatment follow-up 
period.  In addition, in a subset of patients (approximately 12 patients per cohort), more 
frequent plasma samples will be taken following the Day 1 and Day 169 doses (for 
Cohorts A, B, and C) or following the Day 1 and Day 183 doses (for Cohorts D and E) to 
determine PK parameters.  Plasma sample collection time points are detailed in 
Appendices A and C. 
The plasma ISIS 681257 levels over time will be descriptively summarized by treatment 
with stratification by subject immunogenicity status.  Apparent terminal elimination half-
life will be calculated in patients who received ISIS 681257 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 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 Lp(a) between 
ISIS 681257 treated groups and placebo group in the Full Analysis Set. 
The data will be analyzed using an ANCOVA model with the baseline Lp(a) 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 plasma Lp(a) 
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. 
Sample Size Considerations: 
Efficacy: 
Based upon prior clinical trial experience with ISIS 681257, it is estimated that the 
standard deviation of the percent change in Lp(a) is approximately 20%.  With 
23 patients in each ISIS 681257 treatment group and 23 in placebo group there would 
be approximately 90% power to detect a 20% difference in percent change in Lp(a) 
levels between the ISIS 681257 treatment groups and placebo group at an alpha level of 
0.05, assuming 30% reduction in the ISIS 681257 patients and 10% reduction in the 
placebo patients. 
Safety: 
Based upon prior clinical trial experience with ISIS ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in 
the ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, 
with 45 patients in each ISIS 681257 treatment group, there would be approximately 
80% power to detect at least 1 event. 
A total of approximately 270 patients (54 patients per cohort, including 45 patients per 
cohort treated with ISIS 681257) will be randomized to ensure that both the safety and 
efficacy of ISIS 681257 will be adequately characterized in the study. 
Sponsor/Collaborator 
Ionis Pharmaceuticals/Akcea Therapeutics 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
16 
STUDY DESIGN AND TREATMENT SCHEMA 
 
 
SCREENING PERIOD 
Weeks -4 to -1 
TREATMENT PERIOD 
Weeks 1 to 52* 
Dosing per assigned cohort: 
Cohorts A, B, and C:  Every 4 weeks SC 
administration of 20, 40, or 60 mg ISIS 681257 or 
placebo 
Cohort D:  Every 2 weeks SC administration of 
20 mg ISIS 681257 or placebo 
Cohort E:  Every week SC administration of 20 mg 
ISIS 681257 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 enrolled patient reaches 6 months 
of exposure. 
POST-TREATMENT 
EVALUATIONS 
Weeks 4, 10, and 16 after last dose of 
Study Drug 
3 clinical visits for safety, efficacy,  
PK and PD assessments 
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 (16 Weeks 
after last dose of Study Drug) 

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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 
apo(a) 
apolipoprotein(a) 
apoB 
apolipoprotein B 
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 
CMV 
cytomegalovirus 
CRF 
case report form 
CRP 
C-reactive protein 
CVD 
cardiovascular disease 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
dL 
deciliter 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
DNA 
phosphorothioate-modified oligodeoxynucleotides 
DSMB 
Data and Safety Monitoring Board 
CKD-EPI 
Chronic Kidney Disease –Epidemiological Collaboration 
Cys C 
Cystatin C 
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 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hr, hrs 
hour(s) 
hsCRP 
CRP measured by high sensitivity assay 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1 beta 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISIS 681257 
antisense inhibitor of apolipoprotein (a) 
IV 
intravenous(ly) 
IXRS 
interactive voice/internet response system 
KIM-1 
kidney injury molecule 1 
kg 
kilogram 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
L 
Liter 
LLN 
lower limit of normal 
m2 
square meter 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram 
MI 
myocardial infarction 
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 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
OxPL 
oxidized phospholipids 
PAD 
peripheral arterial disease 
PBS 
phosphate buffered saline 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PLA2 
Lp(a)-associated Lp-phospholipase A2 
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 

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STUDY GLOSSARY Continued 
Abbreviation 
Definition 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Drug 
ISIS 681257 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
Tg 
transgenic 
Tmax 
time to maximal concentration 
UACR 
urine albumin -creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein- creatinine ratio 
WBC 
white blood cell 
WMA 
World Medical Association 
 
 
 

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1. 
OBJECTIVES 
1.1 
Primary Objective 
To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy and 
safety of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) 
levels in patients with hyperlipoproteinemia(a) and established cardiovascular disease (CVD). 
1.2 
Secondary Objective(s) 
To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol 
(LDL-C), apolipoprotein B (apoB), oxidized phospholipids (OxPL) on apolipoprotein (a) 
[apo(a)] [OxPL-apo(a)] and OxPL on apoB (OxPL-apoB). 
To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in 
in patients with hyperlipoproteinemia(a) and established CVD. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
2.1.1 
Lipoprotein (a) 
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein (Figure 1, Koschinsky and Marcovina 2004) 
in which the apoB component of LDL is linked by a disulfide bond to apolipoprotein(a) [apo(a)], 
the distinct protein component of Lp(a) that is mainly responsible for its signature structural and 
functional properties (Dubé et al. 2012; Kronenberg and Utermann 2013).  Lp(a) is now 
recognized as an independent, genetic, causal risk factor for coronary artery disease (CAD), 
stroke, peripheral arterial disease (PAD), and calcific aortic stenosis (Erquo et al. 2009; 
Nordestgaard et al. 2010; Thanassoulis et al. 2013). 
 

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Figure 1 
Schematic Representation of the Lp(a) Particle.  Lp(a) is Composed of apo(a) 
Covalently Bound to apoB 
Apo(a) contains 10 unique units of kringle IV repeats, of which KIV2 are present in variable copies (1 to > 40) 
conferring structural heterogeneity to Lp(a).  Apo(a) also contains kringle V and an inactive protease-like (P) 
domain.  In this model, 4 KIV2 repeats are shown.  Lp(a) also contains OxPL in the lipid phase of apoB as 
well as covalently bound to apo(a). 
 
Plasma levels of Lp(a) vary substantially among individuals, and most of this variation reflects 
the effects of genetic variation in the LPA gene which encodes the apo(a) protein. 
A second contributor to plasma-level variability are LPA single nucleotide polymorphisms 
(SNPs) that can be associated with either higher or lower Lp(a) levels (Clarke et al. 2009; 
Li et al. 2011).  Significant associations exist between 2 particular LPA variants, rs10455872 and 
rs3798220, increased Lp(a) levels, CVD, and aortic stenosis, with the CVD risk primarily 
mediated by Lp(a) plasma levels rather than an independent effect of the SNPs (Clarke et al. 
2009; Li et al. 2011). 
Lp(a) plasma levels are generally inversely associated with apo(a) size, and can vary by 
> 1,000-fold (0.1 to > 250 mg/dL or ˂ 0.25 to > 625 nmol/L) between individuals (Merki et al. 
2011).  Despite this inter-individual variation, intra-individual Lp(a) levels are thought to be 
generally stable over time along a pre-set genetically determined levels without significant 
impact from dietary or environmental factors, mediating CVD risk throughout the patient’s 
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2.1.2 
Pathophysiology 
Lp(a) adheres to plaque sites and is retained in the artery wall and has proatherogenic and 
pro-inflammatory properties due to its LDL and apo(a) components (Spence and Koschinsky 
2012).  In addition, Lp(a) may be prothrombotic by inhibiting fibrinolysis because of its 
structural similarity to plasminogen and its enhancement of platelet aggregation (Rand et al. 
1998).  In vitro studies have provided evidence for both of these pathogenic mechanisms, but 
in vivo data are not definitive (Dubé et al. 2012).  In humans, Lp(a) is the main lipoprotein 
carrier of OxPL, which may drive the risk associated with Lp(a) (Bergmark et al. 2008; 
Leibundgut et al. 2013; Tsimikas et al. 2014).  In fact, OxPL measured on apoB (OxPL-apoB), 
which largely reflect the OxPL on Lp(a), have been shown to be a prognostic indicator for future 
CV events (Tsimikas et al. 2010; Tsimikas et al. 2012; Tsimikas et al. 2014).  OxPL associated 
with Lp(a) can be subjected to degradation by the Lp(a)-associated Lp-phospholipase A2 (PLA2), 
implicating Lp(a) in novel proinflammatory and atherogenic pathways (Kiechl et al. 2007). 
Hyperlipoproteinemia(a) in humans is associated with increased risk of cardiac death, 
myocardial infarction (MI), stroke, aortic stenosis, and peripheral arterial disease (PAD), 
particularly in subjects with small apo(a) isoforms (Bennett 2008; Erqou et al. 2009; Erqou et al. 
2010; Bertoia et al. 2013; Thanassoulis et al. 2013).  Although prospective, randomized, 
controlled outcomes studies have not been conducted, epidemiological, genome-wide association 
and Mendelian randomized controlled study data to date provide supporting evidence for a role 
of Lp(a) as a risk factor for CVD (Kamstrup et al. 2009).  For example, in the Copenhagen City 
Heart Studies of 42,000 subjects with a 15-year follow-up (Kamstrup et al. 2009) using a 
Mendelian randomization approach, higher Lp(a) levels were related to risk of MI. 
2.1.3 
Current Treatment Options 
In 2010, the European Atherosclerosis Society (EAS) Consensus Panel recommended screening 
for elevated Lp(a) in people at moderate to high risk of CVD to reach a treatment goal of 
˂ 50 mg/dL (125 nmol/L), after therapeutic management of LDL-C (Nordestgaard et al. 2010).  
Approximately 20% of people are estimated to have plasma Lp(a) levels over 50 mg/dL 
(125 nmol/L) and approximately 0.3% to have levels over 175 mg/dL (438 nmol/L).  There are 
no gender differences in Lp(a) concentrations but racial differences have been observed, with 
whites and Asians having lower levels while blacks and Hispanics generally have somewhat 
higher levels (Nordestgaard et al. 2010). 
Lifestyle and diet are thought to have little impact on an individual’s Lp(a) level.  Current 
treatment recommendations from the EAS Consensus Panel are limited to the use of 1 to 3 g of 
niacin (nicotinic acid) daily which could result in an up to 30% reduction in Lp(a).  However, 
niacin is associated with side effects (e.g., flushing) that reduce patient tolerability and 
compliance (Parker et al. 2006; Guyton 2007). 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are neither indicated nor 
formally recommended for treatment of hyperlipoproteinemia(a) but have been reported to 
reduce Lp(a) levels by ~20%-35% in patients with hypercholesterolemia (Desai et al. 2013; 
Raal et al. 2015). 
The other current option for patients with significantly elevated Lp(a) levels (≥ 60 mg/dL) is 
lipoprotein apheresis, either general lipoprotein apheresis (Jaeger et al. 2009;  

