Clinical trial NCT02597127
Conditions: Atherosclerotic Cardiovascular Disease Familial Hypercholesterolemia Diabetes
Sponsor: The Medicines Company
Start date: 2016-01-01; Completion date: 2017-06-07
Enrollment: 501 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a Phase II, placebo-controlled, double-blind, randomized trial in 480 participants with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (for example, diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the efficacy, safety, and tolerability of ALN-PCSSC injection(s).

Detailed description:
Participants will be screened and 480 eligible participants will be randomized: 60 participants per each of six ALN-PCSSC dose groups plus 120 participants total across the placebo groups (20 participants each to match each of the six drug dose groups). Treatment allocation will be stratified by country and by current use of statins or other lipid-modifying therapies. Each participant will receive either one or two injections on Day 1 or a single injection on Day 1 and on Day 90 of blinded ALN-PCSSC or placebo.

Formation of anti-drug antibodies (ADA) will be assessed on Day 1 (prior to and 4 hours after the injection) and on Days 30, 60, 90, 120, 150, 180 (Days 150 and 180 only in participants who receive a second dose of study drug), and 210 or until any ADA response becomes negative within the study duration.

The independent Data Monitoring Committee (DMC) will review safety data beginning after the first 40 participants receive the first injection of ALN-PCSSC or placebo and complete the Day 14 follow-up visit. Thereafter, the DMC will review safety data every 2 months until the end of the trial. A recommendation may be taken to stop or amend the study at any of these reviews.

On Day 1, all eligible participants will be randomized and receive the first subcutaneous (SC) administration of ALN-PCSSC or placebo. After the first study drug administration, the participant will be observed in the clinic for at least 4 hours post injection before being discharged. Participants will return at Day 14 and then at monthly intervals for 6 months. Participants randomized to receive a second dose of study drug will receive the second injection of ALN-PCSSC or placebo at the Day 90 visit.

Efficacy assessments will include the measurement of the effects of ALN-PCSSC on levels of LDL-C lipids and lipoproteins including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), lipoprotein (a) \[Lp(a)\], C-reactive protein (CRP), and proprotein convertase subtilisin/kexin type 9 (PCSK9).

End of study (EOS) evaluations will be conducted at the EOS visit (Day 210). The expected duration of the participants' involvement in the study will be approximately 374 days, which includes screening, study drug administration, the course of single or multiple injections, and the follow-up period to Day 360.

Participants completing the study to Day 210 will be given the opportunity to enroll in a separate long-term extension study. Any participants in whom LDL-C levels have not returned to \>80% of baseline values will continue to be followed as part of this study until either this level has been reached or until a maximum of Day 360, at which point they will be given the opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, adverse events, serious adverse events, concomitant medications, and safety laboratory assessments will be collected.

Objectives:

Primary:

To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180.

Secondary:

To evaluate the effect of ALN-PCSSC on the following:

* LDL-C at Day 90
* LDL-C levels at other time points
* PCSK9 levels over time
* Other lipids, lipoproteins, apolipoproteins
* Proportion of participants achieving pre-specified global lipid guidelines
* Individual responsiveness to different doses
* Duration of lipid-lowering effect of different doses
* Safety and tolerability profile of ALN-PCSSC

Exploratory:

To collect/evaluate the effect of ALN-PCSSC on the following:

* Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction, resuscitated cardiac arrest and non-fatal stroke (ischemic and hemorrhagic)
* Evaluation of ADA for the investigational product

Arms: arm 1: ALN-PCSSC 200 milligram (mg) SC administration once at Day 1 arm 2: ALN-PCSSC 300 mg SC administration once at Day 1 arm 3: ALN-PCSSC 500 mg SC administration once at Day 1 arm 4: Saline SC administration once at Day 1 arm 5: ALN-PCSSC 100 mg SC administration twice at Day 1 and Day 90 arm 6: ALN-PCSSC 200 mg SC administration twice at Day 1 and Day 90 arm 7: ALN-PCSSC 300 mg SC administration twice at Day 1 and Day 90 arm 8: Saline SC administration twice at Day 1 and Day 90
Interventions: intervention 1: ALN-PCSSC intervention 2: Normal Saline
Intervention descriptions: intervention 1: ALN-PCSSC is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis and is given as SC injections intervention 2: Saline (sterile, normal, 0.9%) solution given as SC injections

Protocol documents:
Prot_000.pdf: 
Confidential 
1 
Investigational New Drug 
ALN-PCSSC 
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED 
TRIAL TO COMPARE THE EFFECT OF DIFFERENT DOSES 
OF ALN-PCSSC GIVEN AS SINGLE OR MULTIPLE 
SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH HIGH 
CARDIOVASCULAR RISK AND ELEVATED LDL-C  
Protocol No.: MDCO-PCS-15-01 
EuDRACT No.: 2015-003772-74 
PROTOCOL VERSION: Amendment 03: 12 Apr 2016 
Amendment to Protocol Amendment 02: 22 Mar 2016
Drug Development Phase: 
II 
Sponsor: 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Principal Investigator: 
Kausi
, MD 
Sponsor Representatives: 
Medical Director: 
Davi
end, MD 
Project Leader: 
Peter W
d, PhD 
Global Safety Officer: 
Zoya M
a, MD 
Clinical Pharmacologist 
S. Eralp B
hD FAHA 
Issue Date: 
12 April 2016 
CONFIDENTIAL 
Property of The Medicines Company 
May not be used, divulged, published or otherwise disclosed without the consent of  
The Medicines Company 
This study will be conducted in compliance with Good Clinical Practice (GCP) and protection of the subject 
as required by the regulations and directives in operation at this time. 


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PROCEDURES IN CASE OF EMERGENCY 
 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
 
*http://www.themedicinescompany.com/contact/global-medical-info. 
 
. 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: The Medicines Company 
Name of Finished Product: ALN-PCSSC 
Name of Active Ingredient: ALN-PCSSC is a synthetic, chemically modified small interfering ribonucleic acid 
(siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA 
[ALN-60212]) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand. The 
investigational product (ALN-PCSSC) will be administered by subcutaneous (SC) injection as a formulation of 
ALN-60212. It will be supplied as a sterile 100 mg vial (200 mg/mL solution) for SC injection. 
Title of Study: A placebo-controlled, double-blind, randomized trial to compare the effect of different doses of 
ALN-PCSSC given as single or multiple subcutaneous injections in subjects with high cardiovascular risk and 
elevated low-density lipoprotein cholesterol (LDL-C). 
Phase of Development: II 
Study Centers: Multi-center study in North America and Europe (approx
60 sites) 
Principal Investigator: Profess
ik Ray 
Study Period: 
The estimated study period for the study will be 17 to 18 months from first subject enrolled in the study to last 
subject completed. 
Objectives:  
Primary: 
 
To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180. 
Secondary: 
 
To evaluate the effect of ALN-PCSSC on the following: 
o 
LDL-C levels at Day 90 
o 
LDL-C levels at other time points 
o 
PCSK9 levels over time 
o 
Other lipids, lipoproteins, apolipoproteins 
o 
Proportion of subjects achieving prespecified global lipid guidelines 
o 
Individual responsiveness to different doses  
o 
Duration of lipid-lowering effect of different doses  
o 
Safety and tolerability profile of ALN-PCSSC 
Exploratory: 
 
To collect/evaluate the effect of ALN-PCSSC on the following: 
o 
Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction (MI), resuscitated 
cardiac arrest, and non-fatal stroke (ischemic and hemorrhagic) 
o Evaluation of anti-drug antibodies (ADA) for the investigational product 
Methodology: This study will be a Phase II, placebo-controlled, double-blind, randomized trial in 480 subjects 
with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (eg, diabetes and familial 
hypercholesterolemia) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to 
evaluate the efficacy, safety, and tolerability of ALN-PCSSC injection(s).  
Subjects will be screened and 480 eligible subjects will be randomized: 60 subjects per each of six 
ALN-PCSSC dose groups plus 120 subjects total across the placebo groups (20 subjects each to match each of the 
six drug dose groups). Treatment allocation will be stratified by country and by current use of statins or other lipid-
modifying therapies. Each subject will either receive either one or two injections on Day 1 only or a single 
injection on Day 1 and a second injection on Day 90 of blinded ALN-PCSSC or placebo.  


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Formation of ADA will be assessed on Day 1 (prior to and 4 hours after the injection) and on Days 30, 60, 90, 120, 
150, 180 (Days 150 and 180 only in subjects who receive a second dose of study drug), and 210 or until any ADA 
response becomes negative within the study duration. For subjects in whom LDL-C levels have not returned to 
>80% of baseline values, formation of ADA will also be assessed either when LDL-C has returned to normal limits 
or at the 1-year follow-up visit.  
The independent Data Monitoring Committee (DMC) will review safety data beginning after the first 40 subjects 
receive the first injection of ALN-PCSSC or placebo and complete the Day 14 follow-up visit. Thereafter the DMC 
will review safety data every 2 months until the end of the trial. A recommendation may be taken to stop or amend 
the study at any of these reviews. 
On Day 1, all eligible subjects will be randomized and receive the first SC administration of ALN-PCSSC or 
placebo. After first study drug administration, the subject will be observed in the clinic for at least 4 hours post 
injection before being discharged. Subjects will return at Day 14 and Day 30 and then at monthly intervals for 
6 months. Subjects randomized to receive a second dose of study drug will receive the second injection of 
ALN-PCSSC or placebo at the Day 90 visit and will have an extra visit on Day 104 (14 days after the second dose 
on Day 90).  
Efficacy assessments will include the measure the effects of ALN-PCSSC on levels of LDL-C lipids and 
lipoproteins including total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, 
very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (Apo-A1), apolipoprotein B (ApoB), 
lipoprotein(a) [Lp(a)], high sensitivity C-reactive protein (hsCRP), and PCSK9.  
End of study (EOS) evaluations will be conducted at the EOS visit (Day 210). 
Subjects whose LDL-C levels have returned to baseline levels and who have completed the study to Day 210 will 
be given the opportunity to enroll in a separate long-term extension study to collect long-term efficacy and safety 
data.  
Any subjects in whom LDL-C levels have not returned to >80% of baseline values will continue to be followed as 
part of this study until either this level has been reached or until a maximum of Day 360 at which point they will be 
given the opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, adverse events (AEs), 
serious adverse events (SAEs), concomitant medications, and safety laboratory assessments will be collected.  
Number of Subjects: 480 planned; at least 400 evaluable 
Diagnosis and Main Criteria for Selection:  
Subjects may be included if they meet all of the following inclusion criteria prior to randomization: 
1. Male or female subjects ≥18 years of age.  
2. History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial 
hypercholesterolemia, including subjects whose 10-year risk of a cardiovascular [CV] event assessed by 
Framingham Risk Score* or equivalent has a target LDL-C of < 100 mg/dL).  
3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) for ASCVD subjects or ≥2.6 mmol/L (≥100 mg/dL) for 
ASCVD-risk equivalent subjects at screening. 
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. 
5. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) using 
standardized local clinical methodology.  
6. Subjects on statins should be receiving a maximally tolerated dose (investigator’s discretion). 
7. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 days 
before screening with no planned medication or dose change during study participation. 
8. Willing and able to give informed consent before initiation of any study-related procedures and willing to 
comply with all required study procedures. 
 
*By Framingham Risk Score > 20% 
 
Subjects will be excluded from the study if any of the following exclusion criteria apply immediately prior to 
randomization: 


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1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with 
participation in the clinical study, and/or put the subject at significant risk (according to investigator’s [or 
delegate] judgment) if he/she participates in the clinical study. 
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of the 
investigator (or delegate) might interfere with interpretation of the clinical study results. 
3. New York Heart Association (NYHA) class II, III or IV heart failure or last known left ventricular 
ejection fraction <30%. 
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication or via 
ablation. 
5. Any history of hemorrhagic stroke. 
6. Major adverse cardiac event within 6 months prior to randomization. 
7. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood pressure 
>110 mmHg prior to randomization despite anti-hypertensive therapy. 
8. Poorly controlled Type 2 diabetes, ie, glycated hemoglobin A1c (HbA1c) >10.0% prior to randomization. 
9. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the 
liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >2x the 
upper limit of normal (ULN), or total bilirubin elevation >1.5x ULN at screening confirmed by a repeat 
measurement at least 1 week apart. 
10. Serious comorbid disease in which the life expectancy of the subject is shorter than the duration of the 
trial (eg, acute systemic infection, cancer, or other serious illnesses). This includes all cancers with the 
exception of treated basal-cell carcinoma occurring >5 years before screening. 
11. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least 
two methods of contraception (oral contraceptives, barrier methods, approved contraceptive implant, long- 
term injectable contraception, intrauterine device or tubal litigation)**. Women who are >2 years 
postmenopausal defined as ≥1 year since last menstrual period AND if <55 years old with a negative 
pregnancy test within 24 hours of randomization or surgically sterile are exempt from this exclusion. 
12. Males who are unwilling to use an acceptable method of birth control during the entire study period 
(ie, condom with spermicide). 
13. Known history of alcohol and/or drug abuse with the last 5 years. 
14. Treatment with other investigational medicinal products or devices within 30 days or five half˗lives, 
whichever is longer. 
15. Use of other investigational medicinal products or devices during the course of the study. 
16. Any condition that according to the investigator could interfere with the conduct of the study, such as but 
not limited to: 
a. 
Inappropriate for this study, including subjects who are unable to communicate or to cooperate with 
the investigator. 
b. Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, 
scope, and possible consequences of the study (including subjects whose cooperation is doubtful due 
to drug abuse or alcohol dependency). 
c. 
Unlikely to comply with the protocol requirements, instructions, and study-related restrictions 
(eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing 
the study). 
d. Have any medical or surgical condition, which in the opinion of the investigator would put the subject 
at increased risk from participating in the study. 
e. 
Involved with, or a relative of, someone directly involved in the conduct of the study. 
f. 
Any known cognitive impairment (eg, Alzheimer’s disease). 
17. Previous or current treatment (within 90 days of screening) with monoclonal antibodies directed towards 
PCSK9. 


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**For the entire duration of the study 
Subjects excluded for any of the above reasons may not be re-screened for participation at any time if the exclusion 
characteristic has changed. 
Test Product, Dose and Mode of Administration: ALN-PCSSC will be administered as either a single SC 
injection (doses: 200 mg, 300 mg), or two injections (dose: 500 mg) on Day 1 or two SC injections (doses: 100 mg, 
200 mg, or 300 mg) on Day 1 and Day 90.  
Duration of Treatment: The expected duration of the subjects’ involvement in the study will be approximately 
224 days which includes screening, study drug administration, the course of single or multiple injections, and the 
follow-up period to Day 210; if additional follow-up is necessary, the expected maximum duration of involvement 
in the study will be 374 days.  
Single Dose (one or two injections on Day 1):  
 
Screening: Day -14 to -1 
 
Randomization, initiation of study drug: Day 1 
 
Treatment Phase: Day 1 
 
Follow-up:  
o Follow-up: Days 2 to 210; EOS on Day 210  
o Additional Follow-Up (for subjects in whom LDL-C levels have not returned to >80% of 
baseline values; subjects will return each month for follow-up until this level has been reached 
or until Day 360): Days 240, 270, 300, 330, and 360  
Two Doses (one injection each on Day 1 and Day 90):  
 
Screening: Day -14 to -1 
 
Randomization, initiation of study drug: Day 1 
 
Treatment Phase: Day 1 to Day 90 
 
Follow-up:  
o Follow-up: Days 91 to 210; EOS on Day 210  
o Additional Follow-Up (for subjects in whom LDL-C levels have not returned to >80% of 
baseline values; subjects will return each month for follow-up until this level has been reached 
or until Day 360): Days 240, 270, 300, 330, and 360 
Reference Therapy, Dose, and Mode of Administration: Placebo will be administered as either one or two SC 
injections of saline solution. Placebo volume will be matched to test product volume within each dose and injection 
regimen but not between injection regimens. For example, the placebo group for the 200 mg dose will receive 
1.0 mL of placebo whereas the placebo group for the 300 mg dose will receive 1.5 mL of placebo. 
Criteria for Evaluation:  
Efficacy: 
Primary Endpoint: 
 
Percentage change in LDL-C from baseline to Day 180 
Secondary Endpoints: 
 
Percentage change in LDL-C from baseline to Day 90 
 
Percentage change in LDL-C from baseline to Days 14, 30, 60, 104, 120, 150, and 210 
 
Proportion of subjects in each group with LDL-C greater than 80% of the baseline value at 
Day 180 and Day 210 
 
Duration of time on treatment for subjects to return to 80% of baseline or greater LDL-C or PCSK9 
protein  
 
Individual responsiveness defined as the number of subjects reaching on treatment LDL-C levels of 


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<25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 90, 120, and 180  
 
Proportion of subjects in each group with greater or equal to 50% LDL-C reduction from baseline 
at Days 90, 120, and 180  
 
Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 104, 120, 150, 180, and 
210 
 
Percentage change in other lipids, lipoproteins, apolipoproteins, from baseline at each subsequent 
visit to Day 210 
 