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Leebmann et al. 2013; Rosada et al. 2014) or Lp(a)-specific apheresis (Safarova 2012).  While 
very effective at acutely lowering Lp(a) (acute and interval Lp(a) reductions of > 60% and 
> 30% respectively), this treatment option is expensive, burdensome for patients, and 
unavailable/not reimbursed in many countries and regions. 
2.2 
Therapeutic Rationale 
Therapeutic modalities to reduce Lp(a) levels in humans are few, and there are no drugs 
currently available that specifically target Lp(a) alone.  Antisense oligonucleotides (ASOs) are 
emerging as viable therapeutic agents to treat disorders where overexpression of proteins is 
associated with a disease process.  Apo(a) is synthesized primarily in the liver, a target organ for 
ASOs, where it is subsequently covalently linked to the apoB-100 component of LDL to form 
the Lp(a) lipoprotein.  The goal of treatment with ISIS 681257 is to reduce the production of 
apo(a) in the liver and thus, the level of Lp(a) lipoprotein by using an ASO directed against the 
messenger ribonucleic acid (mRNA) of apo(a).  It has been hypothesized that a pharmacologic 
reduction in Lp(a) could slow down or reverse CVD by reducing thrombotic, atherogenic, or 
inflammatory events in patients with elevated Lp(a) levels (Nordestgaard et al. 2010). 
Importantly, there is no evidence that lowering Lp(a) will result in adverse consequences in 
individuals, and there are no reports linking very low Lp(a) to any deleterious effects. 
2.3 
ISIS 681257 
Please refer to the ISIS 681257 Investigator’s Brochure for more details on ISIS 681257 
mechanism of action, chemistry, pre-clinical and clinical experience.  The summary is provided 
below. 
2.3.1 
Mechanism of Action 
ISIS 681257 is a second-generation ASO drug targeted to apo(a), that has been covalently 
bonded to triantennary N-acetyl galactosamine (GalNAc3), a high-affinity ligand for the 
hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO-GalNAc3 conjugate.  
This GalNAc3-conjugate approach results in enhanced ASO delivery to hepatocytes versus 
non-parenchymal cells and has increased ASO potency by approximately 10-fold compared to 
unconjugated ASOs in mice (Prakash et al. 2014). 
The ASO portion of ISIS 681257 is complementary to a region spanning the Exon 24-25 splice 
site at position 3901 of apo(a) transcript sequence (NM_005577.2) and binds to the mRNA by 
Watson and Crick base pairing.  The hybridization (binding) of ISIS 681257 to the cognate 
mRNA results in the Ribonuclease H1 (a non-specific endonuclease that catalyzes the cleavage 
of RNA via hydrolytic mechanism RNase H1-mediated degradation of the apo(a) mRNA, thus 
preventing production of the apo(a) protein).  Maximal antisense-mediated reduction of target 
mRNA levels is typically greater than 90% of control levels in sensitive tissues (Zhang et al. 
2010).  Furthermore, reduction in target mRNA levels using this approach correlates directly 
with a subsequent reduction in target protein levels.  
ISIS 681257 does not have any complementary homology to plasminogen mRNA (Graham et al. 
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2.3.2 
Chemistry 
Chemically, ISIS 681257 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate and phosphodiester linkages (mixed backbone 
design).  The mixed backbone design reduces the total number of phosphorothioate linkages, 
which reduces non-specific interactions with proteins and further enhances potency of GalNAc3 
conjugated ASOs. 
Structurally, the oligonucleotide has 4 regions.  Two (2) of them, the 5 nucleotides at the 5′ end 
and the 5 nucleotides at the 3′ end, are composed of 2′-O-(2-methoxyethyl) (2′-MOE)-modified 
ribonucleotides.  These MOE-modified nucleotides confer (1) increased affinity for the target 
mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to exonucleases and 
endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and (3) amelioration of 
some of the high-dose toxicities, thereby resulting in an improved safety profile compared to 
first-generation antisense drugs containing phosphorothioate-modified oligodeoxynucleotides 
(DNA) (Henry et al. 2000).  The third region, the central portion of the oligonucleotide, is 
composed of 10 oligodeoxynucleotides.  This chimeric design is called a MOE-Gapmer, and 
ISIS 681257 employs this chimeric structure to enable use of the ubiquitous endonuclease that 
specifically hydrolyzes the RNA strand in RNA/DNA hybrids (RNase H1)-mechanism for 
antisense activity.  This is because while the 2′-MOE modification confers increased stability and 
affinity, it does not support RNase H1-catalyzed cleavage of RNA hybridized to 2′-MOE-
modified nucleotides (McKay et al. 1999).  The fourth region is composed of a triantennary 
cluster of GalNAc3 sugars that is linked to the 5ʹ end of ISIS 681257 via a phosphodiester 
linkage.  The GalNAc3 cluster is a high affinity ligand for the ASGPR, a receptor expressed 
primarily on the surface of liver hepatocytes (Stockert 1995).  The GalNAc3 cluster enhances 
delivery of ISIS 681257 to liver hepatocytes over other cell types and enhances potency.  After 
internalization into cells, the GalNAc3 cluster is metabolized to release “free ASO” inside the 
cell (Prakash et al. 2014). 
2.3.3 
Preclinical Experience 
The pharmacology of ISIS 681257 has been examined in apo(a) transgenic (Tg) mice which 
express the entire human apo(a) genomic sequence (Frazer et al. 1995) and nonhuman primates. 
Administration of ISIS 681257, a human apo(a) antisense inhibitor, to mice containing the 
human apo(a) transgene produced dose-dependent reductions in human apo(a) liver mRNA and 
apo(a) plasma protein after 6 weeks of ASO administration at 0.3, 1, 3, and 10 mg/kg/wk. 
When ISIS 681257 was administered to normal chow fed cynomolgus monkeys for 4 weeks at 
the dose of 12 mg/kg/wk, it significantly reduced hepatic apo(a) mRNA by 90% relative to the 
cohort administered phosphate buffered saline (PBS).  As there is an 80% sequence conservation 
between apo(a) and plasminogen nucleotide sequences, plasminogen mRNA levels were also 
measured, and no change compared to the PBS cohort was observed. 
Findings from the chronic toxicology studies with ISIS 681257 (the 26-week mice and 39-week 
monkey studies) were similar to those observed in the 4- and 6-week studies and were not 
considered adverse.  The plasma and tissue concentrations observed for ISIS 681257 in mice and 
monkeys were generally similar to those observed for other unconjugated 20-mer 2ʹ-MOE ASOs 
in this chemical class with and without GalNAc3-conjugation.  However, the proportion of drug 