Proportion of subjects in each group who attain global lipid modification targets for their level of 
ASCVD risk 
Safety: AEs, SAEs, vital signs, clinical laboratory values (hematology, coagulation testing, chemistry, and 
urinalysis), and electrocardiograms (ECGs) will be collected at specified visits through the EOS visit (Day 210). 
AEs, SAEs, and clinical laboratory values will continue to be assessed during the additional monthly follow-up 
visits (for subjects in whom LDL-C levels have not returned to >80% of baseline values). Cardiovascular events 
will be reported as AEs for the compilation of information on CV events such as CV death, non-fatal MI, 
resuscitated cardiac arrest, and non-fatal stroke (ischemic and hemorrhagic). In addition, ADA will be evaluated 
for the investigational product. 
Statistical Methods: 
Sample Size and Power 
The sample size calculation was performed with the assumption (which was based on the observed results from a 
Phase I trial) that the difference in change from baseline between the active dose groups and the placebo group for 
LDL-C will be no less than 30 mg/dL, with a standard deviation of 20 mg/dL, using a Dunnet multiple t-test 
procedure for six comparisons. 
Assuming about a 15% drop out rate, the sample size will be approximately 100 evaluable subjects total across the 
placebo groups and approximately 50 subjects in each of six ALN-PCSSC dose groups. This sample size of at least 
400 evaluable subjects will provide more than 90% power to detect a 30% reduction of LDL-C levels in at least 
one ALN-PCSSC dose group.  
Primary Endpoint Analysis: 
Two sample t-tests will be performed to test the superiority of any dosing group over placebo. A Dunnet multiple t-
test procedure will be applied to adjust for multiple comparisons with six different dosing regimens. 
Secondary and Exploratory Endpoint Analysis: 
The analysis of the secondary and exploratory endpoints will be descriptive. 
Interim Analysis: 
An interim analysis of lipids and PCSK9, unblinded by dose cohort only, will be prepared upon completion of 
Day 90 by the Statistical Reporting Organization. The interim analysis will be performed for all subjects 
completing Day 90 and these data will be used to help select the ALN-PCSSC dose for subsequent clinical trials. 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................13 
1. 
INTRODUCTION ......................................................................................................15 
1.1. 
Background .................................................................................................................15 
1.1.1. 
Disease Overview .......................................................................................................15 
1.1.2. 
PCSK9 Biology and Target Rationale ........................................................................15 
1.1.3. 
Mechanism of RNA Interference ................................................................................16 
1.2. 
ALN-PCSSC, an RNAi Therapeutic for Hypercholesterolemia ................................17 
1.2.1. 
Preclinical Studies ......................................................................................................17 
1.2.2. 
Clinical Studies ...........................................................................................................18 
1.2.3. 
Known and Potential Risks and Benefits....................................................................18 
1.3. 
Study Rationale ...........................................................................................................19 
1.3.1. 
Study Rationale ...........................................................................................................19 
1.3.2. 
Dose Rationale ............................................................................................................19 
1.4. 
Study Population .........................................................................................................19 
2. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................20 
2.1. 
Primary Objective .......................................................................................................20 
2.2. 
Secondary Objectives .................................................................................................20 
2.3. 
Exploratory Objectives ...............................................................................................20 
3. 
TRIAL DESIGN .........................................................................................................21 
3.1. 
Type/Design of Trial ...................................................................................................21 
3.2. 
Schematic Diagram of Trial Design ...........................................................................22 
3.2.1. 
One Dose (one or two injections on Day 1) ...............................................................22 
3.2.2. 
Two Doses (one injection each on Day 1 and Day 90) ..............................................23 
3.3. 
Primary Endpoint(s) ....................................................................................................23 
3.4. 
Secondary Endpoints ..................................................................................................23 
3.5. 
Exploratory Endpoint(s) .............................................................................................24 
3.6. 
Measures to Minimize/Avoid Bias .............................................................................24 
3.6.1. 
Blinded Study Where Pharmacist is Unblinded .........................................................24 
4. 
SUBJECT POPULATION .........................................................................................25 
4.1. 
Number of Subjects ....................................................................................................25 


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4.2. 
Inclusion Criteria ........................................................................................................25 
4.3. 
Exclusion Criteria .......................................................................................................25 
4.4. 
Withdrawal Criteria ....................................................................................................27 
4.4.1. 
Withdrawal from Study Medication ...........................................................................28 
5. 
TREATMENT OF SUBJECTS ..................................................................................29 
5.1. 
Study Medications ......................................................................................................29 
5.1.1. 
ALN-PCSSC ...............................................................................................................29 
5.1.2. 
Placebo ........................................................................................................................29 
5.1.3. 
Packaging and Labeling ..............................................................................................29 
5.1.4. 
Storage ........................................................................................................................29 
5.1.5. 
Accountability .............................................................................................................29 
5.2. 
Concomitant Medications ...........................................................................................30 
5.2.1. 
Prohibited Concomitant Medications .........................................................................30 
5.2.2. 
Permitted Concomitant Medication(s) ........................................................................30 
5.3. 
Restrictions .................................................................................................................30 
5.4. 
Blinding ......................................................................................................................31 
5.4.1. 
Blinding of Study Medication ....................................................................................31 
6. 
SCHEDULE AND SEQUENCE OF PROCEDURES ...............................................32 
6.1. 
Schedule of Events/Assessments ................................................................................33 
6.2. 
General Conduct of the Trial ......................................................................................36 
6.3. 
Screening Period (Days –14 to –1) .............................................................................36 
6.4. 
Randomization ............................................................................................................36 
6.5. 
Follow-Up Visits 1 to 9(Day 14 to Day 210) .............................................................38 
6.6. 
End of Study Visit (Day 210 or Withdrawal) .............................................................39 
6.7. 
Additional Follow-Up Visits (Day 240 to Day 360) ..................................................39 
7. 
PROTOCOL ASSESSMENTS ..................................................................................41 
7.1. 
Assessment of Safety ..................................................................................................41 
7.1.1. 
Adverse Events ...........................................................................................................41 
7.1.2. 
Clinical Laboratory Assessments ...............................................................................41 
7.1.3. 
Electrocardiograms .....................................................................................................41 
7.1.4. 
Assessment of Cardiovascular Events ........................................................................42 
7.1.5. 
Anti-ALN-PCSSC Antibodies ....................................................................................42 
7.2. 
Assessment of Efficacy ...............................................................................................42 


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7.2.1. 
Change from Baseline LDL-C ....................................................................................42 
7.2.2. 
Change from Baseline in Lipids/Lipoproteins ............................................................43 
8. 
ADVERSE EVENTS..................................................................................................44 
8.1. 
Definitions ..................................................................................................................44 
8.1.1. 
Adverse Event .............................................................................................................44 
8.1.1.1. 
AE Severity .................................................................................................................44 
8.1.1.2. 
Study Drug Causality ..................................................................................................44 
8.1.2. 
Serious Adverse Event ................................................................................................45 
8.1.3. 
Medication errors ........................................................................................................45 
8.1.4. 
Adverse Events of Special Interest (AESIs) ...............................................................46 
8.1.5. 
Other Safety Related Information ...............................................................................46 
8.2. 
Procedure for Non-Serious Adverse Event Recording ...............................................47 
8.3. 
Procedure for Serious Adverse Event Reporting ........................................................47 
8.4. 
Procedure for Medication Error Reporting .................................................................47 
8.5. 
Procedure For Reporting Adverse Events Of Special Interest (AESIs) .....................48 
8.6. 
Procedure For Reporting Pregnancies/Lactation Exposure ........................................48 
9. 
DATA COLLECTION ...............................................................................................49 
10. 
STATISTICAL PLAN................................................................................................50 
10.1. 
Sample Size ................................................................................................................50 
10.2. 
Randomization ............................................................................................................50 
10.3. 
General Statistical Considerations and Definitions ....................................................50 
10.3.1. 
General Statistical Methods ........................................................................................50 
10.3.2. 
Analysis Population ....................................................................................................50 
10.3.2.1. 
Intent-to-Treat (ITT) Population .................................................................................50 
10.3.2.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................51 
10.3.2.3. 
Per-Protocol (PP) Population ......................................................................................51 
10.3.2.4. 
Safety Population ........................................................................................................51 
10.3.3. 
Analysis Windows and Baseline ................................................................................51 
10.3.4. 
Missing Data Handling ...............................................................................................51 
10.4. 
Statistical Analyses .....................................................................................................51 
10.4.1. 
Demographic and Background Characteristics ..........................................................51 
10.4.2. 
Study Drug and Concomitant Medications .................................................................51 
10.4.3. 
Efficacy Analysis ........................................................................................................52 


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10.4.3.1. 
Primary Efficacy Endpoints ........................................................................................52 
10.4.3.2. 
Secondary Efficacy Endpoints ....................................................................................52 
10.4.3.3. 
Interim Analysis ..........................................................................................................52 
10.4.4. 
Safety Analysis ...........................................................................................................53 
10.4.4.1. 
Adverse Events ...........................................................................................................53 
10.4.4.2. 
Laboratory Tests .........................................................................................................53 
10.4.4.3. 
Vital Signs ..................................................................................................................53 
10.4.4.4. 
Neurological Examinations ........................................................................................53 
11. 
RECORDS RETENTION ..........................................................................................54 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
12.1. 
Monitoring ..................................................................................................................55 
12.2. 
Auditing ......................................................................................................................55 
12.3. 
Protocol Deviations ....................................................................................................55 
13. 
ETHICS AND RESPONSIBILITY ............................................................................57 
13.1. 
Informed Consent .......................................................................................................57 
13.2. 
Institutional Review Board/Ethics Committee ...........................................................57 
14. 
CONFIDENTIALITY ................................................................................................58 
15. 
INVESTIGATOR AGREEMENT .............................................................................59 
16. 
REFERENCES ...........................................................................................................60 
APPENDIX A. NEUROLOGICAL EXAMINATION ..............................................................63 
APPENDIX B. SAMPSON CRITERIA FOR DIAGNOSING ANAPHYLAXIS .....................67 
APPENDIX C. CLARIFICATION OF LABORATORY ASSESSMENTS TO BE 
PERFORMED IN THE SCREENING PHASE (DAY -14 TO -1) ............................68 
 
LIST OF TABLES 
Table 1: 
Dosing Regimens ........................................................................................................21 
Table 2: 
Investigational Product ...............................................................................................29 
Table 3: 
Study Design and Schedule of Assessments ..............................................................33 
Table 4: 
Common Terminology Criteria for Adverse Events (CTCAE) of Injection 
Site Reaction ...............................................................................................................46 
 
LIST OF FIGURES 
Figure 1: 
Study Design for One Dose ........................................................................................22 


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Figure 2: 
Study Design for Two Doses ......................................................................................23 


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LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESIs 
Adverse Events of Special Interest 
ALT 
alanine aminotransferase  
Apo-A1 
apolipoprotein A1 
Apo-B 
apolipoprotein B 
aPTT 
activated partial thromboplastin 
ASCVD 
atherosclerotic cardiovascular disease  
AST 
aspartate aminotransferase 
BUN 
total protein urea 
CHD 
coronary heart disease 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
dL 
Deciliter(s) 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EU 
European Union 
FDA 
Food and Drug Administration 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPV 
Global Pharmacovigilance Department 
HbA1c 
glycated hemoglobin A1C 
HDL-C 
high density lipoprotein cholesterol 
hsCRP 
high sensitivity C-reactive protein  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IFN-γ 
interferon-gamma 
IL6 
interleukin 6  
INR 
International normalized ratio  
IRB 
Institutional Review Board 
ITT 
intent-to-treat 


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IWRS 
Interactive web response system 
Kg 
kilogram(s) 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
LNP 
lipid nanoparticles 
Lp(a) 
lipoprotein a 
MD 
multiple dose 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MI 
myocardial infarction 
mITT 
Modified intent-to-treat 
mL 
milliliter(s) 
mm 
millimeter(s) 
mmHg 
millimeters of mercury 
mmol 
Millimole 
mRNA 
messenger ribonucleic acid 
NA 
not applicable 
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PEF 
peak expiratory flow 
pH 
-log[H+] 
pM 
picomolar 
PP 
per protocol 
PT 
protrombin time 
RNA 
ribonucleic acid 
RNAi 
ribonucleic acid interference 
SAD 
single ascending dose 
SAE 
serious adverse event 
SC 
Subcutaneous 
siRNA 
small interfering ribonucleic acid 
TEAE 
treatment emergent adverse event 
TNF-α 
tumor necrosis factor-alpha  
TTR 
Target transthyretin 
ULN 
upper limit of normal 
US 
United States  
VLDL-C 
very low-density lipoprotein cholesterol 
WBC 
white blood count 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This protocol describes a study to evaluate the effect of ALN-PCSSC treatment on low-density 
lipoprotein cholesterol (LDL-C) levels at Day 180. This study will be conducted in compliance 
with Good Clinical Practices (GCP) including the Declaration of Helsinki and all applicable 
regulatory requirements. 
1.1. 
Background 
1.1.1. 
Disease Overview 
According to the World Health Organization (WHO), atherosclerotic cardiovascular disease 
(ASCVD), comprised mainly of coronary heart disease (CHD) and stroke, is the leading cause of 
death worldwide, resulting in 17 million deaths annually [WHO Cardiovascular Statistics, 2011]. 
Data from the INTERHEART case-control study estimates that 45% of myocardial infarctions 
(MI) in Western Europe and 35% of myocardial infarctions in Central and Eastern Europe are 
due to abnormalities in blood lipids [Yusef et al, 2004]. In particular, elevated LDL-C, has been 
shown in multiple studies to be one of the major risk factors for CHD with a continuous and 
graded relationship between plasma LDL-C concentration and CHD risk. For every 30 mg/dL 
(0.78 mmol/L) change in LDL-C, the relative risk for CHD changes by approximately 30% 
[Grundy et al, 2004]. In addition a large meta-analysis of 21 statin studies concluded that for 
every 1 mmol/L (39 mg/dL) reduction in LDL-C (with statin therapy) there is an approximate 
22% reduction in cardiovascular events [CTT et al, 2010]. While statins are the treatment of 
choice for hyperlipidemia and the primary and secondary prevention of ASCVD there is still a 
need for additional lipid-lowering therapies for patients who do not reach target LDL-C levels or 
sufficient percent reductions in LDL-C to attenuate their ASCVD risk. Furthermore, in many 
patients, statin therapy cannot be optimized as patients are either intolerant of statins due to side 
effects (most commonly muscle pain, myopathy myositis) or because of other adverse effects 
such as elevations in liver enzymes. These limitations of contemporary therapy are particularly 
relevant among patients with pre-existing ASCVD such as diabetes, or patients with familial 
hypercholesterolemia who are at the highest risk of future cardiovascular (CV) events, and hence 
require the most intensive and aggressive management of hypercholesterolemia [Davidson et al, 
2005; Nag et al, 2007; Reiner et al, 2011; Stone et al, 2014]. Among these high-risk subjects, less 
than 50% achieved the target LDL-C goal of <100 mg/dL at 6 months post-statin treatment 
despite close monitoring and drug regimen optimization [Foley et al, 2003; Kearney et al, 2008; 
CTT et al, 2010; Foody et al, 2010]. Thus, there remains a clear unmet medical need for 
lowering LDL-C, especially in certain patient populations.  
1.1.2. 
PCSK9 Biology and Target Rationale 
Proprotein convertase subtilisin kexin type 9 (PCSK9) is a member of the subtilisin serine 
protease family. Proprotein convertase subtilisin kexin type 9 is predominantly expressed by the 
liver and is critical for the down regulation of hepatocyte low-density lipoprotein receptor 
(LDLR) expression [Mousavi et al, 2009]. LDL-C levels in plasma are markedly elevated in 
humans with gain of function mutations in PCSK9, classifying them as having severe familial 
hypercholesterolemia [Abifadel et al, 2003]. Data from genetic association studies have 


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identified loss of function alleles in human PCSK9 that result in lower PCSK9 protein levels and 
lower LDL-C levels [Zhao et al, 2006; Hooper et al, 2007; Horton et al, 2009]. In one published 
study, heterozygous individuals (carrying a single copy of a loss of function PCSK9 mutation) 
had significantly lower LDL-C with median levels of approximately 70 mg/dL (1.81 mmol/L) 
[Cohen et al, 2006]. Over a 15-year period of retrospective data analysis, this sustained lowering 
in LDL-C levels translated to an 88% lower risk of risk for CHD. Follow-up publications 
describe two adult individuals that are compound heterozygous for loss of function alleles of 
PCSK9. These individuals lack detectable plasma PCSK9 protein, have LDL-C levels 
≤20 mg/dL, and yet are otherwise healthy [Zhao et al, 2006; Hooper et al, 2007]. Additionally, 
recent human clinical trials with PCSK9 blocking antibodies have shown significant lowering of 
LDL-C in healthy volunteers and across a range of high CV risk populations and with elevated 
LDL-C both with and without statins [Banerjee et al, 2012; Dias et al, 2012; Milazzo et al, 2012; 
Raal et al, 2012; Roth et al, 2012; Stein et al, 2012; Sullivan et al, 2012; Hooper et al, 2013]. 
Thus, the overall scientific and clinical data suggests that PCSK9 is a well-validated drug target 
whose inhibition results in significant LDL-C lowering without otherwise negatively impacting 
overall health most recently culminating in the approval (in Europe and North America) of two 
monoclonal agents to inhibit PCSK9. 
1.1.3. 
Mechanism of RNA Interference 
Ribonucleic acid (RNA) interference (RNAi) is a naturally occurring cellular mechanism for 
regulating gene expression that is mediated by small interfering RNAs (siRNAs). Typically, 
synthetic siRNAs are 19-base to 25-base pair double-stranded oligonucleotides in a staggered 
duplex with a two- to four-nucleotide overhang at one or both of the 3’ ends. Such siRNAs can 
be designed to target an endogenous messenger RNA (mRNA) transcript of a given gene. When 
introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex 
called the RNA-Induced Silencing Complex. This enzyme complex subsequently binds to its 
complementary mRNA sequence, mediating cleavage of the target mRNA and the suppression of 
the target protein encoded by the mRNA [Elbashir et al, 2001].  
Since unmodified siRNAs are rapidly eliminated and do not achieve significant tissue 
distribution upon systemic administration [Soutschek et al, 2004], various formulations are 
currently used to target their distribution to tissues, and to facilitate uptake of siRNAs into the 
relevant cell type. One approach that has been used successfully in vivo, in animal models 
(including in rodents and nonhuman primates) and humans employs intravenous delivery of 
siRNA in lipid nanoparticle (LNP) formulations [Soutschek et al, 2004; Morrissey et al, 2005; 
Geisbert et al, 2006; Judge et al, 2006; Zimmermann et al, 2006; Coelho et al, 2013; Tabernero 
et al, 2013]. Another approach for liver-specific gene silencing is subcutaneously administered 
siRNA conjugated to a N-acetylgalactosamine (GalNAc) carbohydrate ligand [Ashwell and 
Morell, 1974]. Conjugation of a triantennary GalNAc ligand to an siRNA enables hepatocyte 
binding and subsequent cellular uptake via the asialoglycoprotein receptor, resulting in 
engagement of the RNAi pathway and down regulation of hepatic proteins. Single and multiple 
doses of subcutaneously administered siRNA-GalNAc conjugates have been used to target 
transthyretin (TTR) mRNA for the treatment of TTR-mediated amyloidosis. ALN-TTRCSC has 
been found to be generally safe and well tolerated in Phase I and Phase II clinical trials in over 
40 healthy volunteers and 18 subjects with familial amyloidotic cardiomyopathy and senile 