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in hepatocytes compare to nonparenchymal liver cells was greater for ISIS 681257, compared to 
the parent drug ISIS 494372 (without GalNAc3-conjugation), which is the basis for increased 
potency of ISIS 681257 (unpublished results; Geary et al. 2003; Yu et al. 2007; Prakash et al. 
2016). 
The most noteworthy safety finding in the chronic monkey study was a marked platelet reduction 
that occurred in 2 male monkeys in the high-dose group (20 mg/kg/wk) and 1 female animal in 
the mid-dose (10 mg/kg/wk) group beginning on Days 44-135, which led to the subsequent early 
termination (ET) of these 3 animals.  An additional male monkey in the 10 mg/kg/wk dose group 
had a moderate decrease in platelets that was successfully treated with steroids, and was 
terminated at the scheduled 6-month interim sacrifice.  There were no platelet reductions or other 
toxicologically significant findings in monkeys treated with 2 mg/kg/wk for up to 39 weeks.  
There were no marked platelet reductions in mice at doses up to 70 mg/kg/wk for 26 weeks.  
However, mice exposed to ISIS 681257 at doses of ≥ 10 mg/kg/wk for up to 26 weeks showed 
evidence of adverse hepatobiliary effects in both sexes as indicated by increases in ALT (up to 
+ 10.3x), AST (up to + 10.4x), and/or ALP (+ 2.5x).  
Detailed information concerning the preclinical pharmacology and toxicology studies conducted 
with ISIS 681257 can be found in the Investigator’s Brochure. 
2.3.4 
Clinical Experience 
To date, ISIS 681257 has been studied in a single Phase 1 clinical trial of 45 healthy subjects.  
ISIS 681257-CS1 was a Phase 1 double-blind, placebo-controlled, dose-escalation study 
designed to assess the safety, tolerability, PK, and pharmacodynamics (PD) of single and 
multiple doses of ISIS 681257 administered subcutaneously (SC) to 45 healthy subjects with 
Lp(a) ≥ the upper limit of normal (ULN) (30 mg/dL).  Twenty one (21) subjects received 10 to 
120 mg SC (10, 20, 40, 80, and 120 mg) as a single-dose, and 24 subjects received 10, 20, and 
40 mg as multiple doses (6 doses in 22 days:  3 loading doses during the first week on alternate 
days [Days 1, 3, and 5], and then once a week for the next 3 weeks [Days 8, 15, and 22]). 
There were no serious adverse events (SAEs), or clinically-relevant changes in laboratory 
assessments and all subjects completed the treatment and post-treatment follow-up periods. 
Constitutional symptoms such as fever, chills, increase in body temperature and arthralgias have 
been observed following parenteral administration of ASOs, primarily during the initial dosing 
period.  Following SC administration of ISIS 681257 constitutional symptoms were observed in 
4 of the 6 subjects who received a single-dose of 120 mg.  The symptoms were mild in severity 
and resolved spontaneously with or without treatment with acetaminophen. 
Fluctuations in platelet counts to below the lower limit of normal were observed in 5 study 
subjects on active drug and across doses.  These changes were not considered adverse or 
clinically-significant by the Investigator and did not appear to be dose related. 
Two (2) mild AEs of redness at the site of injection occurred 48 to 72 hours after administration 
in 1 subject who received ISIS 681257 in the 20 mg multiple-dose cohort.  Both AEs resolved by 
the time of the subject’s next visit. 

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Following SC administration, ISIS 681257 was absorbed rapidly into the systemic circulation, 
with median time to maximum plasma concentrations (Tmax) ranging from 1 to 4 hours.  Similar 
Tmax values were observed at all dose levels.  Maximum observed plasma concentrations (Cmax) 
and AUC0-24hr were dose-dependent over the studied SC dose range.  The mean peak (Cmax) and 
total exposure (AUC0-24hr) increased proportionally with dose at dose levels ranging from 10 to 
40 mg, and greater than dose proportionally at dose levels ranging from 40 to 120 mg. 
After reaching Cmax, mean plasma concentrations of ISIS 681257 declined in a biphasic fashion 
over time, with an initial, relatively fast distribution phase that dominated the plasma clearance 
followed by a slower elimination phase.  Characterization of the terminal elimination phase 
yielded an apparent terminal elimination half-life of approximately 3 to 4 weeks over a dose 
range of 10 to 120 mg (either single- or multiple-dose), and appeared to be independent of dose.  
This result is consistent with the slow elimination of ISIS 681257 observed from monkey tissues, 
and the comparatively long elimination half-lives observed for this chemical class. 
Plasma trough concentrations (168 hours or 7 days from previous dose) monitored during the 
treatment period in the multiple-dose cohorts increased with increasing dose, consistent with 
expectations (based on preclinical assessments and experience with other compounds of this 
chemical class) that trough plasma concentrations reflect exposure in tissues.  Plasma trough 
concentrations did not increase greatly after the loading period (Day 15), suggesting that 
accumulation in major tissues of distribution had approached steady-state after the loading 
period. 
Overall, the human PK of ISIS 681257 are consistent with the expected PK for compounds 
within this chemical class. 
Detailed information concerning the Phase 1 clinical study conducted with ISIS 681257 can be 
found in the Investigator’s Brochure and recent publication (Viney et al. 2016).   
2.4 
Rationale for Dose and Schedule of Administration 
The Phase 1 study, ISIS 681257-CS1, evaluated 3 multiple-dose cohorts of ISIS 681257, 10 mg, 
20 mg, and 40 mg.  Subjects were randomized (8:2 active:placebo) to receive ISIS 681257 for a 
total of 6 doses administered by SC injection:  3 doses during the first week and then once a 
week for the next 3 weeks.  These doses at this frequency of administration were found to be 
generally well-tolerated and to induce clinically-relevant reductions in LP(a).  
The range of dosing proposed for the present study will provide the equivalent drug exposure of 
5 mg, 10 mg, 15 mg, and 20 mg administered weekly, and is predicted (based on modelling of 
PK/PD data obtained in Phase 1 study) to result in mean reductions from baseline in plasma 
Lp(a) ranging from approximately 60% to 85% at steady-state. 
The highest dose selected for this study, 20 mg per week, is predicted to provide an 
approximately 85% reduction in Lp(a) at steady-state that is expected to be sufficient to bring 
almost all patients with hyperlipoproteinemia(a) into the normal range (Lp(a) ≤ 30 mg/dL). 
The present study will also evaluate safety and efficacy at different dosing frequencies:  every 
4 weeks, every 2 weeks, and weekly.  Patients with hyperlipoproteinemia(a) will require chronic 
treatment and thus every 2 weeks or every 4 weeks dosing regimens, if safe and well-tolerated, 

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may provide advantages over weekly dosing in terms of convenience and compliance for 
patients.  Dosing regimens of 20 mg every 2 weeks and 40 mg every 4 weeks will test if similar 
monthly exposure, at different frequencies of administration, will achieve similar safety and 
similar level of Lp(a) reduction since the reduction achieved by a given dose level is principally 
driven by total exposure, while individual dose levels and the related peak concentration (Cmax) 
may influence tolerance and safety.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study.  
Approximately 270 patients will be randomized in a 5:1 ratio (225 ISIS 681257 and 45 placebo) 
to receive ISIS 681257 or placebo.  Study Drug (ISIS 681257 or placebo) will be administered 
SC 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. 
The treatment portion of the study will be terminated when the last enrolled patient reaches 
6 months of exposure.  All patients will then enter a 16-week post-treatment follow-up period 
irrespective of antecedent duration of treatment. 
The primary analysis time point is at Week 25 for patients who received every 4-week dosing 
(Cohorts A-C) and at Week 27 for patients who received every 2-week dosing or weekly dosing 
(Cohorts D and E, respectively).  For patients continuing treatment beyond the primary analysis 
time point additional supportive efficacy analysis (to evaluate whether the treatment effect is 
maintained) and safety analysis (for the purpose of dose(s) selection) will be repeated at the 
completion of Study Drug treatment. 
Patients ≥ 18 and ≤ 80 years old with elevated plasma Lp(a) levels (≥ 60 mg/dL ) and a clinical 
diagnosis of CVD are eligible for enrollment upon meeting the study specific eligibility criteria.  
Patients will be on standard-of-care preventative therapy for other than elevated Lp(a) 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 
• Evidence of cardiac ischemia on exercise testing, or imaging study 
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).  Patients who are determined 
to be eligible, based on screening assessments, will be enrolled in the study at Day 1 and 

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randomly assigned to 1 of the 5 parallel dosing cohorts, with each cohort having a 5:1 ratio to 
receive ISIS 681257 or matching volume of placebo, respectively, by SC injection for a 
minimum of 6 months and up to 52 weeks. 
Following the End-of-Treatment, patients will enter the 16-week post-treatment follow-up 
period. 
3.2 
Number of Study Centers 
This is a multicenter, multinational study. 
3.3 
Number of Patients 
Approximately 270 patients will be randomized in this study, with approximately 54 patients 
assigned to each of the 5 treatment cohorts. 
3.4 
Overall Study Duration and Follow-up 
The length of patients’ participation in the study may be up to 18 months (72 weeks), which 
includes a 4-week screening period, an up to 52-week treatment period with Study Drug 
(ISIS 681257 or placebo), and a 16-week post-treatment follow-up period.  The treatment portion 
of the study will be complete when the last enrolled 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. 
3.4.2 
Treatment 
For each patient minimum treatment duration is 6 months and maximum of 52 weeks.  Patients 
will continue treatment in the study until the last patient enrolled reaches 6 months of exposure.  
All patients will then enter a 16-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 681257 or placebo) will be administered by SC injection once 
weekly, once every 2 weeks, or once every 4 weeks, depending on cohort assignment. 
3.4.3 
Post-Treatment 
Patients when completed dosing will enter the 16-week post-treatment follow-up period and will 
return to the Study Center for 3 follow-up visits 4, 10, and 16 weeks after their last injection of 
Study Drug as per Appendix A (Follow-up). 
The final study visit for each patient will be 16 weeks after the last dose of Study Drug. 
3.5 
End-of-Study 
The End-of-Study is defined as last patient, last visit. 

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3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be established to review safety, 
tolerability and efficacy (as needed) data collected on ISIS 681257 during this study.  The 
DSMB will be constituted to include expertise in medical specialties relevant to the safety of 
antisense drugs (nephrology, hepatology, hematology), and the underlying disease state of the 
patients (cardiology).  Specialist members of the DSMB will be informed and consulted on all 
relevant treatment-related SAEs, and changes of relevant laboratory parameters that trigger 
stopping rules (Section 8.6) within 48 hours of receipt of such results.  In addition, all accrued 
safety data relevant to each of medical area specialist will be forwarded at regular intervals for 
review.  
Based on its ongoing assessment of the safety and tolerability of ISIS 681257, 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). 
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 
1:1:1:1:1 ratio to 1 of the 5 parallel-dose cohorts (Cohorts A, B, C, D, or E).  Within each dose 
cohort, patients will be randomized in a 5:1 ratio to receive ISIS 681257 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. 

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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 a 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). 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria at 
within 4 weeks of Study Day 1or 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. Clinical diagnosis of CVD defined as documented coronary artery disease (CAD), stroke, 
or peripheral artery disease 
4. Lp(a) plasma level ≥ 60 mg/dL  
5. Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk 
factors  
6. 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, proprotein convertase subtilisin/kexin type 9 
[PCSK9s] 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 
7. Females:  must be non-pregnant and non-lactating and either: 
a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) 
 

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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 16 weeks after the last dose of Study Drug 
(ISIS 681257 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 
8. 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 16 weeks 
after the last dose of ISIS 681257 
5.2 
Exclusion Criteria 
1. Within 6 months of Screening:  acute coronary syndrome, major cardiac surgery, or 
stroke 
2. Within 3 months of Screening:  coronary or peripheral arterial revascularization, major 
non-cardiac surgery, or lipoprotein apheresis  
3. Heart failure New York Heart Association (NYHA) class IV 
4. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg) 
5.  History of acute kidney injury within the past 12 months 
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 with a history of major bleed or high-risk of bleeding diathesis  
11. Recent history of, or current drug or alcohol abuse 
12. Clinically-significant abnormalities in screening laboratory values that would render a 
patient unsuitable for inclusion, including the following: 

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a. Urine protein/creatinine (P/C) ratio ≥ 0.25 mg/mg.  In the event of a P/C ratio above 
this threshold, eligibility may be confirmed by a quantitative total urine protein 
measurement of ˂ 500 mg/24-hr 
b. Positive test (including trace) for blood upon urinalysis.  In the event of a positive 
test, eligibility may be confirmed with a urine microscopy showing ≤ 5 red blood 
cells (RBCs) per high power field 
c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN 
d. Estimated GFR ˂ 60 mL/min (as determined by the Cockcroft-Gault Equation for 
creatinine clearance) 
e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in 
which case total bilirubin must be ≤ 3 mg/dL 
f. Alkaline phosphatase (ALP) > ULN 
g. Platelet count ˂ LLN 
13. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors 
14. Treatment with another investigational drug, biological agent, or device within 1 month 
of Screening, or 5 half-lives of investigational agent, whichever is longer 
15. Treatment with any 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 
16. BMI > 40 kg/m2  
17. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 
8 weeks of Screening 
18. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
19. 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 
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.  A 4-week period is provided for completing 
screening assessments and determining patient eligibility for the study.  Abnormal screening 

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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. 
6.1.2 
Treatment Period 
During the treatment period, patients will report to the study center for clinic visits.  Patients will 
receive 20 mg doses of Study Drug administered by SC injection once every 4 weeks for up to 
52 weeks in Cohort A, 40 mg doses of Study Drug administered by SC injection once every 
4 weeks for up to 52 weeks in Cohort B, 60 mg doses of Study Drug administered by SC 
injection once every 4 weeks for up to 52 weeks in Cohort C, 20 mg doses of Study Drug 
administered by SC injection once every 2 weeks for up to 52 weeks in Cohort D, or 20 mg 
doses of Study Drug administered by SC injection once per week for up to 52 weeks in Cohort E 
(Section 8.1). 
Collection and measurement of vital signs, physical examination results, ECGs, clinical 
laboratory parameters (Appendix B), ISIS 681257 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 12 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 681257.  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). 
6.1.3 
Post-Treatment Period 
Each patient will be followed for safety assessments for 16 weeks after their last dose of 
Study Drug.  During the post-treatment follow-up period, patients will return to the Study Center 
for 3 outpatient visits at Weeks 4, 10, and 16 after the last dose of Study Drug 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.  A list of these analytes is 
contained in Appendix B. 
Blood chemistry and urine samples (excluding 24-hour urine collection) should be taken be 
taken after fasting for at least 10 hours.  During this time the patient can drink water and they 
should ensure that they consume sufficient water in order to not become dehydrated.  

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If tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or 
missing, a repeat test specimen should be re-drawn as soon as possible (ideally within 1 week). 
Hematology samples will be collected every 14 days.  Each time a hematology lab is drawn and 
sent to the central laboratory for analysis, an additional sample must 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. 
Blood and urine samples for renal function testing and assessment of biomarkers of renal damage 
will also be collected every 14 days and sent to the central laboratory for analysis, per 
Section 8.5.2.  If there are no test results available within 14 days of the last set of results for 
parameters considered critical to patient safety, the Investigator will contact the patient to hold 
dosing until a new test set is obtained and reviewed. 
All lab samples sent to the central laboratory are received on the next day 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 on the day of sample collection, and should be entered as soon as 
possible into the eCRF to inform the Sponsor and CRO study monitoring teams. 
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 (Grade 3 or Grade 4) 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. 
All lab alerts received, including those related to platelet, liver, or renal function 
monitoring/stopping rules, are reviewed promptly by the Sponsor and the CRO Medical 
Monitors who discuss them and 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 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, the Investigator must also 
be contacted by phone.  

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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, B, and C at Weeks 5, 13, 21, 25, 33, 41, 49, and 53  
• Cohorts D and E at Weeks 5, 13, 21, 27, 33, 41, 49, and 53 
In all cohorts, ECGs will be conducted during the post-treatment follow-up period at 4, 10, and 
16 weeks after the last dose of Study Drug. 
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. 
6.2.4 
PK Sampling 
Blood samples for the determination of plasma ISIS 681257 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 16 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 16 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: 

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• 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 1 or more 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 
†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 before visits requiring fasted blood 
sampling. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 681257 or Placebo) characteristics are listed in Table 1. 
Study Drug (ISIS 681257 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. 