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systemic amyloidosis [ALN-TTRSC-001; EudraCT 2012-004203-12; and ALN-TTRSC-002; 
EudraCT 2013-002856-33].  
1.2. 
ALN-PCSSC, an RNAi Therapeutic for Hypercholesterolemia 
ALN-PCSSC Solution for Injection (subcutaneous [SC] use) is comprised of the PCSK9 siRNA, 
ALN-60212, formulated in phosphate buffer. The PCSK9 siRNA is a chemically synthesized 
double stranded oligonucleotide covalently linked to a ligand containing GalNAc residues. This 
synthetic investigational RNAi therapeutic has been designed to suppress the liver production of 
PCSK9 when administered via SC injection. Inhibition of PCSK9 synthesis through an RNAi 
mechanism has the potential to lower tissue and circulating plasma PCSK9 protein levels, 
resulting in higher expression of LDLR in the liver, and consequently lower LDL-C levels in the 
blood stream. The initial proposed indication for ALN-PCSSC is the treatment of subjects with 
hypercholesterolemia who are not achieving therapeutic LDL-C goals despite maximally 
tolerated lipid-lowering therapy, or for subjects who are intolerant of statins. 
1.2.1. 
Preclinical Studies 
The safety pharmacology and toxicology of ALN-PCSSC was evaluated in a series of in vitro 
and in vivo nonclinical studies. 
The drug substance in ALN-PCSSC (ALN-60212) is designed to match the human and 
cynomolgous monkey mRNA transcripts for PCSK9, sharing a substantial partial match to the 
rat PCSK9 mRNA. ALN-60212 was informatically identified from a large collection of possible 
siRNAs targeting PCSK9 based on its predicted potency and selectivity. ALN-PCSSC reduced 
the expression of PCSK9 in Hep3B liver cells with a median inhibitory concentration of 20 pM 
and inhibited hPCSK9 serum protein levels in a transgenic mouse model with a single dose 
effective dose causing 50% inhibition of approximately 2 mg/kg and an effective dose causing 
80% inhibition of approximately 6 mg/kg. In single- and multi-dose regimen studies in 
cynomolgus monkeys, ALN-PCSSC exhibited dose-dependent sustainable suppression of 
PCSK9 protein that was paralleled by lowering of serum LDL-C with the same kinetics. The 
time to reach PCSK9 and LDL-C nadir was approximately 20 days and there was no difference 
in time to nadir between different dose levels. In single-dose studies, the maximal mean PCSK9 
and LDL-C inhibition was 85% and 68%, respectively, which was observed at the two highest 
doses of ALN-PCSSC administered (6 and 10 mg/kg); however, the duration of PCSK9 silencing 
and LDL-C lowering was markedly extended at the higher 10 mg/kg dose. In multi-dose studies, 
the maximal mean PCSK9 and LDL-C inhibition was 93% and 74%, respectively, which was 
similar to that observed in the single-dose study. Following discontinuation of ALN-PCSSC 
administration, recovery of PCSK9 levels was slow, returning to baseline after 100 days in the 
single-dose study and only showing partial recovery between doses in the multi-dose regimen. 
There were no ALN-PCSSC-related changes to the levels of high-density lipoprotein cholesterol 
(HDL-C) or triglycerides in any of the groups. As expected, total cholesterol levels were reduced 
by up to 30% reflecting the decrease in LDL-C. 
Good Laboratory Practices (GLP) compliant repeat-dose studies of 4 and 15 weeks duration have 
been conducted in rats and monkeys. These studies included toxicokinetic analysis of 
ALN-PCSSC in plasma and in tissues, including the liver which is the target organ and the 
kidney which is the main organ of elimination. The GLP 4-week toxicology studies in rats and 


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monkeys involved every other week administration of ALN-PCSSC at dose levels of 10, 50, and 
250 mg/kg and once a week administration of 10 mg/kg for rats and 30 mg/kg for monkeys. The 
GLP 15-week toxicology studies in rats and monkeys involved once monthly administration of 
ALN-PCSSC at dose levels of 10, 50, and 250 mg/kg and once every other week administration 
of 125 mg/kg for rats and 25 mg/kg for monkeys. Each toxicology study also included an 8-week 
treatment-free recovery period for all dose groups. ALN-PCSSC was well tolerated in all studies 
and there were no dose-limiting toxicities. The most common findings were related to the 
pharmacological effects of ALN-PCSSC on lipid profiles. There were consistent decreases in 
LDL-C and total cholesterol which were expected. Histopathological findings included 
vacuolation in hepatocytes of rats and lymph node macrophages of monkeys and the presence of 
basophilic granules in hepatocytes of monkeys and kidneys of rats. These microscopic findings 
were not associated with changes in clinical pathology parameters and are consistent with class 
effects of oligonucleotides and were not considered adverse. In a non-GLP dose-range-finding 
study conducted in monkeys, ALN-PCSSC did not stimulate pro-inflammatory cytokines, 
activate complement, or impact coagulation. ALN-PCSSC also did not stimulate 
pro-inflammatory cytokines following single dose administration to mice. In a cardiovascular 
and respiratory study in telemetered conscious cynomolgus monkeys, ALN-PCSSC had no 
immediate or delayed effects on clinical observations, qualitative or quantitative 
electrocardiogram (ECG) parameters, hemodynamic parameters, respiration rate, or body 
temperature at any dose level. In addition, ALN-PCSSC did not induce gene mutations or 
chromosomal damage in a battery of in vitro and in vivo genotoxicity studies. 
Further information is in the Investigator’s Brochure (IB).   
1.2.2. Clinical Studies 
One ongoing Phase I study has been conducted to date (Study ALN-PCSSC-001). This was a 
randomized, single-blind, placebo-controlled, single-dose escalation and multiple-dose study of 
ALN-PCSSC administered SC to subjects with elevated LDL-C. The study was conducted in two 
phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase. During the SAD 
phase, 24 subjects were assigned to either receive placebo or one of five doses of ALN-PCS 
ranging from 25 mg to 800 mg. Those who received doses of at least 100 mg saw their LDL-C 
drop at least 40%; at the 500 mg dose, LDL-C levels dropped as much as 78%. At 140 days after 
the treatment was given, subjects still had an average LDL-C reduction of about 40%. 
In the MD phase, 45 subjects received multiple doses of either ALN-PCS (125mg weekly x4, 
250 mg bi-weekly x2, 300 mg and 500 mg twice given 1 month apart) or placebo. These subjects 
had maximal LDL-C reductions of 80% and average LDL-C reductions of 50% to 60%. To date, 
the drug appears to be generally safe and well tolerated. One subject on statin comedication had 
elevated liver enzymes with alanine aminotransferase (ALT) >4x the upper limit of normal 
(ULN), which resolved on stopping the statin. 
1.2.3. 
Known and Potential Risks and Benefits 
Subjects taking part in this clinical study will receive guideline recommended standard of care as 
background therapy (including maximally-tolerated statin therapy and/or other LDL-C lowering 
therapies ) when administered ALN-PCSSC or placebo. Reduction of LDL-C has been 


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associated with reduced CV risk both by epidemiology and in controlled clinical trials. The 
safety profile observed to date is considered acceptable for this clinical trial. 
An expanded risk-benefit summary is provided in the IB.  
1.3. 
Study Rationale 
1.3.1. 
Study Rationale 
The overall safety data from ALN-PCSSC in nonclinical studies and clinical data from the Phase 
I ALN-PCSSC-001 study, the ALN-PCS02-001 study, and multiple PCSK9 antibody studies 
demonstrated that potent lowering of PCSK9 is well-tolerated in human subjects and support the 
dose and dosing schedule proposed in this Phase II study.  
Results of this study will be used to select a dose(s) for future studies. 
1.3.2. 
Dose Rationale 
Previous studies using PCSK9-targeting siRNAs formulated in LNPs (ALN-PCS02) or using 
PCSK9 antibodies, and one Phase I study with ALN-PCSSC in which subjects received single-
doses ascending from 25 mg to 800 mg, have demonstrated that substantial lowering of PCSK9 
is safe and well-tolerated in humans. Doses for the Phase I study were calculated using the rat 
and monkey no observed adverse effect levels (NOAELs) based on body weight and body 
surface area (mg/m2). Collectively, the results of nonclinical studies with ALN-PCSSC 
supported a starting dose of 25 mg for subjects participating in the SAD phase of the previous 
Phase I study. 
In Phase I Study ALN-PCSSC-001, clinically significant reductions in LDL-C levels were seen 
with single ALN-PCSSC doses as low as 25 mg with larger decreases seen with higher doses and 
a plateau at 300 mg. Subjects at ALN-PCSSC doses of 300 mg or higher had maximal LDL-C 
reductions of up to 78.1% and average least squares mean group nadir reductions of 50 to 59%. 
In the MD phase, 45 subjects received multiple doses of either ALN-PCS (125 mg weekly x4, 
250 mg biweekly, 300 mg and 500 mg twice given 1 month apart) or placebo. Subjects at ALN-
PCSSC doses of 300 mg or higher had maximal LDL-C reductions of 83% and average least 
squares mean group nadir LDL-C reductions of 53.4% to 59.9% at all dose levels tested.   
Based on the interim results of the Phase I Study ALN-PCSSC-001, where maximum effect on 
LDL-C was seen by 84 days and a significant effect was still observed at 180 days, the Phase II 
study has been designed to test the efficacy of a single dose (200 mg, 300 mg, or 500 mg) or two 
doses 90 days apart (100 mg, 200 mg, or 300 mg). This will allow dose selection for Phase III. 
The dosing regimens used in Phase II are therefore fully supported by the findings of the Phase I 
study. 
1.4. 
Study Population 
This study will include male or female subjects ≥18 years of age with a history of ASCVD or 
ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 diabetes, familial 
hypercholesterolemia), or a >20% ten-year risk of a CV event assessed by Framingham Risk 
Score or equivalent and receiving maximum-tolerated lipid-lowering therapy. 


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2. 
TRIAL OBJECTIVES AND PURPOSE 
This trial is designed to evaluate the efficacy, safety, and tolerability of ALN-PCSSC 
injection(s).  
2.1. 
Primary Objective  
The primary objective of this study is to evaluate the effect of ALN-PCSSC treatment on LDL-C 
levels at Day 180. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the effect of ALN-PCSSC on the 
following:  
 LDL-C levels at Day 90 
 LDL-C levels at other time points 
 PCSK9 levels over time 
 Other lipids, lipoproteins, apolipoproteins 
 Proportion of subjects achieving pre-specified global lipid guidelines 
 Individual responsiveness to different doses  
 Duration of lipid-lowering effect of different doses  
 Safety and tolerability profile of ALN-PCSSC 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are to collect and evaluate the effect of ALN-PCSSC on the 
following: 
 CV events such as CV death, non-fatal MI, resuscitated cardiac arrest, and non-
fatal stroke (ischemic and hemorrhagic) 
 Evaluation of anti-drug antibodies (ADA) for the investigational product 


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3. 
TRIAL DESIGN 
3.1. 
Type/Design of Trial 
This study will be a Phase II, placebo-controlled, double-blind, randomized trial in subjects with 
ASCVD or ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia) and 
elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate the 
efficacy, safety, and tolerability of ALN-PCSSC injection(s). The study will be a multi-national, 
multi-center study (approximately 60 centers). Informed consent will be obtained from subjects 
before the initiation of any study-specific procedures.  
Subjects will be screened and 480 eligible subjects will be randomized: 60 subjects per each of 
six ALN-PCSSC dose groups plus 120 subjects total across the placebo groups (20 subjects each 
to match each of the six dose groups) as outlined in Table 1. Treatment allocation will be 
stratified by country and by current use of statins or other lipid-modifying therapies. Each 
subject will receive either one or two injections of ALN-PCSSC or placebo at the doses specified 
in Table 1. 
TABLE 1: 
DOSING REGIMENS 
Drug and dose 
No. Subjects 
Randomized 
Volume (mL) 
Single Dose: One or Two injections on Day 1 
Placebo for 200 mg 
20 
1.0 
200 mg ALN-PCSSC 
60 
1.0 
Placebo for 300 mg 
20 
1.5 
300 mg ALN-PCSSC 
60 
1.5 
Placebo for 500 mg 
20 
2.5a 
500 mg ALN-PCSSC  
60 
2.5a 
Two Doses: One Injection on Day 1 and Day 90 
Placebo for 100 mg 
20 
0.5 
100 mg ALN-PCSSC  
60 
0.5 
Placebo for 200 mg 
20 
1.0 
200 mg ALN-PCSSC  
60 
1.0 
Placebo for 300 mg 
20 
1.5 
300 mg ALN-PCSSC  
60 
1.5 
a 500 mg will be administered as two injections, one of 300 mg (1.5 mL),  
and one of 200 mg (1.0 mL) in two different injection sites. 1.5 mL is the maximum 
injection volume for a single injection site.  
An independent Data Monitoring Committee (DMC) will review safety data beginning after the 
first 40 subjects have received the first dose of ALN-PCSSC or placebo and complete the Day 14 
follow-up visit. Thereafter the DMC will review safety data every 2 months until the end of the 
trial. A recommendation may be taken to stop the study at any of these reviews.  
All eligible subjects will be randomized and receive the first SC administration of ALN-PCSSC 
or placebo on Day 1. Subjects randomized to receive a second dose of study drug will receive the 


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3.2.2. 
Two Doses (one injection each on Day 1 and Day 90) 
The study design for two doses is presented in Figure 2. 
Figure 2: 
Study Design for Two Doses 
 
 
3.3. 
Primary Endpoint(s) 
The primary endpoint of this trial is percentage change in LDL-C from baseline to Day 180. 
3.4. 
Secondary Endpoints 
The secondary endpoints of this trial are: 
 Percentage change in LDL-C from baseline to Day 90 
 Percentage change in LDL-C from baseline to Days 14, 30, 60, 104, 120, 150, and 
210  
 Proportion of subjects in each group with LDL-C greater than 80% of the baseline 
value at Day 180 and Day 210 
 Duration of time on treatment for subjects to return to 80% of baseline or greater 
LDL-C or PCSK9 protein 
 Individual responsiveness defined as the number of subjects reaching on treatment 
LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 90, 
120, and 180  
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline at Days 90, 120, and 180 
 Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 104, 120, 
150, 180, and 210 
 Percentage change in other lipids, lipoproteins, apolipoproteins from baseline at each 
subsequent visit to Day 210 
Randomization (Day 1) 
Treatment Phase 
(Day 1 to Day 90)
Follow-up 
and EOS (Day 210)
(Day 91 to Day 210)
Additional Follow-up
(for subjects in whom LDL-C 
levels have not returned to 
>80% of baseline values; 
Day 210 to Day 360)
Screening
(Day -14 to Day -1)
D1
Study drug
dosing
FU4
D90
 3
Study drug
dosing
FU1
D14
 2
FU2
D30
 3
FU3
D60
 3
FU5
D104
 3
FU6
D120
 3
FU7
D150
 3
FU8
D180
 3
FU9
D210
 3
FU10
D240
 3
FU11
D270
 3
FU12
D300
 3
FU13
D330
 3
FU14
D360
 3
Study Assessments


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 Proportion of subjects in each group who attain global lipid modification targets for 
their level of ASCVD risk 
3.5. 
Exploratory Endpoint(s)  
The exploratory endpoints of this trial are: 
 CV events such as CV death, non-fatal MI, resuscitated cardiac arrest, and non-fatal 
stroke (ischemic and hemorrhagic) 
 Evaluation of ADA for the investigational product  
3.6. 
Measures to Minimize/Avoid Bias 
3.6.1. 
Blinded Study Where Pharmacist is Unblinded  
The study will be conducted using a double-blind design, with placebo matched by volume 
within each dose and regimen but not between regimens. Specifics on how the blind for the study 
drug is maintained are provided in Section 5.4.1. Allocation of treatment is not disclosed to the 
study team. Study medication will be prepared by the unblinded hospital pharmacist and will be 
dispensed in a blinded syringe as randomized by the interactive web response system (IWRS). 
Pharmacists will be required by signature to keep the study personnel blinded. Blinding is 
achieved by placing an over label on each unique syringe dispensed by the pharmacist. The over 
label will cover the outside of the syringe masking the color of the solution within.  