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7.1.1 
ISIS 681257 
ISIS 681257 vials contains 100 mg/mL ISIS 681257 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 681257 vials.  
Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 681257 
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 681257 or placebo) 
labeled in accordance with specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drug 
(ISIS 681257 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 681257 will be administered to patients by Study Center staff as follows: 
Cohort A: a single SC dose of 20 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort B: a single SC dose of 40 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 
Cohort C: a single SC dose of 60 mg once every 4 weeks for up to 52 weeks and a 
maximum of 13 doses 

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Cohort D: a single SC dose of 20 mg every 2 weeks for up to 52 weeks and a maximum of 
26 doses 
Cohort E: a single SC dose of 20 mg every week (weekly) for up to 52 weeks and a 
maximum of 52 doses 
Self-administration for patients in Cohorts D and E will be allowed after appropriate training of 
patient and/or caregiver. 
Patients in Cohorts A, B, and C should receive 1 dose every 4 weeks, patients in Cohort D 
should receive 1 dose every 2 weeks and patients in Cohort E 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 at least 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 681257 or placebo) preparation and administration 
Table 2 
Study Drug Dosing Information 
Cohort 
Treatment 
Volume to Administer/Dose 
# Doses 
Total ISIS 681257 
A 
20 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.2 mL  
≤ 13 
≤ 260 mg 
B 
40 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.4 mL  
≤ 13 
≤ 520 mg 
C 
60 mg ISIS 681257 
or placebo 
(Every 4 weeks) 
0.6 mL  
≤ 13 
≤ 780 mg 
D 
20 mg ISIS 681257 
or placebo 
(Every 2 weeks) 
0.2 mL 
≤ 26 
≤ 520 mg 
E 
20 mg ISIS 681257 
or placebo 
(Every week) 
0.2 mL 
≤ 52 
≤ 1040 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. 

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8.4 
Treatment Precautions 
No specific treatment precautions are required. 
8.5 
Safety Monitoring Rules 
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 Day 1. 
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 lower 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 681257 or placebo).  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  
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:  In the event of an initial clinical laboratory result that meets a stopping 
criterion, patients must not be re-dosed 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 681257 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 pharmacokinetic 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 pharmacokinetic 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. 

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All patients will have liver chemistry tests monitored every 2 weeks for the first 3 months of the 
study treatment, and monthly thereafter during the Treatment Period. 
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. 
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 and 
Medical Monitors. 

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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 
All patients will have renal function tests monitored every 2 weeks throughout the study.  
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. 
During the course of the study, urinary surveillance will include urinalysis to include urine 
albumin/creatinine ratio (UACR), urine protein/creatinine ratio (UPCR) and urinary red blood 
cells (RBCs), as well as serum creatinine to estimate glomerular filtration rate (eGFR), which 
will be monitored every 2 weeks.  In addition, biomarkers of acute renal injury will also be 
measured every 2 weeks (Appendix B).  Results that exceed predetermined alert values will be 
reviewed, together with related safety data, by the nephrologist on the DSMB as specified in the 
DSMB charter.  eGFR may also be evaluated based upon serum cys-C to further characterize the 
significance of changes in renal function or renal biomarkers. 
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:  Creatinine clearance (by CKD-EPI 
formula) decrease from baseline > 15%, urine Alb/C ratio (UACR) > 2.5 x ULN, or an increase 
in serum creatinine from baseline > 0.25 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. 
In the event of a confirmed (as described in Section 8.5) laboratory result meeting one or more of 
the following criteria, dosing with the Study Drug should be interrupted and the Study Medical 
Monitor informed. 
If any of the following changes from baseline in renal laboratory parameters should occur 
following from Day 1 of Study Drug administration:  
Creatinine clearance (by CKD-EPI formula) decrease from baseline > 25%, urine Alb/C 
ratio (UACR) > 5 x ULN, or an increase in serum creatinine from baseline > 0.5 mg/dL,  
the following additional renal tests should be immediately obtained:  
Fasting serum creatinine, urine culture, 24-hour urine sample for creatinine clearance and 
urine protein, urine microscopy sample with inspection of sediment. 

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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. 
8.5.3 
Safety Monitoring for Platelet Count Results 
All patients will have platelet counts monitored every 2 weeks for the duration of the study and 
must not receive Study Drug without an interpretable platelet count result in the prior 2 weeks.  
In addition, platelet function will be evaluated by aggregometry in all patients at each study site 
visit, with additional functional testing being performed at selected study centers.  
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.  
Lab alerts related to platelet monitoring/stopping rules are issued when:  1) platelet counts are 
< 140,000 mm3; 2) when platelet count is ≥ 30% decreased from baseline, or 3) when 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 D 
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 Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding or clinically-
relevant, non-major bleeding events (which are defined in Section 8.6.3), for example excess 
bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event occurs, the 
Investigator must notify the Sponsor Medical Monitor and additional testing of coagulation 
parameters activated partial thromboplastin time (aPTT), prothrombin time (PT), INR, hepatic 
enzymes, bilirubin and platelet count should be performed. 
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 symptoms should be discussed with the Sponsor Medical Monitor or 
designee to determine whether additional monitoring or laboratory tests are required. 

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8.6 
Stopping Rules  
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 
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 of an estimated creatinine clearance (by CKD-EPI formula) meeting any of the 
following criteria, or any change in renal biomarkers deemed by the nephrologist on the DSMB 
to require further evaluation, a serum creatinine and 24-hour urine sample for creatinine 
clearance and protein should be obtained: 
1. CKD-EPI decrease of > 50% from Baseline 
2. CKD-EPI value < 45 mL/min/1.73 m2 
Dosing of a patient with Study Drug (ISIS 681257 or placebo) will be stopped permanently if 
24-hour urine testing confirms any of the following values in the absence of an alternative 
explanation: 
1. Urine protein is > 2.0 g 
2. Creatinine clearance decrease of > 50% from baseline 
3. Creatinine clearance < 45 mL/min/1.73 m2 
Irrespective of whether the stopping rule is confirmed or not, 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. 

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8.6.3 
Stopping Rule for Platelet Count Results 
Stopping Rules 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 steroids 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 
steroids.  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 
0.5-2 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). 
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; Schulman and Kearon 2005), 
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 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 
irrespective of whether the platelet count rises into the normal range. 
Any unreportable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 
Definition of Major Bleeding Events (Schulman and Kearon 2005): 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more within 
24 hours, or leading to transfusion of 2 or more units of whole or red cells 

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Definition of Clinically-Relevant, Non-Major Bleeding Events (Schulman and Kearon 2005): 
1. Multiple-source bleeding 
2. Spontaneous hematoma > 25 cm2 
3. Excessive wound hematoma (not injection site related) 
4. Macroscopic hematuria (spontaneous or lasting > 24 hours if associated with an 
intervention) 
5. Spontaneous rectal bleeding; epitasis, gingival bleeding, hemoptysis, hematemesis  
6. Bleeding after venipuncture for > 5 minutes 
Table 3 
Actions in Patients with Low Platelet Count 
Platelet Count on Rx 
Drug Dose 
Monitoring 
Normal range, > 140K/mm3 
No action 
Monitor every 2 weeks 
100K-140K/mm3 
No action 
Closer observation 
Monitor every week* 
75K-100K/mm3 
Permanently reduce as follows: 
For Cohort A:  reduce to 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks  
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 weeks 
For Cohort E:  reduce to 10 mg every week 
Closer observation 
Monitor every week* 
50K-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 10 mg every 4 weeks 
For Cohort B:  reduce to 20 mg every 4 weeks 
For Cohort C:  reduce to 30 mg every 4 weeks 
For Cohort D:  reduce to 10 mg every 2 weeks 
For Cohort E:  reduce to 10 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)/ anticoagulant 
medication 
25K-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/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
 
 

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Table 3 
Actions in Patients with Low Platelet Count Continued 
Platelet Count on Rx 
Drug Dose 
Monitoring 
˂ 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 and referral to 
hematologist 
Discontinue antiplatelet 
agents/NSAIDS/anticoagulant 
medication while platelet 
count ˂ 50K/mm3 if possible 
* 
Once a patient commences weekly monitoring this frequency of monitoring should continue irrespective of 
whether the platelet count rises into the normal range. 
** 
Recovery in platelet count may be accelerated by administration of high dose steroids.  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 0.5-2 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 
Section 8.6.3 and 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 8.6.3 
• 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 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 after discontinuing Study Drug.  Following this period, if the platelet count is 
stable (at least 3 consecutive values measured weekly that are stable as determined by the 
Sponsor Medical Monitor and > 100,000/mm3), the next platelet count should be taken within at 
least 6 weeks so that patients are monitored for at least 12 weeks after discontinuing Study Drug. 
Following 6 weeks of Study Drug discontinuation, patients should be strongly encouraged to 
attend planned Study Center visits (including End-of-Treatment Week 53 visit and final 
Post-Treatment Follow-up visit 16 weeks after their last dose of Study Drug) to collect the study 
assessments in accordance with the Schedule of Procedures in Appendix A. 
If the patient declines or is unable to participate in the above, an ET visit (Week 53 visit 
assessments) should be performed at the time of withdrawal, at a minimum, and ideally within 
2 weeks from the last dose of Study Drug. 
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 permanently discontinues Study Drug (see Section 8.8)   
• 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 study procedures 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 study procedures and observations at the time of withdrawal (see 
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, PCSK9 inhibitors, niacin, fibrates, fish oil, other 
products containing omega-3 fatty acids (including OTC preparations) 
• Anti-platelet therapies 
• Testosterone, estrogens, progesterone, growth hormone, or progestins. 
Disallowed Concomitant Therapy 
Use of the following is disallowed: 
• Warfarin, 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 
• 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. 