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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects  
This will be a multi-center study conducted in North America and Europe. A total of 
480 randomized subjects are planned for inclusion in the study: 60 subjects per each of six 
ALN-PCSSC treatment groups plus 120 subjects total across the placebo groups (20 subjects 
each to match each of the six drug groups). Assuming about a 15% drop out rate, the sample size 
will be approximately 100 evaluable subjects total across the placebo groups and approximately 
50 subjects in each of six ALN-PCSSC treatment groups. This sample size of at least 
400 evaluable subjects will provide more than 90% power to detect a 30% reduction of LDL-C 
levels in at least one ALN-PCSSC dose group.  
4.2. 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Male or female subjects ≥18 years of age.  
2. History of ASCVD or ASCVD-risk equivalents (symptomatic atherosclerosis, Type 2 
diabetes, familial hypercholesterolemia, including subjects whose 10-year risk of a 
cardiovascular [CV] event assessed by Framingham Risk Score* or equivalent has a 
target LDL-C of < 100mg/dL).  
3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) for ASCVD subjects or ≥2.6 mmol/L 
(≥100 mg/dL) for ASCVD-risk equivalent subjects at screening. 
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. 
5. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate 
(eGFR) using standardized local clinical methodology. 
6. Subjects on statins should be receiving a maximally tolerated dose (investigator’s 
discretion). 
7. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable 
dose for ≥30 days before screening with no planned medication or dose change during 
study participation. 
8. Willing and able to give written and informed consent before initiation of any 
study-related procedures and willing to comply with all required study procedures. 
*By Framingham Risk Score > 20% 
4.3. 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria apply 
immediately prior to randomization: 
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study, and/or put the subject at significant risk 


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(according to investigator’s [or delegate] judgment) if he/she participates in the clinical 
study. 
2. An underlying known disease, or surgical, physical, or medical condition that, in the 
opinion of the investigator (or delegate) might interfere with interpretation of the clinical 
study results. 
3. New York Heart Association (NYHA) class II, III or IV heart failure or last known left 
ventricular ejection fraction <30%. 
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by 
medication or via ablation. 
5. Any history of hemorrhagic stroke. 
6. Major adverse cardiac event within 6 months prior to randomization. 
7. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood 
pressure >110 mmHg prior to randomization despite anti-hypertensive therapy. 
8. Poorly controlled Type 2 diabetes, ie, glycated hemoglobin A1c (HbA1c) >10.0% prior to 
randomization. 
9. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained ALT, aspartate aminotransferase (AST), elevation 
>2x ULN or total bilirubin elevation >1.5x ULN at screening confirmed by a repeat 
measurement at least 1 week apart. 
10. Serious comorbid disease in which the life expectancy of the subject is shorter than the 
duration of the trial (eg, acute systemic infection, cancer, or other serious illnesses). This 
includes all cancers with the exception of treated basal-cell carcinoma occurring >5 years 
before screening. 
11. Females who are pregnant or nursing, or who are of childbearing potential and unwilling 
to use at least two methods of contraception (oral contraceptives, barrier methods, 
approved contraceptive implant, long- term injectable contraception, intrauterine device 
or tubal litigation)**. Women who are >2 years postmenopausal defined as ≥1 year since 
last menstrual period AND if <55 years old with a negative pregnancy test within 24 
hours of randomization or surgically sterile are exempt from this exclusion. 
12. Males who are unwilling to use an acceptable method of birth control during the entire 
study period (ie, condom with spermicide). 
13. Known history of alcohol and/or drug abuse within the last 5 years. 
14. Treatment with other investigational medicinal products or devices within 30 days or five 
half˗lives, whichever is longer. 
15. Use of other investigational medicinal products or devices during the course of the study. 
16. Any condition that according to the investigator could interfere with the conduct of the 
study, such as but not limited to: 
a. Inappropriate for this study, including subjects who are unable to 
communicate or to cooperate with the investigator 


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b. Unable to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope, and possible consequences of the study 
(including subjects whose cooperation is doubtful due to drug abuse or 
alcohol dependency) 
c. Unlikely to comply with the protocol requirements, instructions, and study-
related restrictions (eg, uncooperative attitude, inability to return for follow-up 
visits, and improbability of completing the study) 
d. Have any medical or surgical condition, which in the opinion of the 
investigator would put the subject at increased risk from participating in the 
study 
e. Involved with, or a relative of, someone directly involved in the conduct of 
the study 
f. Any known cognitive impairment (eg, Alzheimer’s disease) 
17. Previous or current treatment (within 90 days of screening) with monoclonal antibodies 
directed towards PCSK9. 
**For the entire duration of the study 
Subjects excluded for any of the above reasons may not be re-screened for participation at any 
time if the exclusion characteristic has changed. 
4.4. 
Withdrawal Criteria 
All subjects have the right to withdraw at any point during treatment without prejudice. The 
investigator can discontinue any subject at any time if medically necessary. It will be documented 
whether or not each subject completed the clinical study. If for any subject study treatment or 
observations were discontinued, the reason will be recorded and the Sponsor should be notified 
promptly. Reasons that a subject may discontinue participation in a clinical study are considered to 
constitute one of the following: 
 AE 
 Death 
 Subject withdrew consent 
 Physician decision 
 Lost to follow-up 
Upon occurrence of a serious or intolerable AE, the investigator or designee will make every 
possible attempt to confer with the Sponsor before discontinuing the subject, and the DMC will 
be notified. 
It is imperative to obtain complete follow-up data for all randomized subjects whether or not 
they receive their assigned treatment or have discontinued study drug. Every attempt should be 
made to collect follow-up information except for those subjects who specifically withdraw 
consent release of such information. All procedures and laboratory specimens or tests requested 
for evaluation following administration of the Study Drug should be carried out when possible 


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whether or not a subject continues to receive treatment according the protocol. Subjects will not 
be replaced in this trial. 
4.4.1. 
Withdrawal from Study Medication 
In the event a subject withdraws or is withdrawn from the study medication (eg, receives first 
injection and not second injection), the investigator will inform the Medical Monitor and the 
Sponsor immediately. If there is a medical reason for withdrawal, the subject will remain under 
the supervision of the investigator for protocol-specified safety follow up procedures. The DMC 
may be notified.  
As noted in Section 4.4, it is imperative to obtain complete follow-up data for all randomized 
subjects whether or not they receive their assigned treatment or have discontinued study drug. 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Study Medications 
5.1.1. 
ALN-PCSSC 
Treatments will be assigned as outlined in Table 1. Study drug (ALN-PCSSC) information is 
described in Table 2. 
TABLE 2: 
INVESTIGATIONAL PRODUCT 
 
Investigational Product 
Product Name: 
ALN-PCSSC 
Dosage Form: 
Solution for Injection 
Unit Dose 
100 mg vial (200 mg/mL) 
Route of Administration 
SC use 
Physical Description 
Clear, colorless to pale yellow solution essentially free of 
particulates 
Manufacturer 
AAI Pharma Inc., Charleston, SC, United States (US). 
5.1.2. 
Placebo 
Placebo will be supplied by the clinical study site as sterile normal saline 0.9% for SC injection. 
Placebo will be administered as an SC injection in an amount matched to the doses within each 
injection regimen (see Table 1). 
5.1.3. 
Packaging and Labeling 
Study drug will be provided by Catalent Pharma Solutions, Philadelphia, Pennsylvania, US. 
Medication labels will comply with regulatory requirements. The storage conditions for each 
medication provided will be described on the medication label. 
The ALN-PCSSC Solution for Injection (subcutaneous use) is packaged in 2 mL glass vials with 
a fill volume of no less than 0.55 mL. The container closure system consists of a Type I glass 
vial, a Teflon-faced 13 mm stopper, and a flip-off aluminum seal.  
5.1.4. 
Storage 
ALN-PCSSC will be stored in a secure refrigerator or at the appropriate conditions as specified 
in the Pharmacy Manual. Access should be strictly limited to the investigator, pharmacists, and 
their designees. No special procedures for the safe handling of ALN-PCSSC are required.  
5.1.5. 
Accountability 
The investigator or designee must maintain an inventory record of study drugs received and 
administered to assure the regulatory authorities and the Sponsor that the investigational new 
drug will not be dispensed to any person who is not a subject under the terms and conditions set 
forth in this protocol. Drug accountability forms and/or specific instructions can be found in the 
Pharmacy Manual. 


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The study drug supplied for use in this study is to be prescribed only by the principal investigator 
or designated sub-investigators and may not be used for any purpose other than that outlined in 
this protocol. 
During the study, all used study drug containers (eg, empty vials/bottles) will be kept until the 
monitor has reviewed the accountability records. 
All unused study drug will be destroyed on site (or returned to the packaging and labeling facility 
for destruction if destruction on site is not possible) once the study drug has been inventoried and 
the monitor has reviewed the accountability records. In the event that study drug(s) needs to be 
returned for any other reason, the site will receive a written request listing the drug lot number(s) 
to be returned and the reason for the return request. 
5.2. 
Concomitant Medications 
5.2.1. 
Prohibited Concomitant Medications 
The following medications/treatments are not permitted to be added during the study: 
 Medications used to lower LDL-C (eg, statins, ezetimibe, lomitapide, mipomersen, 
niacin, colesevelam, bile acid absorption inhibitors, monoclonal antibodies for 
PCSK9).  
5.2.2. 
Permitted Concomitant Medication(s)  
The following medications/treatments are permitted during the study: 
 Hormone replacement therapy  
 Lipid-lower medications; subjects on lipid-lower medications (such as statins and/or 
ezetimibe) should be on a stable dose for ≥30 days before screening with no planned 
medication or dose change during study participation 
 Prescription medications prescribed to treat pre-existing medical conditions such as 
diabetes and hypertension 
 Prescription or nonprescription medications, when necessary to treat an AE, and at 
the discretion of the investigator 
5.3. 
Restrictions  
Subjects will have to comply with the following restrictions during the study: 
 Fasted for at least 8 hours for all visits for fasting lipids and glucose blood samples 
 Blood donation will not be allowed at any time during the study  
 Must refrain from unaccustomed strenuous physical exercise for 48 hours before the 
screening and any study visit until the follow-up has been completed  


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5.4. 
Blinding  
5.4.1. 
Blinding of Study Medication  
This is a double-blind placebo-controlled study. Study medication will be blinded within each 
injection regimen: either one or two injections on Day 1 or a single injection on Day 1 and on 
Day 90. Only the pharmacist will have knowledge of the treatment assignment.  
Randomization via an automated IWRS will be used to assign subjects to blinded study drug. 
The clinical study site pharmacist will maintain the double blind according to site-specific 
procedures and the Pharmacy Manual. It should be noted that ALN-PCSSC may be visually 
distinguishable from placebo; therefore, syringes containing dispensed study drug will be 
masked in the pharmacy prior to transfer to the clinic. 


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6. 
SCHEDULE AND SEQUENCE OF PROCEDURES 
The Schedule of Events/Assessments (Table 3) summarizes the study assessments by time point.  
This study consists of 10 (one dose) or 11 (two doses) visits and four phases: 
Single Dose (one or two injections on Day 1):  
 Screening: Day -14 to -1 
 Randomization, initiation of study drug: Day 1 
 Treatment Phase: Day 1 
 Follow-up:  
o Follow-up: Days 2 to 210; end of study (EOS) on Day 210  
o Additional Follow-Up (for subjects in whom LDL-C levels have not returned to 
>80% of baseline values; subjects will return each month for follow-up until this 
level has been reached or until Day 360): Days 240, 270, 300, 330, and 360 
Two Doses (one injection each on Day 1 and Day 90):  
 Screening: Day -14 to -1 
 Randomization, initiation of study drug: Day 1 
 Treatment Phase: Day 1 to Day 90 
 Follow-up 
o Follow-up: Days 91 to 210; EOS on Day 210  
o Additional Follow-Up (for subjects in whom LDL-C levels have not returned to 
>80% of baseline values; subjects will return each month for follow-up until this 
level has been reached or until Day 360): Days 240, 270, 300, 330, and 360 
The expected duration of the subjects’ involvement in the study will be approximately 224 days, 
which includes screening, study drug administration, the course of one or two injections, and the 
follow-up period to Day 210.  
Subjects whose LDL-C levels have returned to baseline levels and who have completed the study 
to Day 210 will be given the opportunity to enroll in a separate long-term extension study in 
order to collect long-term efficacy and safety data. 
Any subjects in whom LDL-C levels have not returned to >80% of baseline values by Day 210 
will continue to be followed on a monthly visit schedule as part of this study until either this 
level has been reached or a maximum of Day 360 at which point they will be given the 
opportunity to enroll in the long-term extension study. At each visit, LDL-C levels, AEs, SAEs, 
concomitant medications, and safety laboratory assessments will be collected. For these subjects, 
the expected maximum duration of involvement in the study will be 374 days.  


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6.1. Schedule of Events/Assessments  
TABLE 3: 
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS 
 
 
Screening 
Randomization 
and Treatment 
 
Follow-Up 
End of 
Study 
(EOS) 
Additional Follow-Up (for subjects in 
whom LDL-C levels have not returned 
to >80% of baseline values)  
Treatment Phase 
 
Follow-Up 
Study Day:  
One Dose 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
NA 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (±3) 
Study Day:  
Two Doses 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
FU5 
104 
(± 3)a 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (± 3) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including prior 
meds) 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examinationb 
(including full 
neurological 
examination) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
Xc 
X 
X 
X 
Xc 
X 
X 
X 
X 
X 
 
12 Lead ECGd 
X 
X 
 
 
 
 
 
 
 
 
X 
 
HbA1cg 
Xf 
X 
 
 
 
X 
 
 
 
X 
 
X (Day 270 and 360) 
Clinical labs 
(local)e,k 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Clinical labs 
(central) e,g,k 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening 
Randomization 
and Treatment 
 
Follow-Up 
End of 
Study 
(EOS) 
Additional Follow-Up (for subjects in 
whom LDL-C levels have not returned 
to >80% of baseline values)  
Treatment Phase 
 
Follow-Up 
Study Day:  
One Dose 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
NA 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (±3) 
Study Day:  
Two Doses 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
FU5 
104 
(± 3)a 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (± 3) 
Fasting lipids 
and lipoproteins 
(local) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
(local) 
Xf 
Xh 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test 
(local) 
Xi 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Anti-ALN-
PCSSC (ADA) 
antibodiesk 
 
Xl 
 
X 
Xm 
Xm 
 
X 
Xa,m 
Xa,m 
X 
Xn 
Efficacy 
parameters 
(LDL-C, 
lipids,PCSK9)o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Xp 
Study drug 
administration 
 
X 
 
 
 
X 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA = anti-drug antibodies; AE = adverse event; ECG = electrocardiogram; FU=follow-up; EOS = end of study; hsCRP=high sensitivity C-reactive protein; IL6=interleukin 6; IFN-γ=interferon gamma; 
LDL-C = low-density lipoprotein cholesterol; NA = not applicable; PCSK9 = proprotein convertase subtilisin/kexin type 9; SAE = serious adverse event;TNF-α=tumor necrosis factor alpha. 
a Subjects who receive a second dose of study drug on Day 90 only. b Physical examination at Screening includes recording of height and weight.  
c Vital signs: blood pressure, heart rate, temperature, and respiration will be measured. On Day 1 and Day 90 (subjects who receive a second dose of study drug only), vital signs will be measured 
prior to injection and at 4 hours after injection. 
d ECG is performed prior to the injection on Day 1. 


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e Hematology, chemistry (including glucose, liver and renal function), and coagulation testing to be performed by local laboratory at screening. Hematology, chemistry (including glucose,  liver and 
renal function, hsCRP, IL6, IFN-γ, and TNF-α), and coagulation testing to be performed by central laboratory from randomization onwards. Blood samples for determination laboratory values will be 
performed prior to study drug injection where relevant. All laboratory testing will be performed with subjects in a fasted state. See Appendix C for a list of laboratory parameters. 
f Lab tests performed in participating institution’s laboratory. Results must be available before the start of study drug injection on Day 1 to confirm subjects meet eligibility criteria. 
g Lab tests performed by study’s designated Central Lab facility from randomization to EOS. In addition, subjects in whom LDL-C levels have not returned to >80% of baseline values by Day 210 will 
continue to be followed on a monthly visit schedule as part of this study either until this level has been reached or until Day 360 at which point they will be given the opportunity to enroll in the 
long-term extension study. 
h Urinalysis collection is prior to the injection on Day 1. 
i Women of childbearing potential only. Urine pregnancy test performed and results available prior to the injection on Day 1 and Day 90 (for subjects randomized to receive injections on two days). 
j Women of childbearing potential will have a pregnancy test at each additional follow-up visit until lipids return to >80% of baseline values. 
k Additional aliquots of plasma and serum will be collected at each time point and stored for future analyses. 
l Two ADA samples will be drawn on Day 1: one before the injection and one 4 hours after the injection. 
m An additional blood draw for anti-ALN-PCSSC antibodies is not required at these visits; a stored serum sample will be used for ADA testing.  
n For subjects in whom LDL-C levels have not returned to >80% of baseline values, formation of ADA will be assessed at the last visit.  
o Efficacy parameters will include LDL-C, total cholesterol, triglycerides, HDL-C, non-HDL-C, very low-density lipoprotein (VLDL-C), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), 
lipoprotein(a) [Lp(a)], high sensitivity C-reactive protein (hsCRP), and PCSK9. 
p Efficacy parameters will include basic lipid panel (LDL-C, HDL-C, total cholesterol, triglycerides) and PCSK9; non-HDL-C and VLDL-C will be derived from the lipid panel.  
 
 


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6.2. 
General Conduct of the Trial 
Written informed consent will be obtained for this study by the principal investigator or sub-
investigator from all subjects before the performance of any protocol-specific procedure. 
6.3. 
Screening Period (Days –14 to –1) 
The following procedures will be performed within 2 weeks prior to randomization: 
 Informed consent 
 Medical history 
 Physical examination (including height and weight and full neurological examination 
[see Appendix A]) 
 Assessment of inclusion/exclusion criteria 
 Vital signs 
 12-lead ECG 
 HbA1c (local) 
 Local clinical laboratory (hematology, chemistry [including fasting glucose, liver and 
renal function] and coagulation testing) (see Appendix C) 
 Urinalysis (local) 
 Pregnancy test (local) 
 Fasting lipids/lipoproteins (local) 
 Concomitant medications 
 Central laboratoryfor the following efficacy parameters: lipid panel, LDL-C by beta 
quantification, PCSK9, hsCRP, lipoprotein a [Lp(a)], apolipoprotein A1 [Apo-A1] 
and apolipoprotein B [Apo-B]) and the following safety parameters: inflammatory 
biomarkers, hsCRP and inflammatory markers interleukin 6 (IL6), interferon-gamma 
(IFN-γ) and tumor necrosis factor-alpha (TNF-α) 
All local screening laboratory tests will be analyzed in-house at the participating institution’s 
laboratory. Results must be available before the start of study drug injection on Day 1 to confirm 
subjects meet eligibility criteria (see Section 4). The results of all local screening laboratory tests 
should be reviewed prior to randomization. If these results confirm an exclusion criterion or suggest 
any contraindication to treatment with ALN-PCSSC, the subject must not be randomized. All Central 
laboratory assessments drawn during screening are not required to be reviewed prior to randomization. 
Please refer to Appendix C for details of laboratory tests performed during the screening period. 
6.4. 
Randomization 
The following procedures will be performed prior to the injection:  
 Assessment of inclusion/exclusion criteria 


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 Randomization 
 Vital signs: blood pressure, heart rate, temperature, and respiration will be measured 
prior to injection  
 12-lead ECG 
 HbA1c (central) 
 Central clinical laboratory (hematology, chemistry [including fasting glucose, liver 
and renal function, hsCRP and inflammatory markers (IL6, IFN-γ, and TNF-α), and 
coagulation testing)  
 Urinalysis (local) 
 Pregnancy test (local) (women of childbearing potential only) 
 Assessment of ADA (central)  
 Central laboratory for efficacy parameters (lipid panel, LDL-C by beta quantification, 
PCSK9, hsCRP, lipoprotein a [Lp(a)], apolipoprotein A1 [Apo-A1] and 
apolipoprotein B [Apo-B]) 
 Concomitant medications 
 AE reporting 
 SAE reporting 
The following procedures will be performed after the injection:  
 Vital signs: blood pressure, heart rate, temperature, and respiration (4 hours after 
injection) 
 ADA (4 hours after injection) (central) 
 Concomitant medications 
 AE reporting 
 SAE reporting 
Randomization should only occur once subject eligibility is confirmed. Randomization via an 
automated IWRS will be used to assign subjects to study drug. All treatment groups will be 
studied concurrently. A total of 480 randomized subjects are planned for inclusion in the study: 
60 subjects per each of six ALN-PCSSC treatment groups plus 120 subjects total across the 
placebo groups (20 subjects each to match each of the six drug groups).  
Study drug administration will occur at this visit for all subjects (only dose for those randomized 
to receive a single dose and the first of two doses for those randomized to receive two). 
Study drug preparation: The pharmacist will prepare the study drug under aseptic conditions. 
The amount (in mL) of study drug to be administered will be determined based on the assigned 
dose level for the cohort. On study drug dosing days, the pharmacist or designee will withdraw 
the required amount of study drug into one or more syringes to be administered to the subject on 


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that day. The procedure for preparing study drug and the volume to be loaded into each syringe 
is provided in the Pharmacy Manual.  
Study drug administration: Subjects will be administered placebo or ALN-PCSSC by SC 
injection(s). Study drug injection will be administered by qualified clinical study site staff under 
the supervision of the investigator or designee and the injection site will be marked and mapped 
for later observation. The site of injection is the abdomen. If more than one injection is planned 
as per randomization, the first should be on one side of the abdomen and the second on the 
opposite side of the abdomen. Do not inject into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, or skin infections. 
If a local reaction around the injection site occurs, photographs of the injection site should be 
obtained at first presentation and at each of the follow-up visits until the injection site reaction 
resolves. Injection site reactions must be reported as described in Section 8.5. Detailed 
instructions for study drug administration are found in the Pharmacy Manual.  
6.5. 
Follow-Up Visits 1 to 9(Day 14 to Day 210) 
Subjects will return to the study center 14 days (± 2 days) after study drug administration for 
Follow-Up Visit 1, 30 days (± 3 days) after study drug administration for Follow-Up Visit 2, and 
monthly (±3 days) after that for Follow-Up Visits 3 to 7. The following procedures will be 
performed at these visits: 
 Vital signs: blood pressure, heart rate, temperature, and respiration will be measured 
at each visit. For subjects who receive a second dose of study drug, vital signs will be 
measured prior to injection and at 4 hours after injection 
 HbA1c: At Day 90 and Day 180 (central) 
 Central clinical laboratory (hematology, chemistry [including fasting glucose, liver 
and renal function, hsCRP and inflammatory markers IL6, IFN-γ and TNF-α], and 
coagulation testing)  
 ADA: at Day 30, Day 60, Day 90, Day 120, Day 150, and Day 180 (Note: Day 150 
and Day 180 only in subjects who receive a second dose of study drug. An additional 
blood draw for ADA testing at Day 60, Day 90, Day 150, and Day 180 is not 
required; a stored serum sample will be used.) (central) 
 Central laboratory for efficacy parameters (lipid panel, LDL-C by beta quantification, 
PCSK9, hsCRP, lipoprotein a [Lp(a)], apolipoprotein A1 [Apo-A1] and 
apolipoprotein B [Apo-B]) 
 Study drug administration: Second dose at Follow-Up Visit 4 (Day 90) for subjects 
randomized to receive two doses  
 Pregnancy test (local; women of childbearing potential only): At Day 14 and monthly 
beginning at Day 30 through Day 180 
 Concomitant medications 
 AE reporting 
 SAE reporting 


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6.6. 
End of Study Visit (Day 210 or Withdrawal) 
A subject’s participation in the study is complete when: 
 All ongoing SAEs have been followed to resolution 
 The following procedures/assessments have been completed  
o Vital signs 
o Physical examination (including full neurological examination [see Appendix A]) 
o 12-lead ECG 
o Central clinical laboratory (hematology, chemistry [including fasting glucose, 
liver and renal function, hsCRP and inflammatory markers IL6, IFN-γ and 
TNF-α], and coagulation testing)  
o Urinalysis (local) 
o Pregnancy test (local) 
o ADA (central) 
o Central laboratory for efficacy parameters  (lipid panel, LDL-C by beta 
quantification, PCSK9, hsCRP, lipoprotein a [Lp(a)], apolipoprotein A1 
[Apo-A1] and apolipoprotein B [Apo-B]) 
o Concomitant medications 
o AE reporting 
o SAE reporting 
6.7. 
Additional Follow-Up Visits (Day 240 to Day 360) 
Subjects in whom LDL-C levels have not returned to >80% of baseline values will return 
monthly (±3 days) for Follow-Up Visits 10 to 14 (Days 240, 270, 300, 330, and 360) either until 
this level has been reached or until Day 360. The following procedures will be performed at 
these visits: 
 HbA1c: At Day 270 and Day 360 (central) 
 Central clinical laboratory (hematology, chemistry [including fasting glucose, liver 
and renal function, hsCRP and inflammatory markers IL6, IFN-γ and TNF-α], and 
coagulation testing)  
 ADA at the last visit(central) 
 Lipids/lipoproteins (LDL-C, HDL-C, total cholesterol, triglycerides) and PCSK9; 
non-HDL-C and very low-density lipoprotein-cholesterol [VLDL-C] will be derived 
from the lipid panel (central) 
 Pregnancy test (local) at each additional follow-up visit until LDL-C has returned to 
> 80% of baseline values  
 Concomitant medications 


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 AE reporting 
 SAE reporting 
 


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7. 
PROTOCOL ASSESSMENTS 
7.1. 
Assessment of Safety  
7.1.1. 
Adverse Events  
Subjects will be carefully monitored for AEs by the investigator during the designated study 
period (see Section 8 for details).  
7.1.2. 
Clinical Laboratory Assessments 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 3). Additional 
aliquots of plasma or serum will be collected at each time point and stored for any clinically indicated 
efficacy or safety analyses to be conducted at the end of the study.  
Subjects will be in a fasted state for all clinical laboratory assessments. Screening lab tests as detailed 
in the Schedule of Assessments and Section 6.3 will be performed by each participating institution’s 
laboratory (Appendix C). Results from these screening tests must be available before the start of study 
drug injection on Day 1 to confirm subjects meet eligibility criteria. Details regarding the processing, 
shipping, and analysis of samples will be provided in the Laboratory Manual. Note: Efficacy 
laboratory assessments (eg, LDL-C and PCSK9) are described in Section 7.2. 
Laboratory assessments may include:  
Hematology: hemoglobin, hematocrit, erythrocytes, reticulocytes, platelet counts, mean cell 
hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell 
count, differential blood count. 
Coagulation: prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin (aPTT). Blood samples for determination of coagulation parameters will be performed 
prior to start of study drug injection on Day 1. 
Biochemistry: AST, ALT, alkaline phosphatase, gamma glutamyl transferase, uric acid, total 
bilirubin, sodium, creatine phosphokinase, albumin, total protein urea (BUN), creatinine, 
potassium, chloride, glucose (fasting), HbA1c, inorganic phosphate, hsCRP (fasting), eGFR, 
calcium, tryptase (as required), and inflammatory markers IL6, IFN-γ and TNF-α. 
Urinalysis: Urinalysis will be performed at the time points defined in the Schedule of Assessments 
and evaluated by dipstick analyses at the investigational site local lab (a standardized dipstick test will 
be supplied by the Central Laboratory). Urinalysis will be performed from a sample of mid-stream 
urine. In case of abnormal results, microscopy and other assessments will be performed at the local 
lab. The following parameters will be assessed: Nitrite, protein, glucose, ketone, urobilinogen, 
bilirubin, red blood cells/erythrocytes, white blood cells (WBC)/leukocytes, pH, urine sediment 
(microscopic examination will be only performed in the event of abnormalities).  
Urine pregnancy: Urine pregnancy testing will be conducted locally at the visits specified in the 
Schedule of Assessments. 
7.1.3. 
Electrocardiograms 
ECGs will be collected at baseline and at the EOS visit only unless clinically indicated. 


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7.1.4. 
Assessment of Cardiovascular Events 
Information on CV events such as CHD death, major coronary events, and stroke will be 
collected as AE data. 
7.1.5. 
Anti-ALN-PCSSC Antibodies  
Additional sample for analysis of the induction of antibodies will be collected at the time points 
in the Schedule of Assessments (Table 3).  
Aliquots of serum samples will be obtained and frozen, to permit future analysis of the effect of 
ALN-PCSSC on the expression of these exploratory biomarkers. Biological samples for biomarker 
research will be retained on behalf of the Sponsor for a maximum of 15 years following the last 
subject's last visit in the study. Details regarding the collection, processing, storage, and shipping will 
be in the Study Laboratory Manual.  
7.2. 
Assessment of Efficacy 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 3). Subjects will 
be in a fasted state for all efficacy laboratory assessments. Parameters to be assessed will include: total 
cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-B), Lp(a), hsCRP, 
and PCSK9.  
7.2.1. 
Change from Baseline LDL-C 
The primary efficacy endpoint is the percentage change in LDL-C from baseline to Day 180.  
In addition, this study will assess:  
 Percentage change in LDL-C from baseline to Day 90 
 Percentage change in LDL-C from baseline to Days 14, 30, 60, 104, 120, 150, and 
210 
 Proportion of subjects in each group with LDL-C greater than 80% of the baseline 
value at Day 180 and Day 210 
 Duration of time on treatment for subjects to return to 80% of baseline or greater 
LDL-C or PCSK9 protein  
 Individual responsiveness defined as the number of subjects reaching on treatment 
LDL-C levels of <25 mg/dL, <50 mg/dL, 70 mg/dL, and <100 mg/dL at Days 90, 
120, and 180  
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline at Days 90, 120, and 180  
Blood samples for determination of LDL-C (β-quantification) concentrations will be collected at the 
time points in the Schedule of Assessments. Details regarding the collection, processing, shipping, and 
storage of the samples will be provided in a Laboratory Manual.  


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7.2.2. 
Change from Baseline in Lipids/Lipoproteins 
Secondary efficacy assessments will include the measure the effects of ALN-PCSSC on levels of 
lipids and lipoproteins including total cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, 
VLDL-C, Apo-A1, Apo-B, Lp(a), hsCRP, and PCSK9.  
 Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 104, 120, 
150, 180, and 210  
 Percentage change in other lipids, and apolipoproteins from baseline at each 
subsequent visit to Day 210 
 Proportion of subjects in each group who attain global lipid modification targets for 
their level of ASCVD risk 
Additional aliquots of plasma and serum will be collected at each time point and stored for 
additional analyses, including future analysis of biomarkers of CV risk. 
Plasma samples will be analyzed using a validated enzyme linked immunosorbent assay to determine 
PCSK9 protein concentration. Full details of the analytical methods used will be described in a 
separate bioanalytical report.  


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8. 
ADVERSE EVENTS  
8.1. 
Definitions 
8.1.1. 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product. 
Planned hospital admissions and/or surgical operations for an illness or disease that existed before the 
subject was randomized in a clinical study are not to be considered AEs. 
Adverse events or abnormal test findings will be followed until the event (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the Sponsor/investigator. 
8.1.1.1. 
AE Severity 
The severity of an AE will be assessed by the investigator. The investigator should ensure that any 
subject experiencing an AE receives appropriate medical support until the event resolves. 
Adverse events will be graded on a 3-point scale and reported as indicated on the case report form. 
The intensity of an AE is defined as follows: 
1 = Mild: Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: Inability to work or perform normal daily activity. 
8.1.1.2. 
Study Drug Causality 
The relationship of an AE to study treatment will be assessed with consideration to the following 
criteria: 
 Temporal relationship to the initiation of study medication 
 Response of the event to withdrawal of study medication 
 AE profile of concomitant therapies 
 Clinical circumstances during which the AE occurred 
 Subject’s clinical condition and medical history  
 
Categorization of causality will be designated by the investigator as stated below: 
 Reasonable possibility - There are facts (evidence) or arguments to suggest a causal 
relationship between the event and study drug 


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 No reasonable possibility – There are few to no facts (evidence) or arguments to 
suggest a causal relationship between the event and study drug 
8.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening, ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred (it does not include an event that, had it 
occurred in a more severe form, might have caused death) 
 Results in a significant, persistent or permanent change, impairment, damage or 
disruption in the subject's body function/structure, physical activities and/or quality of 
life 
 Requires in-subject hospitalization or prolongs hospitalization 
 Is a congenital anomaly/birth defect 
 Is another medically significant event that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above (eg, allergic bronchospasm requiring 
intensive treatment in an emergency department or home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse) 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or measure of 
the intensity of an AE, while the criteria for serious AEs are indications of adverse subject outcomes 
for regulatory reporting purposes. A severe AE need not necessarily be considered serious and a 
serious AE need not be considered severe. For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE. On the other hand, an MI that may be considered minor 
could also be an SAE if it prolonged hospitalization. 
8.1.3. 
Medication errors 
Medication error refers to any unintended error in the dosing and administration of the study product 
as per instructions in the protocol. Medication Errors generally fall into four categories as follows:  
1. Wrong medication 
2. Wrong dose (including dosing regimen, strength, form, concentration, amount); 
3. Wrong route of administration; 
4. Wrong subject (ie, not administered to the intended subject) 
Medication Errors include occurrences of underdose of the study product(s). 
Underdose: Unintentional administration of an insufficient quantity of study drug; ie, 
incomplete administration of study drug as drawn for injection. 


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8.1.4. 
Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (serious or nonserious) is one of scientific and medical concern 
specific to the Sponsor’s product or program, which warrants ongoing monitoring and rapid 
communication by the investigator to the sponsor. The SAE/AESI form should be utilized for 
reporting the AESI even if a serious outcome may not apply. 
In this study, injection site reactions including individual signs or symptoms at the injection site 
reported following study drug administration will be collected as an AESI.  
Signs or symptoms of injection site reaction will be evaluated by the Common Terminology Criteria 
for Adverse Events (CTCAE) criteria of Injection Site Reaction (General disorders and administration 
site conditions) to determine the event’s grade (severity) (see Table 4).  
TABLE 4: 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) OF INJECTION SITE REACTION  
Grade I: 
Tenderness with or without associated symptoms (eg, warmth, erythema, 
itching) 
Grade II: 
Pain; lipodystrophy; edema; phlebitis 
Grade III 
Ulceration or necrosis; severe tissue damage; operative intervention 
indicated 
Grade IV 
Life-threatening consequences; urgent intervention indicated 
Grade V 
Death  
Reference source: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Published 28 May 
2009. 
As indicated in Section 6.4, if a local reaction around the injection site occurs, photographs should be 
obtained either by the investigator or another health care professional at first presentation and at each 
of the follow-up visits until the injection site reaction resolves.  
8.1.5. 
Other Safety Related Information 
A comprehensive term that encompasses safety information for which global regulations require 
collection, evaluation, and/or reporting to Regulatory Authorities. Other safety-related 
information includes, but is not limited to, reports of the following: 
 Abnormal neurological examination, eg, peripheral sensory and motor evaluation, an 
assessment of gait, pain, position, strength and reflexes (Appendix A) 
 Potential anaphylactic reactions assessed by Sampson criteria (Appendix B) 
 Suspected transmission via a medicinal product of an infectious agent 
 Drug interactions 
 Occupational exposure 
Report the occurrence of suspected transmission via a medicinal product of an infectious agent, 
drug interactions, or occupational exposure to the Sponsor's GPV department as per Section 8.3, 
Procedure for Serious Adverse Event Reporting. Note: The Special Situations event does not 
need to be serious to be reported on the SAE/AESI Report form. 