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8.10.2 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
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 of 
platelet count, liver and renal function as described in Sections 6.2.1, 8.5.1-8.5.3, and 8.6.1-8.6.3. 
Patients will be required to have platelet counts every 2 weeks 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. 
Patients will also be required to have renal function testing and assessment of biomarkers of 
renal damage every 2 weeks, and must not receive Study Drug if there are no test results for 
parameters considered critical to patient safety available within the prior 2 weeks.  In such a case 
the Investigator must contact the patient to hold dosing until these 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 
potential hepatic and renal risks, the importance of adherence to the monitoring program.  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. 
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 

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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 is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the Study Drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening, that is, poses an immediate risk of death at the time of the event 
• An AE or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the patient at immediate risk of 
death.  It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• 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) 

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• 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 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.  When the Investigator is reporting by telephone, it is 
important to speak to someone in person versus leaving a message.  An Initial Serious Adverse 
Event Form should be completed and a copy should be emailed or faxed to the Sponsor or 
designee.  The contact information for reporting SAEs is as follows:  
Attention:  
 
Email: 
 
 
Fax: 
 
 
Phone: 
 
 
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.  

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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 681257 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 681257 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 
• 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). 

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9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drug (ISIS 681257 or placebo) due to the event is characterized by 1 of 
the following. 
• None:  No changes were made to Study Drug (ISIS 681257 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) 
• 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) 

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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 (Grade 3 or Grade 4) 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. 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the patient’s consent to 
participate in the study 
• The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the patient’s consent to participate in the study and the timing of the 
procedure or treatment.  The condition is documented in the patient’s medical history. 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
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9.5.3 
Dosing Errors 
Study Drug (ISIS 681257 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 681257 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 
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. 

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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 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-C) and at Week 27 for patients who received every 2-week or 
weekly dosing (Cohorts D and E, 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. 
10.1.1 
Primary Endpoint(s) 
The primary efficacy endpoint is the percent change in Lp(a) from baseline at the primary 
analysis time point achieved by ISIS 681257 compared to pooled placebo. 
Lp(a) levels will be analyzed from patient blood samples taken at specified time points 
throughout the study. 
10.1.2 
Secondary Endpoints 
The secondary endpoints include the following parameters from baseline at the primary analysis 
time point for ISIS 681257 compared to placebo: 
• Percent change from baseline in LDL-C  
• Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL 
• Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL 
• Percent change from baseline in apoB 
• Percent change from baseline in OxPL-apo(a) 
• Percent change from baseline in OxPL-apoB 
10.1.3 
Safety Endpoints 
The safety analysis will be performed using the following parameters: 
• AEs  
• Vital signs and weight 
• Physical examinations  

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• 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 
• ECGs 
• Use of concomitant medications 
10.1.4 
Dose Selection 
Dose selection for 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 clinically-meaningful reduction in plasma Lp(a) 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.   
10.2 
Sample Size Considerations 
Based upon prior clinical trial experience with ISIS 681257 (Viney et al. 2016), it is estimated 
that the standard deviation of the percent change in Lp(a) is approximately 20%.  With 
23 patients in each ISIS 681257 treatment group and 23 in placebo group there would be 
approximately 90% power to detect a 20% difference in percent change in Lp(a) levels between 
the ISIS 681257 treatment groups and placebo group at an alpha level of 0.05, assuming 30% 
reduction in the ISIS 681257 patients and 10% reduction in the placebo patients. 
Based upon prior clinical trial experience with Ionis ASOs, assuming the incidence rate of 
platelet count below lower limit of normal (LLN) in placebo treated patients is 1.9%, in the 
ISIS 681257 treated patients is 3.8%, twice the incidence rate observed in placebo, with 
45 patients in each ISIS 681257 treatment group, there would be approximately 80% power to 
detect at least 1 event. 
Therefore, approximately 270 patients (54 patients per cohort, including 45 patients per cohort 
treated with ISIS 681257) will be randomized to ensure that both the safety and efficacy of 
ISIS 681257 will be adequately characterized in the study. 
10.3 
Analysis Populations 
Full Analysis Set (FAS):  All patients who are randomized, received at least 1 dose of Study 
Drug (ISIS 681257 or placebo), and have a Baseline Lp(a) 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 every 4-week 
doses of Study Drug for patients randomized in Cohorts A, B, and C or at least 10 every 2-week 
doses for patients randomized in Cohort D or 20 weekly doses for patients randomized in 
Cohort E, 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. 

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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 Study Drug, and 
have sufficient data for the analysis of PK parameters.  This population will be used for analysis 
of PK data. 
10.4 
Definition of Baseline 
Baseline for Lp(a), LDL-C, apoB, OxPL-apo(a), OxPL-apoB, and other lipid measurements will 
be defined, the pre-dose measurement on Day 1 or 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. 
10.6.2 
Safety Analysis 
10.6.2.1 
Adverse Events 
Treatment duration and amount of Study Drug (ISIS 681257 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 681257 or placebo) will be summarized. 

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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 681257 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 analysis of the primary endpoint will be the pairwise comparison of percent change 
from baseline to primary analysis time point in fasting Lp(a) between ISIS 681257 treatment 
groups and pooled placebo group in the FAS.  The data will be analyzed using an analysis of 
covariance (ANCOVA) model with the Baseline Lp(a) 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. 
10.6.3.2 
Analysis of Secondary Efficacy Endpoints 
• Percent change from baseline at the primary analysis time point in fasting LDL-C will be 
compared between each ISIS 681257 treatment groups  and pooled placebo group using 
an ANCOVA model with baseline as covariate 
• Proportion of patients who achieve ≤ 50 mg/dL in fasting Lp(a) at the primary analysis 
time point will be compared between each ISIS 681257 treatment group and pooled 
placebo group using a logistic regression model with Baseline Lp(a) as a covariate.  
Proportion of patients who achieve ≤ 30 mg/dL in fasting Lp(a) at the primary analysis 
time point will be analyzed similarly 

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• Percent change from baseline at the primary analysis time point in fasting apoB, 
OxPL-apo(a) and OxPL-apoB will be compared between ISIS 681257 treatment groups 
and pooled placebo group using an ANCOVA model with baseline as covariate 
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 681257 in plasma (as total full 
length oligonucleotides, including fully conjugated, partially conjugated, and unconjugated 
ISIS 681257) will be determined and summarized by treatment with stratification by subject 
immunogenicity status using descriptive statistics. 
In addition, non-compartmental PK analysis of ISIS 681257 concentrations will be carried out on 
each individual patient data set in patients who received ISIS 681257 treatment, and the plasma 
disposition half-life (t1/2λz) associated with the apparent terminal elimination phase will be 
calculated, if appropriate, using available data at the End-of-Treatment and the post-treatment 
follow-up period from the equation, t1/2λz = 0.693/λz, where λz is the rate constant associated with 
the apparent terminal elimination phase. 
For patients in the PK subgroup only, non-compartmental PK analysis of ISIS 681257 will be 
carried out on each individual patient data set in patients who received ISIS 681257 treatment.  
The maximum observed drug concentration (Cmax) and the time taken to reach Cmax (Tmax) will 
be obtained directly from the concentration-time data.  Following single dosing (Day 1), area 
under the plasma concentration-time curve from time zero (pre-dose) to 24 hours after the dose 
(AUC0-24hr) will be calculated using the linear trapezoidal rule.  Following multiple dosing, 
AUC0-24hr and area under the plasma concentration-time curve during the time of each sampled 
dosing interval (tau,τ) at steady-state (AUCτ) will be calculated using the linear trapezoidal rule. 
Other PK parameters, as appropriate, may be determined or calculated at the discretion of the PK 
scientist.  Plasma PK parameters will be summarized using descriptive statistics with 
stratification by subject immunogenicity status.  Exposure-response relationships between 
selected PD [e.g., Lp(a)] and PK measures (including but may not be limited to plasma trough 
concentrations) may be explored (including with and without stratification by IM status) in this 
study, or in a separate population PK analysis with all clinical studies combined. 
The immunogenicity (IM) of ISIS 681257 will be assessed before, during, and after treatment 
with Study Drug (ISIS 681257 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 681257 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 681257 or placebo) are 
administered. 
Importantly, patients should be informed of the possibility and risks of a reduction in platelet 
count, and other potential risks (hepatic and renal), 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. 
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 
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. 

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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 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  Elements should include: 

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• Patient files containing completed 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 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Bennett CF. Pharmacological properties of 2ʹ-O-methoxyethyl-modified oligonucleotides. In: Crooke ST, editor. 
Antisense Drug Technology: Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis 
Group 2008; 365-400. 
Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized 
phospholipids in human plasma. J Lipid Res 2008; 49: 2230-2239. 
Bertoia ML, Pai JK, Lee J-H, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll 
Cardiol 2013; 61(21): 2169-2179. 
Clarke R, Peden JF, Hopewell JC, et al; PROCARDIS Consortium. Genetic variants associated with Lp(a) 
lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528. 
Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin 
kexin type 9, significantly reduces lipoprotein (a) in hypercholesterolemic patients receiving statin therapy: an 
analysis from the LAPLACE-TIMI 57 Trial. Circ 2013; 128: 962-969. 
Dubé JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a): more interesting than ever after 50 years. Curr 
Opin Lipidol 2012; 23(2): 133-140. 
Erqou S, Kaptoge S, Perry PL, et al; Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk 
of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302(4): 412-423. 
Erqou S, Thompson A, Di Angelantonio E, et al. Apoliporotein(a) isoforms and the risk of vascular disease. JACC 
2010; 55(19): 2160-2167. 
Frazer KA, Narla G, Zhang JL, Rubin E. The apolipoprotein(a) gene is regulated by sex hormones and acute-phase 
inducers in YAC transgenic mice. Nat Gen 1995; 9: 424-431. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2ʹ-O-(2-
methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma 
lipoprotein (a) levels in humans. J Lipid Research 2016; 57: 340-351. 
Guyton JR. Niacin in cardiovascular prevention: mechanisms, efficacy, and safety. Curr Opin Lipidol 2007; 18: 
415-420. 
Henry S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in 
mice. J Pharmacol Exp Ther 2000; 292(2): 468-479. 
Jaeger BR, Richter Y, Nagel D, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to 
reduce high lipoprotein(a) levels and major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009; 6(3): 
229-239. 
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and 
increased risk of myocardial infarction. JAMA 2009; 301(22): 2331-2339. 
Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 
activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb 
Vasc Biol 2007; 27: 1788-1795. 
Koschinsky ML and Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into 
lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 2004; 15(2): 167-174. 
Kronenberg F and Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013; 273: 6-30. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
67 
Leebmann J, Roeseler E, Julius U, et al; Pro(a)LiFe Study Group. Lipoprotein apheresis in patients with maximally 
tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: 
Prospective observational multicenter study. Circ 2013; 128: 2567-2576. 
Leibundgut G, Scipione C, Yin H, et al. Determinants of binding of oxidized phospholipids on apolipoprotein(a) and 
lipoprotein(a). J Lipid Res 2013; 54: 2815-2830. 
Li Y, Luke MM, Shiffman D, Devlin JJ. Genetic variants in the apolipoprotein(a) gene and coronary heart disease.  
Circ Cardiovasc Genet 2011; 4(5): 565-573. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 274: 1715-1722. 
Merki E, Graham M, Taleb A, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) in 
transgenic mice. JACC 2011; 57(15): 1611-1621. 
Nordestgaard BG, Chapman MJ, Ray K, et al; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as 
a cardiovascular risk factor: current status. Euro Heart J 2010; 31: 2844-2853. 
Parker K, Brunton L, Goodman LS, et al. Goodman & Gilman's the pharmacological basis of therapeutics. New 
York, NY. McGraw-Hill. 2006; ISBN 0-07-142280-142283. 
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; 42: 8796-8807. 
Prakash TP, Yu J, Migawa MT, et al. Comprehensive structure-activity relationship of triantennary N-Acetyl 
galactosamine conjugated antisense oligonucleotides for targeted delivery to hepatocytes. J Med Chem 2016 
Mar 24; 59(6): 2718-2733. 
Provan D, Stasi R, Newland AC. et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolucomab in homozygous familial 
hypercholesterolemia (TESLA Part B): a randomized, double blind, placebo controlled trial. Lancet 2015; 385: 
341-350. 
Rand ML, Sangrar W, Hancock MA, et al. Apoliprotein(a) enhances platelet responses to the thrombin receptor – 
activating peptide SFLLRN. Arterio Thromb Vasc Biol 1998; 18: 1393-1399. 
Rosada A, Kassner U, Vogt A, et al. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) 
levels reduce the incidence of cardiovascular events? Artif Organs 2014; 38: 135-141. 
Safarova M. Specific lipoprotein(a) apheresis reduces atherosclerosis progression. 80th Congress of the European 
Atherosclerosis Society, Milan, Italy 28 May 2012. 
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. 
Schulman S and Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization 
Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medical products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692-694. 
Spence JD and Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity. Arterioscler Thromb Vasc Biol 2012; 
32: 1550-1551. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev 
1995; 75: 591-609. 
Thanassoulis G, Campbell CY, Owens DS, et al; CHARGE Extracoronary Calcium Working Group. Genetic 
associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368(6): 503-512. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
68 
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circ 2012; 126: 
2020-2035. 
Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal 
coronary events. J Am Coll Cardiol 2010; 56: 946-955. 
Tsimikas S, Willeit P, Willeit J, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke 
outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60: 2218-2229. 
Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary 
artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 
2014; 63: 1724-1734. 
Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people 
with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 
388(10057): 2239-2253. 
Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second-
generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.  Drug Metab Dispos 
2007; 35: 460-468.  
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692. 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
69 
 
 
 
 
 
 
 
14. 
APPENDICES 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol 
 
9 December 2016 
 
70 
 
 
 
 
 
 
 
Appendix A 
Schedule of Procedures 
 
Schedule of Procedures for Every Week and Every 2-Week Dosing Cohort 
Schedule of Procedures for Every 4-Week Dosing Cohorts 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
71 
Appendix A Schedule of Procedures – Every Week and Every 2-Week Dosing 
 
Screen 
Treatment Period 
Follow-up 
Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13
17 
21 
25 
27 
28 
29 
33 
37 
41 
45 
49 
53/ET
4* 
10*
16* 
Study Day 
-28 to -1 
1 
2j 
29
57
85
113
141 
169 
183
184j
185j 
190o
197
225
253
281
309
337
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3a 
0 
2 
2 
2 
3 
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 
Inclusion/Exclusion Criteria 
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 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
URINALYSIS PERFORMED EVERY 14 DAYS 
X 
X 
X 
Renal Biomarkers m 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS m 
Xl 
Xl 
Xl 
Serum Creatinine f 
 
SERUM CREATININE PERFORMED EVERY 14 DAYS n 
X 
X 
X 
Genetic Testing 
 
X 
 
Chemistry Panel e, f 
X 
EVERY 14 DAYS 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology e, f 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS b 
Xl 
Xl 
Xl  
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 i 
 
X3 
X1
X 
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
72 
Appendix A Schedule of Procedures – Every Week and Every 2-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up 
Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
27 
28 
29 
33
37 
41
45 
49 
53/ET
4* 
10*
16* 
Study Day 
-28 to -1 
1 
2j
29
57
85 
113
141
169
183
184j
185j 
190o 
197 225
253 281 309
337
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3a 
0 
2 
2 
2 
3 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
FSH (women only, if 
applicable)e, g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test g 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Archived Serum & Plasma 
Samples e, h 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
PD Panel e 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid Panel e 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Lp(a) Characterization 
 
X 
 
 
Study Drug:  SC Injection 
 
WEEKLY SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 through Week 53/Day 365)k 
 
 
 
Adverse Events 
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 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
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. 
b 
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. 
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 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours. 
f 
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 as per Section 6.2.1.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
g 
Women who are not surgically sterile or post-menopausal. 
h 
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.) in this or subsequent clinical studies of 
ISIS 681257. 
i 
Refer to Appendix C for PK Sampling schedule. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
73 
Appendix A Schedule of Procedures – Every Week and Every 2-Week Dosing Continued 
j 
Visit only required for patients in PK subgroup. 
k 
Patients will continue treatment in the study until the last patient enrolled reaches 6 months of exposure.  All patients will then enter a 16-week post-treatment 
follow-up period. 
l 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then every 6 weeks. 
m 
Samples for renal biomarkers will be collected.  Urine samples will be collected as part of urinalysis collection.  Blood samples for CysC will be collected as a 
part of chemistry panel at visits when chemistry panel is performed, or as stand-alone sample at other time points.  Sample analysis will be conducted in 
accordance with Safety Monitoring for Renal Function (Section 8.5.2). 
n 
Collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone sample at other time points. 
o 
Week 28 visit is only required for patients on Every 2-Week dosing schedule and who are assigned to the PK sub-group. 
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8 hours post SC injection 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
74 
Appendix A Schedule of Procedures – Every 4-Week Dosing 
 