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The occurrences of abnormal neurological examination and anaphylactic reaction must be 
recorded on the source documentation and eCRF, and if the events are serious must be reported 
to the Sponsor's GPV department using the SAE Report form. 
8.2. 
Procedure for Non-Serious Adverse Event Recording 
All nonserious AEs that occur during the designated study period from randomization up to EOS 
must be assessed and recorded on the source documents and electric case report forms (eCRFs), 
regardless of causal relationship to the study drug. Note: For subjects in whom LDL-C levels 
have not returned to >80% of baseline values by Day 210, AEs will continue to be assessed at 
additional monthly follow-up visits (Day 240, Day 270, Day 300, Day 330, and Day 360) until 
the final observation.  
8.3. 
Procedure for Serious Adverse Event Reporting 
NOTE: This procedure may need to be followed for reporting AESIs or Other Safety Related 
information as noted in Section 8.1.5 and Section 8.5. 
All SAEs that occur during the designated study period (from randomization through the EOS 
visit) must be reported to the Sponsor’s Global Pharmacovigilance Department (GPV) within 
24 hours of awareness of the event using the provided study specific SAE/AESI Report Form. 
The completion and processing of the SAE/AESI Report Form should be per the instructions in 
the provided SAE/AESI Report Form completion guidelines. In addition to completing the 
SAE/AESI Report Form, each SAE/AESI must be entered on the appropriate page of the eCRF. 
Note: For subjects in whom LDL-C levels have not returned to >80% of baseline values by 
Day 210, SAEs will continue to be assessed at additional monthly follow-up visits (Day 240, 
Day 270, Day 300, Day 330, and Day 360) until the final observation.  
When death occurs with an SAE, the cause of death must be reported as an SAE. “Fatal” will be 
reported as the outcome for these events. 
The investigator must assess the causality for each SAE/AESI. 
The Sponsor will contact the investigator, if necessary, to clarify any of the event information. 
The investigator should provide any follow-up information for the event to the Sponsor on an 
updated SAE/AESI report form as soon as it becomes available. 
If the investigator is notified of a SAE/AESI that occurs post-study period, that he or she wishes 
to report to the Sponsor (eg, an event suspected to be causally related to study drug), the event 
should be reported through the process described above.  
Where appropriate, if required by local regulations or procedures, the investigator should report 
these events to the Institutional Review Board (IRB)/Ethics Committee (EC) and/or national 
regulatory authority in addition to the Sponsor. 
8.4. 
Procedure for Medication Error Reporting 
Medication errors (with or without an associated AE) need to be recorded as medication errors in 
the eCRF as described in Section 8.2. 


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Medication errors with an associated SAE need to be recorded as medication errors in the eCRF 
and reported to the Sponsor’s GPV department as described in Section 8.3. 
A mis-dosing protocol deviation (refer to Section 12.3) would need to be reported as a 
medication error if it was an “unintended error” as defined in Section 8.1.3. 
8.5. 
Procedure For Reporting Adverse Events Of Special Interest 
(AESIs) 
The AESI of Injection Site Reaction has been identified for the study product(s) in this protocol 
as per Section 8.1.4. Nonserious AESIs should be reported to The Medicines Company (MDCO) 
GPV within 72 hours and serious AESIs should be reported to MDCO GPV within 24 hours. In 
both instances, the reporting procedure provided in Section 8.3 should be followed. The 
SAE/AESI form should be utilized for reporting the AESI even if a serious outcome may not 
apply.  
8.6. 
Procedure For Reporting Pregnancies/Lactation Exposure 
Occurrences of pregnancy/lactation exposure in a study subject or study subject’s partner should 
be reported within 24 hours using the Pregnancy/Lactation Exposure Reporting form. In cases 
where a pregnancy/lactation exposure occurs with a SAE, the SAE reporting form should be 
used to report the SAE/AESI and the Pregnancy Reporting form should be used to report the 
pregnancy. When a pregnancy occurs without any concurrent SAE, the Pregnancy Reporting 
form may be submitted alone. The pregnancy must be followed through to outcome of 
pregnancy. Any pregnancy discovered after consent to follow-up need to be reported. 


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9. 
DATA COLLECTION 
An electronic data capture (EDC) system will be used for this trial. All users will be trained on 
the technical features of the EDC as well as the content of the eCRF by qualified personnel prior 
to gaining access to the EDC. A UserID/Password will be granted after training. This ID is not to 
be shared amongst the study staff. All users must have a unique account to enter or review data. 
The eCRF should be filled out by the site 3 days after each visit. It is not expected that the eCRF 
will serve as source for any data collected in this trial. If there is a reason for a site to do so, it 
must be approved by MDCO and documented in the site files. 
Prior to the database being locked, the investigator or designee will review, approve, and 
sign/date each completed eCRF corresponding to the blinded pages and the appropriate 
unblinded designee will similarly address the unblinded section of the eCRF. This signature 
serves as attestation of the investigator’s responsibility for ensuring that all data entered into the 
eCRF are complete, accurate, and authentic. After the end of the trial, a copy of the data will be 
provided to the site. This copy will contain the final data, an audit trail of activity on the data, 
and any queries and answers that were posted for data clarification. 


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10. 
STATISTICAL PLAN 
10.1. 
Sample Size 
The sample size calculation was performed with the assumption (which was based on the 
observed results from a Phase I trial) that the difference in change from baseline between the 
active dose groups and the placebo group for LDL-C will be no less than 30 mg/dL, with a 
standard deviation of 20 mg/dL, using a Dunnet multiple t-test procedure for six comparisons. 
Assuming about a 15% drop out rate, the sample size will be approximately 100 evaluable subjects 
total across the placebo groups and approximately 50 subjects in each of six ALN-PCSSC treatment 
groups. This sample size of at least 400 evaluable subjects will provide more than 90% power to 
detect a 30% reduction of LDL-C levels in at least one ALN-PCSSC dose group. 
10.2. 
Randomization  
Subjects will be screened and 480 eligible subjects will be randomized by the IWRS system: 
60 subjects per each of six ALN-PCSSC treatment groups plus 120 subjects total across the 
placebo groups (20 subjects each to match each of the six drug groups). Treatment will be 
stratified by country and by current use of statins or other lipid-modifying therapies. Each 
subject will either receive either one or two injections on Day 1 only or a single injection on 
Day 1 and a second injection on Day 90 of blinded ALN-PCSSC or placebo. 
10.3. 
General Statistical Considerations and Definitions 
10.3.1. 
General Statistical Methods 
All study-collected data will be summarized by treatment group using descriptive statistics, 
graphs, and/or raw data listings. Categorical variables will be summarized using counts and 
percentages. Percentages are based on the number of subjects in the analysis set for whom there 
are non-missing data, unless otherwise specified. Continuous variables, including changes from 
baseline, will be summarized using descriptive statistics (n, mean, standard deviation, median 
and interquartile range [first and third quartiles], minimum and maximum).  
A Statistical Analysis Plan  will be written after finalizing of the eCRF and before database lock. 
The specifications in this document will detail the implementation of all the planned statistical 
analyses in accordance with the principal features stated in the protocol.  
Statistical analyses will be carried out using SAS statistical analysis software version 9.2 or 
higher (SAS Institute, Inc., Cary, North Carolina, US).  
10.3.2. 
Analysis Population 
The following populations will be used for data analyses and/or presentation. 
10.3.2.1. Intent-to-Treat (ITT) Population  
All subjects randomized into the trial. Treatment classification will be based on the randomized 
treatment. This population will be used to assess the randomness of treatment allocation. 


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10.3.2.2. Modified Intent-to-Treat (mITT) Population 
All randomized subjects who receive at least one dose of study drug and have both the baseline 
and the 180 day follow-up LDL-C assessment. Treatment classification will be based on the 
randomized treatment. This will be the primary population for analysis of the primary and 
secondary endpoints. 
10.3.2.3. Per-Protocol (PP) Population 
All mITT subjects who received all randomized treatments and the 180 day follow-up LDL-C 
assessment. The PP population will be finalized during a data review before database lock. This 
will be the supportive population for analysis of the primary and secondary endpoints.  
10.3.2.4. Safety Population 
All subjects who received at least one dose of study drug. Treatment classification will be based 
on the actual treatment received. This will be primary population for the safety analyses.  
10.3.3. 
Analysis Windows and Baseline 
The observational period for each subject includes the screening period (from Day -14 to 
Day -1), the EOS visit (Day 210 or withdrawal date). The time at which LDL-C levels have 
returned to >80% of baseline values will be the last observation. Any lab results collected after 
the last observation will not be included in the planned efficacy analysis. Safety events after the 
last observation, even if collected on the eCRF, will not be included in the planned statistical 
analysis. However, all data, including that reported after the defined observational period, will be 
included in the subject data listings.  
Unless otherwise specified, for evaluations that are collected at multiple occasions prior to 
initiation of study drug, the last evaluation will be considered the "Baseline" evaluation for 
analysis. 
Two samples for lipids and PCSK9 will be taken prior to initiation of study drug (one at 
screening and one prior to randomization on Day 1). The average value of the two samples will 
be used as the baseline evaluation. 
10.3.4. 
Missing Data Handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from the 
associated analysis. 
10.4. 
Statistical Analyses 
10.4.1. 
Demographic and Background Characteristics 
Subject demographics and baseline characteristics (including medical history) will be 
summarized by treatment group using the ITT, mITT, PP, and safety populations. 
10.4.2. 
Study Drug and Concomitant Medications 
Summaries of each prior (pre-baseline) medication and concomitant (baseline or later) 
medication will be provided by treatment. Separate summaries will be provided for prior 


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medication use. Medications will be coded using the WHO drug dictionary. Subjects will be 
counted only once within each period by medication. 
10.4.3. 
Efficacy Analysis 
10.4.3.1. Primary Efficacy Endpoints 
The primary endpoint is the percentage change in LDL-C from baseline to Day 180. 
Two sample t-tests will be performed to test the superiority of any dosing group over placebo. A 
Dunnet multiple t-test procedure will be applied to adjust for multiple comparisons with six 
different dosing regimens.  
10.4.3.2. Secondary Efficacy Endpoints 
The secondary objectives of this study are to evaluate the effect of ALN-PCSSC on the 
following: 
 Percentage change in LDL-C from baseline to Day 90 
 Percentage change in LDL-C from baseline to Days 14, 30, 60, 104, 120, 150, and 
210 
 Proportion of subjects in each group with LDL-C greater than 80% of the baseline 
value at Day 180 and Day 210 
 Duration of time on treatment for subjects to return to 80% of baseline or greater 
LDL-C or PCSK9 protein  
 Individual responsiveness defined as the number of subjects reaching on treatment 
LDL-C levels of <25 mg/dL, <50 mg/dL, 70 mg/dL, and <100 mg/dL at Days 90, 
120, and 180  
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline at Days 90, 120, and 180 
 Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 104, 120, 
150, 180, and 210 
 Percentage change in other lipids, lipoproteins, and apolipoproteins from baseline at 
each subsequent visit to Day 210 
 Proportion of subjects in each group who attain global lipid modification targets for 
their level of ASCVD risk 
10.4.3.3. Interim Analysis 
An interim analysis of lipids and PCSK9, unblinded by dose cohort only, will be prepared upon 
completion of Day 90 by the Statistical Reporting Organization. The interim analysis will be 
performed for all subjects completing Day 90 and these data will be used to help select the 
ALN-PCSSC dose for subsequent clinical trials. 


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10.4.4. 
Safety Analysis 
The safety objectives of this study are to evaluate the safety and tolerability profile of 
ALN-PCSSC. 
10.4.4.1. Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for coding 
AEs. An AE (classified as preferred term) occurring during the double-blind treatment period 
will be counted as a treatment emergent AE (TEAE) either if it is not present at baseline or if it is 
present at baseline but increased in severity during the treatment period. 
The number (percentage) of subjects reporting TEAEs for each preferred term will be tabulated 
by system-organ class, by system-organ class and severity, and by system-organ class and 
relationship to study drug. If more than one event occurred with the same preferred term for the 
same subject, the subject will be counted only once for that preferred term using the most severe 
or related occurrence for the summary by severity, or relationship to study drug, respectively. 
Incidences of injection site reactions will also be presented by dose group (see also Section 8.1.4). 
Time to first injection site reaction will be analyzed. The severity and duration of injection site 
reactions, as well as their signs and symptoms, will also be summarized.  
10.4.4.2. Laboratory Tests 
Laboratory values will be summarized by treatment group, including changes and percent 
changes from baseline at each time point. Analyses will also be performed for each lab parameter 
by treatment group for incidence rates of potentially clinical significant values for subjects 
without potentially clinical significant value at baseline. 
Numerical values of laboratory parameters from different local laboratories with different units 
and normal ranges will be converted to the conventional units and normalized to a standard set of 
reference/normal ranges. The normalization process will be performed and separated by each of 
the laboratory parameters. 
10.4.4.3. Vital Signs 
Change and percent change from baseline in vital signs will be summarized descriptively at each 
scheduled time point by treatment group. 
10.4.4.4. Neurological Examinations 
The percentage of subjects with a treatment-emergent abnormal neurological examination and 
the specific abnormality reported will be summarized by treatment group. 


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11. RECORDS RETENTION 
United States Food and Drug Administration (FDA) regulations require all investigators 
participating in clinical drug trials to maintain detailed clinical data for one of the following 
periods: 
 At least 2 years following the date on which a New Drug Application is approved 
by the FDA or 
 Two years after the Sponsor notifies the investigator that no further application is to 
be filed with the FDA 
Similarly, current European Union (EU) Directives/Regulations and International Conference on 
Harmonisation (ICH) guidelines collectively require that essential clinical trial documents 
(including case report forms) other than patient’s medical files must be retained for the following 
time period: 
The sponsor and investigator shall retain the essential documents relating to a clinical 
trial for at least 5 years after its completion. They shall retain the documents for a longer 
period, where so required by other applicable requirements or by an agreement between 
the sponsor and the investigator.  Essential documents shall be archived in a way that 
ensures that they are readily available, upon request, to the competent authorities.  The 
medical files of trial subjects shall be retained in accordance with national legislation 
and in accordance with the maximum period of time permitted by the hospital, institution 
or private practice. 
 For at least 15 years after completion or discontinuation of the trial 
 Or 2 years after the last approval of a marketing application in an ICH region and 
until there are no pending or contemplated marketing applications in an ICH region 
 Or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product 
Investigators shall retain the documents for a longer period, where so required by applicable 
local requirements. 
To comply with these requirements, the investigator will not dispose of any records relevant to 
this study without either (1) written permission from the Sponsor or (2) providing an opportunity 
for the Sponsor to collect such records. The investigator shall take responsibility for maintaining 
adequate and accurate hard copy source documents of all observations and data generated during 
this study, including any data clarification forms  received from the Sponsor. Such 
documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other 
regulatory agencies. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Monitoring 
The Sponsor has ethical, legal, and scientific obligations to carefully follow this study in 
accordance with established research principles and applicable regulations. The investigator, as 
part of his responsibilities, is expected to cooperate with the Sponsor in ensuring that the study 
adheres to the protocol and GCP requirements.  
As part of a concerted effort to fulfill these obligations, the Sponsor's monitor will visit the 
center(s) during the study in accordance with the Monitoring Plan set forth for this trial. The 
investigator will permit the Sponsor to monitor the study as frequently as is deemed necessary 
and provide access to medical records/source documents to ensure that data are being recorded 
adequately, that data are verifiable and that protocol adherence is satisfactory.  
12.2. 
Auditing 
The Sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, 
drug supply, presence of required documents, the informed consent process, and comparison of 
eCRFs with source documents. The investigator agrees to permit audits conducted at a 
reasonable time in a reasonable manner. 
Regulatory authorities worldwide may also inspect the investigator during or after the study. The 
investigator should contact the Sponsor immediately if this occurs, and must permit regulatory 
authority inspections. 
12.3. 
Protocol Deviations 
This study will be conducted as described in this protocol, except for an emergency situation in 
which the protection, safety, and well-being of the subject requires immediate intervention, 
based on the judgment of the investigator (or a responsible, appropriately trained professional 
designated by the investigator). In the event of a significant deviation from the protocol due to an 
emergency, accident, or mistake, the investigator or designee must contact the Sponsor, or their 
agent, at the earliest possible time by telephone. This will allow an early joint decision regarding 
the subject’s continuation in the study. The investigator and the Sponsor will document this 
decision. The IRB/EC will be informed of all protocol changes by the investigator in accordance 
with the IRB/EC established procedure. No deviations from the protocol of any type will be 
made without complying with all the IRB/EC established procedures. 
The following Protocol Deviations will require additional information in the eCRF explaining 
why the deviation occurred and what will be done to prevent it from re-occurring: 
 Injection not administered for any reason other than subject safety or withdrawal 
 Wrong dose (dose concentration, wrong dose, wrong treatment, wrong regimen, 
wrong injection site)* 
 Missed assessment as per the Schedule of Events/Assessments (Table 3) at Baseline, 
Days  90, 180, and 210 (EOS) visit  


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 Inclusion criteria violation 
 Exclusion criteria violation 
 Subject not adhering to protocol subject restrictions 
 Subject taking any prohibited concomitant medication 
*If the mis-dosing was unintended (ie, a medication error), the error should be reported as 
per instructions in Section 8.4, Procedure for Medication Error Reporting. 