Screen 
Treatment Period 
Follow-up 
Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 
53/ET
4* 
10*
16* 
Study Day 
-28 to -1 
1 
2j 
29 
57 
85 
113
141
169
170j
171j
176j 183j
197
225
253
281
309
337
365 
*Post Last Dose
Visit Window +/- Days 
0 
-3a 
0 
2 
2 
2 
3 
3 
3 
0 
0 
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 
Inclusion/Exclusion Criteria 
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 
Physical Examination 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Body Weight and Height d 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
12- lead ECG (triplicate) 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
X 
URINALYSIS PERFORMED EVERY 14 DAYS 
X 
X 
X 
Renal Biomarkers 
X 
RENAL BIOMARKERS PERFORMED EVERY 14 DAYS m 
Xl 
Xl 
Xl 
Serum Creatinine f 
 
SERUM CREATININE PERFORMED EVERY 14 DAYS n 
 
 
 
Genetic Testing 
 
X 
 
 
Chemistry Panel e 
X 
EVERY 14 DAYS 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology e, f 
X 
HEMATOLOGY PERFORMED EVERY 14 DAYS b 
X 
X 
X 
Platelet Function 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Plasma PK - ISIS 681257 i 
 
X3 
X1
X 
X 
X 
X 
X 
X3 
X1 
X2 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
ISIS 681257 Antibodies 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
FSH (women only, if 
applicable) e, g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
75 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
Screen 
Treatment Period 
Follow-up 
Period 
Study Week 
-4 to -1 
1 
1 
5 
9 
13 
17 
21 
25 
26 
27 
29 
33 
37 
41 
45 
49 
53/ET
4* 
10*
16* 
Study Day 
-28 to -1 
1 
2j 
29 
57 
85 
113
141
169
170j
171j
176j 
183j
197
225
253
281
309
337
365 
*Post Last Dose 
Visit Window +/- Days 
0 
-3a 
0 
2 
2 
2 
3 
3 
3 
0 
0 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Serum Pregnancy Test g 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archived Serum & Plasma 
Samples e, h 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PD Panel e 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Lipid Panel e 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Lp(a) Characterization 
 
X 
 
 
Study Drug:  SC Injection 
 
EVERY 4-WEEK SUBCUTANEOUS ADMINISTRATION OF STUDY DRUG (Week 1 through Week 49/Day 337)k
 
 
 
Adverse Events 
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 
All procedures and study samples are to be done pre-dose at respective visits, unless specified 
a 
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. 
b 
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. 
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 
Blood samples to be collected after an overnight fast of at least 10 hours and preferably not more than 12 hours. 
f 
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 for 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 as per Section 6.2.1.  Any case of a platelet count ≤ 50,000/mm3 should be reported in an expedited fashion to the Sponsor. 
g 
Women who are not surgically sterile or post-menopausal. 
h 
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.) in this or subsequent clinical studies of 
ISIS 681257. 
i 
Refer to Appendix C for PK Sampling schedule. 
j 
Visit only required for patients in PK subgroup. 
k 
Patients will continue treatment in the study until the last patient enrolled reaches 6 months of exposure.  All patients will then enter a 16-week post-treatment 
follow-up period. 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
76 
Appendix A Schedule of Procedures – Every 4-Week Dosing Continued 
 
l 
During follow-up period, hematology sampling for platelet values and urine renal biomarker samples are taken every 14 days for 6 weeks after last dose of 
Study Drug, then every 6 weeks. 
m 
Samples for renal biomarkers will be collected.  Urine samples will be collected as part of urinalysis collection.  Blood samples for CysC will be collected as a 
part of chemistry panel at visits when chemistry panel is performed, or as stand-alone sample at other time points.  Sample analysis will be conducted in 
accordance with Safety Monitoring for Renal Function (Section 8.5.2). 
n 
Collected as a part of chemistry panel at visits when chemistry panel is performed, or as stand-alone sample at other time points.  
 
Time (time is in reference to Study Drug administration): 
1 
24-hr from previous dose of Study Drug 
2 
48-hr from previous dose of Study Drug 
3 
Pre-dose, 1, 2, 4, 8, hrs post SC injection 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
77 
 
 
 
 
 
 
 
Appendix B 
List of Laboratory Analytes 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
78 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 681257 or other similar 
oligonucleotides. 
Clinical Chemistry 
Panel 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Total protein 
• Albumin 
• Calcium 
• Magnesium 
• Phosphorus 
• Glucose 
• BUN 
• Creatinine 
• Cholesterol 
• 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) 
• Drug/Alcohol screen 
• TSH 
• Free T4 
• Free T3 
 
Coagulation 
• aPTT (sec) 
• PT (sec) 
• INR 
• Fibrinogen 
• Plasminogen 
 
PD Panel 
• Lp(a) 
• OxPL-apoB 
• OxPL-apo(a) 
• OxPL-plasminogen 
 
Lipid Panel 
• Total Cholesterol 
• LDL cholesterol 
• HDL cholesterol 
• ApoB 
• Triglycerides 
• VLDL 
Lp(a) Characterization 
• Apo(a) isoforms 
 
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 681257 (total full 
length ASO) levels in 
plasma 
 
Immunogenicity 
• Anti-ISIS 681257 
antibodies 
 
Genetic Testing 
• LPA SNPs associated 
with elevated Lp(a)  
 
Inflammatory 
• hs-CRP  
 
Urinalysis 
• Color 
• Appearance 
• Specific gravity 
• pH 
• P/C Ratio(UPCR) 
• Protein 
• A/C Ratio(UACR) 
• Blood 
• Ketones 
• Urobilinogen 
• Glucose 
• Bilirubin 
• Leukocyte esterase 
• Nitrate 
• Microscopic 
examination2  
 
Renal Urine 
Biomarkers 
• 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 681257 with plasma 
constituents 
2 
Will be performed on abnormal findings unless otherwise specified 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
79 
 
 
 
 
 
 
 
Appendix C 
PK Sampling Schedule 
 
Sampling Schedule for Every Week Dosing Cohort 
Sampling Schedule for Every 2-Week Dosing Cohort 
Sampling Schedule for Every 4-Week Dosing Cohorts 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
80 
Appendix C PK Sampling Schedule 
Blood samples for the determination of plasma ISIS 681257 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 681257 
with plasma constituents.  Extensive PK samples will be collected in PK subgroup only (10 subjects per cohort) (see tables below): 
Sampling Schedule for Every Week Dosing Cohort 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
1 
5 
9 
13 
17 
21 
25 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
183 
184 
185 
197 
253 
365 
*Post Last Dose 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
1, 2, 4, 
& 8-hr1 
24-hr2 48-hr3 Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
81 
Appendix C PK Sampling Schedule Continued 
Sampling Schedule for Every 2-Week Dosing Cohort 
 
Treatment Period 
Follow-up Period 
Study 
Week 
1 
1 
5 
9 
13 
17 
21 
25 
27 
28 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
183 
184 
185 
190 
197 
253 
365 
*Post Last Dose 
All 
Patients 
Pre-
dose 
NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
PK Sub-
group 
Only 
Pre-
dose, 
1, 2, 
4, & 
8-hr1 
24-hr2 Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 1, 
2, 4, & 
8-hr1 
24-hr2 48-hr3 
Anytime Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
82 
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 
25 
26 
27 
29 
37 
53 
4* 
10* 
16* 
Study 
Day 
1 
2 
29 
57 
85 
113 
141 
169 
170 
171 
176 
183 
197 
253 
365 
*Post Last Dose  
All 
Patients 
Pre-
dose NA 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose 
Pre-
dose, 
NA 
NA 
NA 
NA 
NA 
Pre-
dose 
Pre-
dose 
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 
Pre-
dose, 
1, 2, 4, 
and 
8-hr1 
24-hr2 48-hr3 Anytime Anytime Pre-
dose 
Pre-
dose 
Pre-
dose 
Anytime 
Anytime 
Anytime 
1 
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 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
83 
 
 
 
 
 
 
 
Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
84 
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 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
85 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
  
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
86 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
Continued 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
87 
 
 
 
 
 
 
 
Appendix E 
Additional Laboratory Tests for Patients with 
Platelet Count ˂ 100,000/mm3 
 
 
 

ISIS 681257-CS6 
CONFIDENTIAL 
Amendment 3 
Protocol  
 
9 December 2016 
 
88 
Appendix E Additional Laboratory Tests for Patients with Platelet Count ˂ 100,000/mm3 
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 
Fibrinogen 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
hsCRP 
von Willebrand factor (vWF) Antigen 
Serology for: 
HBV, HCV, HIV (if not done recently for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
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 
Platelet Antibody Bead Array (PABA)