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13. 
ETHICS AND RESPONSIBILITY 
This study will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the FDA regulations, the ICH GCP guidelines, the Declaration of 
Helsinki and other local regulations, as applicable. 
13.1. 
Informed Consent 
Written informed consent will be obtained from all subjects before any study-related procedures 
(including any pre-treatment procedures) are performed. The investigator(s) has both ethical and 
legal responsibility to ensure that each subject being considered for inclusion in this study is 
given a full explanation of the protocol. This shall be documented on a written informed consent 
form (ICF), which shall be approved by the same IRB or EC responsible for approval of this 
protocol. Each ICF shall include the elements required by ICH, Part E6, Section 4.8 and any 
applicable local regulations. The investigator agrees to obtain approval from the Sponsor of any 
written ICF used in the study, preferably prior to submission to the IRB or EC.  
Once the appropriate essential information has been provided to the subject and fully explained 
by the investigators (or a qualified designee) and it is felt that the subject understands the 
implications of participating, the subject and the investigator (or designee) shall sign the IRB- or 
EC-approved written ICF. The subject shall be given a copy of the signed ICF, and the original 
shall be filed appropriately, according to the institution. A second copy may be filed in the 
subject's medical record, if allowed by the institution. 
13.2. 
Institutional Review Board/Ethics Committee 
This protocol, the written ICF and any materials presented to subjects shall be submitted to the 
IRB or EC identified with this responsibility. Notification in writing of approval must come from 
the IRB or EC chairman or secretary, to the investigator, either as a letter or as a copy of the 
appropriate section of the IRB or EC meeting minutes where this protocol and associated ICF 
were discussed. The investigator will not participate in the decision. If the investigator is an IRB 
or EC member, the written approval must indicate such non-participation in the voting session. 
The investigator will submit status reports to the IRB or EC as required by the governing body. 
The IRB or EC must be notified by the investigator in writing of the interruption and/or 
completion of the study; the investigator must promptly report to the IRB or EC all changes in 
research (protocol amendments) and will not make such changes without IRB or EC approval, 
except where necessary to eliminate apparent immediate hazards to human subjects. In cases 
where it is necessary to eliminate immediate hazards to subjects, the IRB or EC must then be 
notified of the change as per local requirements. The investigator is required to maintain an 
accurate and complete record of all written correspondence to and received from the IRB or EC 
and must agree to share all such documents and reports with the Sponsor. 


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14. 
CONFIDENTIALITY 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without written prior permission 
from the Sponsor. However, authorized regulatory officials and Sponsor personnel will be 
allowed full access to the records. All medications provided and subject bodily fluids and/or 
other materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the Sponsor. 
Only unique subject numbers in eCRFs will identify subjects. Their full names may, however, be 
made known to a product regulatory agency or other authorized official if necessary. 
With respect to the clinical trial data that is received from countries in the European Economic 
Area and Switzerland, MDCO has certified adherence to the US- EU and the US-Swiss Safe 
Harbor Principles. 


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15. 
INVESTIGATOR AGREEMENT 
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it 
contains all the ethical, legal and scientific information necessary to conduct this study. I will 
personally conduct the study as described. 
I will provide copies of the protocol to all physicians, nurses and other professional personnel 
responsible to me who will participate in the study. I will discuss the protocol with them to 
assure myself that they are sufficiently informed regarding the investigational new drug ALN-
PCSSC, the concurrent medications, the efficacy and safety parameters and the conduct of the 
study in general. I am aware that this protocol must be approved by the Institutional Review 
Board (IRB) or Ethics Committee (EC) responsible for such matters in the Clinical Study 
Facility where ALN-PCSSC will be tested prior to commencement of this study. I agree to 
adhere strictly to the attached protocol. I understand that this IRB or EC approved protocol will 
be submitted to relevant regulatory authorities by the Sponsor, as appropriate. I agree that 
clinical data entered on case report forms by me and my staff will be utilized by the Sponsor in 
various ways such as for submission to governmental regulatory authorities and/or in 
combination with clinical data gathered from other research sites, whenever applicable. I agree to 
allow Sponsor monitors and auditors full access to all medical records/source documents at the 
research facility for subjects screened or randomized in the study. 
I agree to provide all subjects with informed consent forms, as required by government and ICH 
regulations. I further agree to report to the Sponsor any adverse experiences in accordance with 
the terms of this protocol, ICH guideline, Part E6, Section 4.11 and applicable local regulations. 
 
 
 
Principal Investigator  (Signature) 
 
Date 
 
Principal Investigator  (Printed Name) 
 
 
 
Institution Name 
 
 
 


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APPENDIX A. NEUROLOGICAL EXAMINATION 
MOTOR FUNCTION  
When assessing motor function, from a neurological perspective, the assessment should focus on 
arm and leg movement. You should consider the following:  
1. Muscle size  
2. Muscle tone  
3. Muscle strength  
4. Involuntary movements  
5. Posture, gait  
Symmetry is the most important consideration when identifying focal findings. Compare one 
side of the body to the other when performing your assessment.  
Limb assessment of a conscious patient usually involves a grading of strength.  
Grade Strength  
Grade strength Description 
5 
Full range of motion against gravity and resistance; normal muscle strength 
4 
Full range of motion against gravity and a moderate amount of resistance; 
slight weakness 
3 
Full range of motion against gravity only, moderate muscle weakness 
2 
Full range of motion when gravity is eliminated, severe weakness 
1 
A weak muscle contraction is palpated, but no movement is noted, very 
severe weakness 
0 
Complete paralysis 
NB: In a conscious patient, the single best test to quickly identify motor weakness is the 
“drift test”. Have the patient hold their arms outward at 90 degrees from the body. With 
palms up, have the patient close their eyes and hold the arms for a couple of minutes. 
“Drifting” will occur if one side is weak.  
Lower Extremities  
Assess the patient in a supine position. Ask him/her to separate both legs to test for hip 
abduction. Then ask the patient to bring the legs back together to test for hip adduction. Sit the 
patient on the side of the bed to assess knee flexion and extension. Ask the patient to flex and 
extend the knee. If able to do this, apply resistance as these movements are repeated. Test plantar 
and dorsiflexion by having the patient push down against your hand with their foot and then pull 
up against your hand with their foot. Remember to compare the left side to the right side.  
Upper Extremities  
Assess ability to flex elbow (biceps) and straighten (triceps). Assess ability to raise shoulders and 
return to a resting position. Assess wrist flexion and extension. Test each function with 


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resistance. For focused upper extremity assessment, assess each digit for flexion, extension and 
lateral movement.  
SENSORY FUNCTION  
When assessing sensory function remember that there are three main pathways for sensation and 
they should be compared bilaterally:  
1. Pain and temperature sensation.  
2. Position sense (proprioception).  
3. Light touch.  
Pain can be assessed using a sterile pin. Light touch can be assessed with a cotton wisp. To test 
proprioception, grasp the patient's index finger from the middle joint and move it side to side and 
up and down. Have the patient identify the direction of movement. Repeat this using the great 
toe.  
Sensory Tests:  
A number of tests for lesions of the sensory cortex can be done. Examples include the following:  
 Stereognosis: The ability to recognize an object by feel. Place a common object 
in the persons hand and ask them to identify the object.  
 Graphesthesis: “Draw” a number in the palm of the person’s hand and ask them 
to identify the number.  
 Two-Point Discrimination: Simultaneously apply two pin pricks to the skin 
surface. Continually repeat the test while bringing the two pins closer together, 
until the individual can no longer identify two separate stimuli. The finger tips are 
the most sensitive location for recognizing two point differences while the upper 
arms, thighs and back are the least sensitive.  
 Extinction: Touch the same spot on both sides of the body at the same time (eg, 
the left and right forearms. Ask the individual to describe how many spots are 
being touched. Normally, both sides are felt; with sensory lesions the individual 
will sense only one.  
 Point Locations: Touch the surface of the skin and remove the stimulus quickly. 
Ask the individual to touch the spot where the sensation was felt. Sensory lesions 
can impair accurate identification, even if they retain their sensation of light 
touch.  
TONE and REFLEXES 
Upper motor neuron problems (brain and spinal cord) are associated with increased tone. Lower 
motor neuron problems are associated with decreased tone.  
Look at the muscles on each side of the body in pairs. Assess for symmetry of bulk.  
Evaluation of the stretch reflexes assesses the intactness of the spinal reflex arc at various spinal 
cord levels. The limb should be relaxed while applying a short and snappy blow with a reflex 


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hammer. Hold the hammer loosely in a relaxed manner, making a wrist action. Allow the 
hammer to bounce.  
Reflex responses:  
0 No response 
1+ Diminished, low normal 
2+ Average, normal 
3+ Brisker than normal  
4+ Very brisk, hyperactive 
Lower motor neuron disease is associated with 0 or 1+, upper motor neuron disease is associated 
with 3+ or 4+.  
Biceps Reflex (C5 – C6)  
Support the forearm on the examiners forearm. Place your thumb on the bicep tendon (located in 
the front of the bend of the elbow; midline to the anticubital fossa). Tap on your thumb to 
stimulate a response.  
Triceps Reflex (C7-C8)  
Have the individual bend their elbow while pointing their arm downward at 90 degrees. Support 
the upper arm so that the arm hangs loosely and “goes dead”. Tap on the triceps tendon located 
just above the elbow bend (funny bone).  
Brachioradialis Reflex (C5-C6):  
Hold the person’s thumb so that the forearm relaxes. Strike the forearm about 2-3 cm above the 
radial styloid process (located along the thumb side of the wrist, about 2-3 cm above the round 
bone at the bend of the wrist). Normally, the forearm with flex and supinate.  
Quadriceps Reflex (Knee jerk) L2 – L4  
Allow the lower legs to dangle freely. Place one hand on the quadriceps. Strike just below the 
knee cap. The lower leg normally will extend.and the quadriceps will contract.  
If the patient is supine: Stand on one side of the bed. Place the examiners forearm under the thigh 
closest to the examiner, lifting the leg up. Reach under the thigh and place the hand on the thigh 
of the opposite leg, just above the knee cap. Tap the knee closest to the examiner, (the one that 
has been lifted up with the examiners forearm).  
Achilles Reflex (ankle jerks) L5 – S2:  
Flex the knee and externally rotate the hip. Dorsiflex the foot and strike the Achilles tendon of 
the heel. In conscious patients, kneeling on a chair can help to relax the foot.  
Heel Lift  
While the patient is supine, bend the knee and support the leg under the thigh. Have the leg “go 
dead”. Briskly jerk the leg to lift the heel of the bed. Normally, the leg will remain relaxed and 
the heel will slide upward; increased tone will cause the heel and leg to stiffen and lift off the 
bed.  
 
 


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Babinski Response:  
Dorsiflexion of the great toe with fanning of remaining toes is a positive Babinski response. This 
indicates upper motor neuron disease. It is normal in infants.  
CEREBELLAR FUNCTION  
The cerebellum is responsible for muscle coordination and balance on the same side. To test 
cerebellar function use the following tests:  
1. Finger to finger test: have the patient touch their index finger to your index finger (repeat 
several times).  
2. Finger to nose test: perform with eyes open and then eyes closed.  
3. Tandem walking: heel to toe on a straight line.  
4. Romberg test: stand with feet together and arms at their sides. Have patient close his/her 
eyes and maintain this position for 10 seconds. If the patient begins to sway, have them 
open their eyes. If swaying continues, the test is “positive” or suggestive of cerebellum 
problems.  
Dizziness that occurs in response to position changes is usually blood pressure initiated. If the 
patient sways during a Romberg test, but stops when the eyes are opened, the problem is 
probably visual or CN VIII (vestibular). 
 


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APPENDIX B. SAMPSON CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced PEF, 
hypoxemia 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, painful abdominal cramps, vomiting) 
3. Reduced blood pressure after exposure to a known allergen for that patient (minutes to 
several hours): 
a. Infants and children: low systolic blood pressure (age specific) or > 30% decrease in 
systolic blood pressure* 
b. Adults: systolic blood pressure <90 mmHg or >30% decrease from that person’s 
baseline 
*Low systolic blood pressure for children is age specific and defined as: <70 mmHg for age 
1 month to 1 year; <70 mmHg + [2 x age] for age 1 to years; <90 mmHg for age 11 to 17 years. 
Source: Sampson et al, 2005; Sampson et al, 2006. 


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APPENDIX C. CLARIFICATION OF LABORATORY ASSESSMENTS 
TO BE PERFORMED IN THE SCREENING PHASE (DAY 
-14 TO -1) 
Screening Labs Local / 
central Lab 
Comments 
Hematology 
 
Local lab 
Standard panel to include Hb, WBC and platelets as a minimum 
Chemistry 
Local lab 
 
Standard chemistry panel to include BUN and electrolytes, serum 
creatinine, glucose. (Taken at same time as fasting lipids so glucose 
measurement is fasting).  
Liver function tests to include ALT, AST and total bilirubin which 
are exclusion criteria 
Coagulation 
 
Local lab 
Standard coagulation panel to include PTT or aPTT, INR and PT 
(if part of local coagulation panel) 
Inflammatory 
biomarkers 
 
Central lab 
hsCRP and inflammatory markers (IL6, IFN-γ, and TNF-α) will be 
measured only at the central lab 
HbA1c 
 
Local lab 
HbA1c is an exclusion criteria 
Fasting 
lipids 
and lipoproteins 
 
Local lab 
Standard lipid and lipoprotein panel to include LDL-C and 
triglyceride which are inclusion criteria 
Fasting lipids 
 
Central lab 
Sample taken at same time as local lab sample and shipped to 
Medpace. (With the sample from the randomization visit these two 
samples will provide the baseline lipid measurements for the 
study). 
PCSK9 
Central lab 
Sample taken at same time as local lab sample and shipped to 
Medpace.  
(With the sample from the randomization visit these two samples 
will provide the baseline PCSK9 measurements for the study). 
Urinalysis 
Local lab 
Done using dipsticks provided by central lab.  Abnormal specimens 
sent to local lab for further testing. 
Urine 
Pregnancy 
testing 
Local lab 
Done using dipsticks provided by central lab.  To be conducted for 
eligible women at all visits. 
Note: Local lab assessments for eligibility are not expected to include the full panel measured by 
Medpace, which are measured for the purpose of the study and the study report. 


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Laboratory assays beyond the specific inclusion/exclusion criteria during screening are 
performed to exclude significant medical conditions making the subject unsuitable for the study 
as per exclusion criteria 10 and 16d. 
 

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STATISTICAL ANALYSIS PLAN 


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Protocol No.: MDCO-PCS-15-01 
 
A placebo-controlled, double-blind, randomized trial to compare the effect of 
different doses of ALN-PCSSC given as single or multiple subcutaneous 
injections in subjects with high cardiovascular risk and elevated LDL-C. 
 
EuDRACT No.: 2015-003772-74 
PROTOCOL VERSION: Amendment 01, 11 Jan 2016 
 
 


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TABLE OF CONTENTS 
1. 
TRIAL DESIGN ...........................................................................................................5 
1.1. 
Type/Design of Trial .....................................................................................................5 
1.2. 
Objective of Trials ........................................................................................................6 
1.3. 
Schematic Diagram of Trial Design .............................................................................6 
1.4. 
Schedule and Sequence of Procedures .........................................................................7 
2. 
GENERAL CONDUCT OF TRIAL ..........................................................................11 
2.1. 
Screening Period (Days –14 to –1) .............................................................................11 
2.2. 
Randomization ............................................................................................................11 
2.3. 
Follow-Up Visits 1 to 7 ..............................................................................................12 
2.4. 
End of Study Visit (Follow-Up Visit 8; Day 210 or Withdrawal) .............................12 
2.5. 
Interim Analysis ..........................................................................................................13 
2.6. 
Assessment of Safety ..................................................................................................13 
2.6.1. 
Adverse Events ...........................................................................................................13 
2.6.2. 
Clinical Laboratory Assessments ...............................................................................13 
2.6.3. 
Electrocardiograms .....................................................................................................13 
2.6.4. 
Assessment of Cardiovascular Events ........................................................................14 
2.6.5. 
Anti-ALN-PCSSC Antibodies ....................................................................................14 
2.7. 
Assessment of Efficacy ...............................................................................................14 
3. 
ADVERSE EVENTS..................................................................................................15 
3.1. 
Adverse Event .............................................................................................................15 
3.2. 
AE Severity .................................................................................................................15 
3.3. 
Study Drug Causality ..................................................................................................15 
3.4. 
Serious Adverse Event ................................................................................................16 
3.5. 
Medication Errors .......................................................................................................16 
3.6. 
Adverse Events of Special Interest (AESIS) ..............................................................17 
4. 
MEASURES TO MINIMIZE/AVOID BIAS .............................................................17 
5. 
STATISTICAL PLAN................................................................................................18 
5.1. 
Sample Size ................................................................................................................18 
5.2. 
Randomization ............................................................................................................18 
5.3. 
General Statistical Considerations and Definitions ....................................................18 
5.3.1. 
General Statistical Methods ........................................................................................18 


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5.3.2. 
Analysis Population ....................................................................................................18 
5.3.2.1. 
Intent-to-Treat (ITT) Population .................................................................................18 
5.3.2.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................19 
5.3.2.3. 
Per-Protocol (PP) Population ......................................................................................19 
5.3.2.4. 
Safety Population ........................................................................................................19 
5.3.3. 
Analysis Windows and Baseline ................................................................................19 
5.3.4. 
Missing data handling .................................................................................................19 
5.4. 
Statistical Analyses .....................................................................................................19 
5.4.1. 
Demographic and Background Characteristics ..........................................................19 
5.4.2. 
Study Drug ..................................................................................................................20 
5.4.3. 
Concomitant Medications ...........................................................................................20 
5.4.4. 
Efficacy Analysis ........................................................................................................20 
5.4.4.1. 
Primary Efficacy Endpoints ........................................................................................20 
5.4.4.2. 
Endpoints ....................................................................................................................20 
5.4.4.3. 
Exploratory Efficacy Endpoints .................................................................................21 
5.4.5. 
Safety Analysis ...........................................................................................................21 
5.4.5.1. 
Adverse Events ...........................................................................................................21 
5.4.5.2. 
Laboratory Tests .........................................................................................................21 
5.4.5.3. 
Clinical Laboratory Assessments ...............................................................................21 
5.4.5.4. 
Vital Signs ..................................................................................................................22 
5.4.5.5. 
Neurological Examinations ........................................................................................22 
6. 
COMPUTER METHODS ..........................................................................................23 
7. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL ............................24 
8. 
REFERENCES ...........................................................................................................25 
 
 


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1. 
TRIAL DESIGN 
1.1. 
Type/Design of Trial  
This study will be a Phase II, placebo-controlled, double-blind, randomized trial in subjects with 
ASCVD or ASCVD-risk equivalents (for example diabetes and familial hypercholesterolemia) 
and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to evaluate 
the efficacy, safety, and tolerability of ALN-PCSSC injection(s). The study will be a multi-
national, multi-center study (approximately 60 centers). Informed consent will be obtained from 
subjects before the initiation of any study-specific procedures.  
Subjects will be screened and 480 eligible subjects will be randomized: 60 subjects per each of 
six ALN-PCSSC dose groups plus 120 subjects total across the placebo groups (20 subjects each 
to match each of the six dose groups) as outlined in Ta
tion will be 
stratified by country and by c
d-modifying therapies. Each 
subject will receive either one
 or placebo at the doses specified 
in
. 
Table 1: 
g Regimens 
Drug 
dose 
No. 
ects 
Randomiz
ume (mL) 
Single Dose: 
tions on Day 1 
Placebo for 200 mg
1.0 
200 mg ALN
1.0 
Placebo for 300 mg
1.5 
300 mg ALN
1.5 
Placebo for 500 mg
2.5a 
500 mg ALN
2.5a 
Two Doses: O
ay 1 and Day 90 
Placebo for 100 mg
0.5 
100 mg ALN
0.5 
Placebo for 200 mg
1.0 
200 mg ALN
1.0 
Placebo for 300 mg
1.5 
300 mg ALN
1.5 
An independent Data Monitoring Committee (DMC) will review safety data beginning after the 
first 40 subjects have received the first dose of ALN PCSSC or placebo and complete the Day 14 
follow-up visit. Thereafter the DMC will review safety data every 2 months until the end of the 
trial. Following each formal data review, the Sponsor (in consultation with the IDMC and the 
Executive Committee [EC]) may decide to stop or recommend a modification to study conduct. 
All eligible subjects will be randomized and receive the first SC administration of ALN-PCSSC 
or placebo on Day 1. Subjects randomized to receive a second dose of study drug will receive 
their second injection of ALN-PCSSC or placebo at the Day 90 visit.  


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After first study drug administration, the subject will be observed in the clinic for at least 4 hours 
post injection and will then be discharged. Subjects will return on Day 14 and then at monthly 
intervals for 6 months. Any subjects in whom LDL-C levels have not returned to >80% of 
baseline values will continue to be followed. 
1.2. 
Objective of Trials  
Primary: 
 To evaluate the effect of ALN-PCSSC treatment on LDL-C levels at Day 180. 
Secondary: 
 To evaluate the effect of ALN-PCSSC on the following: 
 LDL-C levels at other time points 
 PCSK9 levels over time 
 other lipids, lipoproteins, apolipoproteins 
 the proportion of subjects achieving prespecified global lipid guidelines 
 individual responsiveness to different doses  
 duration of lipid-lowering effect of different doses  
 the safety and tolerability profile of ALN-PCSSC 
Exploratory: 
 To collect/evaluate the effect of ALN-PCSSC on the following: 
 Cardiovascular (CV) events such as CV death, non-fatal myocardial infarction 
(MI), major coronary events (coronary heart disease [CHD] death, resuscitated 
cardiac arrest, non-fatal MI), ischemic stroke, and hemorrhagic stroke  
 Anti-drug antibodies (ADA) for the investigational product 
1.3. 
Schematic Diagram of Trial Design 
 
 One Dose (one or two injections on Day 1) 
The study design for one dose is presented in Figure 1 . 


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Figure 1: 
Study Design for One Dose 
 
 Two Doses (one injection each on Day 1 and Day 90) 
The study design for two doses is presented in Figure 2. 
Figure 2: 
Study Design for Two Doses 
 
Note: Any subjects in whom LDL-C levels have not returned to >80% of baseline values will continue to be followed. 
1.4. 
Schedule and Sequence of Procedures 
The Schedule of Events/Assessments (Table 2) summarizes the study assessments by time point. 
This study consists of 10 visits and four phases: 
Single Dose (one or two injections on Day 1):  
 Screening: Day -14 to -1 
 Randomization, initiation of study drug: Day 1 
Randomization (Day 1) 
Treatment Phase 
(Day 1 to Day 90)
Follow-up 
and EOS (Day 210)
(Day 91 to Day 210)
Additional Follow-up
(for subjects in whom LDL-C 
levels have not returned to 
>80% of baseline values; 
Day 210 to Day 360)
Screening
(Day -14 to Day -1)
D1
Study drug
dosing
FU4
D90
 3
Study drug
dosing
FU1
D14
 2
FU2
D30
 3
FU3
D60
 3
FU5
D104
 3
FU6
D120
 3
FU7
D150
 3
FU8
D180
 3
FU9
D210
 3
FU10
D240
 3
FU11
D270
 3
FU12
D300
 3
FU13
D330
 3
FU13
D360
 3
Study Assessments


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 Treatment Phase: Day 1 
 Follow-up: Days 2 to 210; EOS on Day 210  
Two Doses (one injection each on Day 1 and Day 90):  
 Screening: Day -14 to -1 
 Randomization, initiation of study drug: Day 1 
 Treatment Phase: Day 1 to Day 90 
 Follow-up: Days 91 to 210; EOS on Day 210  
The expected duration of the subjects’ involvement in the study will be approximately 224 days, 
which includes screening, study drug administration, the course of one or two injections, and the 
follow-up period to Day 210. 
Any subject in whom LDL-C levels have not returned to >80% of baseline values, will continue 
to be followed. 
 


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Schedule of Assessments 
Table 2: 
Study Design and Schedule of Assessments 
One Dose: 
Screening 
Randomization 
and Treatment 
 
Follow-Up 
End of 
Study 
(EOS) 
Additional Follow-Up (for subjects in 
whom LDL-C levels have not returned 
to >80% of baseline values)  
Two Doses: 
Treatment Phase 
 
Follow-Up 
Study Day 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
FU5 
104 
(± 3)a 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (± 3) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
(including prior 
meds) 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
(including full 
neurological 
examination) 
X 
 
 
 
 
 
 
 
 
 
X 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12 Lead 
ECGcc 
X 
X 
 
 
 
 
 
 
 
 
X 
 
HbA1c 
X 
X 
 
 
 
X 
 
 
 
X 
 
X (day 270 and 360) 
Clinical labsd,j 
Xe 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisd,f 
(local) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy 
testh 
(local) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi 
Anti-ALN-
PCSSC (ADA) 
antibodiesj 
 
Xk 
 
X 
 
 
 
X 
 
 
X 
Xl 
Efficacy 
parameters 
(LDL-C, 
lipids,PCSK9)
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Xn 
Study drug 
administration 
 
X 
 
 
 
X 
 
 
 
 
 
 


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One Dose: 
Screening 
Randomization 
and Treatment 
 
Follow-Up 
End of 
Study 
(EOS) 
Additional Follow-Up (for subjects in 
whom LDL-C levels have not returned 
to >80% of baseline values)  
Two Doses: 
Treatment Phase 
 
Follow-Up 
Study Day 
-14 to -1 
1 
FU1 
14 
(± 2) 
FU2 
30 
(± 3) 
FU3 
60 
(± 3) 
FU4 
90 
(± 3) 
FU5 
104 
(± 3)a 
FU6 
120 
(± 3) 
FU7 
150 
(± 3) 
FU8 
180 
(± 3) 
FU9 
210 
(± 3) 
FU10 (Day 240) (± 3) 
FU11 (Day 270) (± 3) 
FU12 (Day 300) (± 3) 
FU13 (Day 330) (± 3) 
FU14 (Day 360) (± 3) 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAE reporting 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA = anti-drug antibodies; AE = adverse event; ECG = electrocardiogram; FU=follow-up; EOS = end of study;; hsCRP=high sensitivity C-reactive protein; IL6=interleukin 6; IFN-γ=interferon gamma; LDL-C = low-density 
lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; SAE = serious adverse event;TNF-α=tumor necrosis factor alpha. 
a Subjects who receive a second dose of study drug on Day 90 only. 
b Vital signs: blood pressure, heart rate, temperature, and respiration will be measured prior to injection and at 4 hours after injection 
c ECG is performed prior to the injection on Day 1. 
d Hematology, chemistry (including glucose, HbA1c, liver and renal function, hsCRP, IL6, IFN-γ, and TNF-α), and coagulation testing. Blood samples for determination laboratory values will be performed prior to study drug 
injection where relevant. All laboratory testing will be performed with subjects in a fasted state. 
e Lab tests performed in participating institution’s laboratory. Results must be available before the start of study drug injection on Day 1 to confirm subjects meet eligibility criteria 
f Lab tests performed by study’s designated Central Lab facility from randomization to EOS. In addition, subjects in whom LDL-C levels have not returned to >80% of baseline values by Day 210 will continue to be followed up on 
a monthly visit schedule until Day 360, or until this level has been reached. 
g Urinalysis collection is prior to the injection on Day 1. 
h Urine pregnancy test performed and results available prior to the injection on Day 1 and Day 90 (for subjects randomized to receive injections on two days). Additional urine pregnancy test may be required due to local 
regulations. 
i Women of childbearing potential will have a pregnancy test at each additional follow-up visit until lipids return to >80% of baseline values. 
j Two ADA samples will be drawn on Day 1: one before the injection and one 4 hours after the injection. 
k Additional aliquots of plasma and serum will be collected at each time point and stored for future analyses. 
l at final observation 
m Efficacy parameters will include LDL-C, total cholesterol, triglycerides, HDL-C, non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 (Apo-AI), apolipoprotein B (Apo-B), lipoprotein(a) [Lp(a)], C-reactive 
protein (CRP), and PCSK9. 
n Efficacy parameters will include basic lipid panel  (LDL-C, HDL-C, total cholesterol, triglycerides) and PCSK9; non-HDL-C and VLDL-C will be derived from the lipid panel. 
 
 


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2. 
GENERAL CONDUCT OF TRIAL 
2.1. 
Screening Period (Days –14 to –1) 
The following procedures will be performed within 2 weeks prior to randomization: 
 Informed consent 
 Medical history 
 Physical examination 
 Assessment of inclusion/exclusion criteria 
 Vital signs 
 12-lead electrocardiogram (ECG) 
 Clinical laboratory assessments (hematology, chemistry [including liver and renal 
function], HbA1c, urinalysis, and coagulation testing)  
 Urinalysis (local) 
 Pregnancy test (local) 
 Assessment of lipids/lipoproteins: 
 Concomitant medications 
 Central laboratory assessments (lipid panel, BQ LDL-c,PCSK9, hsCRP, Lp(a), Apo 
AI and Apo B) 
2.2. 
Randomization 
The following procedures will be performed prior to the injection:  
 Assessment of inclusion/exclusion criteria 
 Randomization 
 Vital signs: blood pressure, heart rate, temperature, and respiration will be measured 
prior to injection  
 12-lead ECG 
 Clinical laboratory assessments (hematology, chemistry [including liver and renal 
function], HbA1c, and coagulation testing)  
 Urinalysis (local) 
 Pregnancy test (local) 
 Assessment of ADA  
 Assessment of lipids/lipoproteins 
 Concomitant medications 


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 AE reporting 
 Serious Adverse Event (SAE) reporting 
The following procedures will be performed after the injection:  
 Vital signs: blood pressure, heart rate, temperature, and respiration (4 hours after 
injection) 
 Assessment of ADA (4 hours after injection) 
 Concomitant medications 
 AE reporting 
 SAE reporting 
Study drug administration will occur at this visit for all subjects (only dose for those randomized 
to receive a single dose and the first of two doses for those randomized to receive two). 
2.3. 
Follow-Up Visits 1 to 7 
 
Subjects will return to the study center 14 days (± 2 days) after study drug administration for 
Follow-Up Visit 1, 30 days (± 3 days) after study drug administration for Follow-Up Visit 2, and 
monthly (±3 days) after that for Follow-Up Visits 3 to 7. The following procedures will be 
performed at these visits: 
 Vital signs: blood pressure, heart rate, temperature, and respiration will be measured 
prior to injection and at 4 hours after injection 
 Clinical laboratory assessments (hematology, chemistry [including liver and renal 
function], urinalysis, and coagulation testing)  
 Assessment of ADA: At Follow-Up Visit 2 (Day 30) and Follow-Up Visit 5 (Day 
120) 
 Assessment of lipids/lipoproteins 
 Study drug administration: Second dose at Follow-Up Visit 4 (Day 90) for subjects 
randomized to receive two doses  
 Concomitant medications 
 AE reporting 
 SAE reporting 
2.4. 
End of Study Visit (Follow-Up Visit 8; Day 210 or Withdrawal) 
A subject’s participation in the study is complete when: 
 All ongoing SAEs have been followed to resolution. 
 The following procedures/assessments have been completed. 
o Vital signs 


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o 12-lead ECG 
o Clinical laboratory assessments (hematology, chemistry [including liver and 
renal function], urinalysis, and coagulation testing)  
o Urinalysis (local) 
o Pregnancy test (local) 
o Assessment of ADA  
o Assessment of lipids/lipoproteins 
o Concomitant medications 
o AE reporting 
o SAE reporting 
 LDL-C levels have returned to >80% of baseline values. 
2.5. 
Interim Analysis 
An interim analysis of lipids and PCSK9, unblinded by dose cohort only, will be prepared upon 
completion of Day 90 by the Statistical Reporting Organization. The interim analysis will be 
performed for all subjects completing Day 90 and these data will be used to help select the ALN 
PCSSC dose for subsequent clinical trials. 
2.6. 
Assessment of Safety 
2.6.1. 
Adverse Events  
Subjects will be carefully monitored for adverse events (AEs) and for adverse events of special 
interest (injection site reactions) by the investigator during the designated study period. 
2.6.2. 
Clinical Laboratory Assessments 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 2).  
Additional aliquots of plasma or serum will be collected at each time point and stored for safety 
analyses to be conducted at the end of the study.  
Subjects will be in a fasted state for all clinical laboratory assessments. Screening lab tests will 
be performed by each participating institution’s laboratory. Results from these Screening tests 
must be available before the start of study drug injection on Day 1 to confirm subjects meet 
eligibility criteria.  
Urinalysis will be performed at the time points defined in the Schedule of Assessments and 
evaluated. 
2.6.3. 
Electrocardiograms 
ECGs will be collected at baseline and at the EOS visit only unless clinically indicated. 


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2.6.4. 
Assessment of Cardiovascular Events 
Information on CV events such as CHD death, major coronary events, and stroke will be 
collected as AE data. 
2.6.5. 
Anti-ALN-PCSSC Antibodies 
Additional sample for analysis of the induction of antibodies will be collected at the time points 
in the Schedule of Assessments (Table 2).  
Aliquots of serum samples will be obtained and frozen, to permit future analysis of the effect of 
ALN-PCSSC on the expression of these exploratory biomarkers.  
For the assessment of immunogenicity the following will be performed:    
 The incidence of subjects testing ADA positive 
 Review of safety data of ADA positive patients (AE, SAE, AESI) 
 Determination of clinically relevant differences in safety findings between ADA 
positive and ADA negative patients who received PCSSC when possible 
2.7. 
Assessment of Efficacy 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 2).  
Subjects will be in a fasted state for all efficacy laboratory assessments. Parameters to be 
assessed will include: total cholesterol (TC), triglycerides, LDL-C, high-density lipoprotein 
cholesterol (HDL-C), non-HDL-C, very low-density lipoprotein (VLDL), apolipoprotein A1 
(Apo-AI), apolipoprotein B (Apo-B), lipoprotein(a) [Lp(a)], C-reactive protein (CRP), and 
PCSK9.  
Blood samples for determination of LDL-C (β-quantification) concentrations will be collected at 
the time points in the Schedule of Assessments.  
Plasma samples will be analyzed using a validated enzyme linked immunosorbent assay to 
determine PCSK9 protein concentration. 


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3. 
ADVERSE EVENTS 
3.1. 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
Planned hospital admissions and/or surgical operations for an illness or disease that existed 
before the drug was given or the subject was randomized in a clinical study are not to be 
considered AEs. 
Adverse events or abnormal test findings will be followed until the event (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the Sponsor/Investigator. 
Incidences of injection site reactions will also be presented by dose group. Time to first injection 
site reaction will be analyzed. The severity and duration of injection site reactions, as well as 
their signs and symptoms, will also be summarized. 
3.2. 
AE Severity 
The severity of an AE will be assessed by the investigator. The investigator should ensure that 
any subject experiencing an AE receives appropriate medical support until the event resolves. 
Adverse events will be graded on a 3-point scale and reported as indicated on the case report 
form. The intensity of an AE is defined as follows: 
1 = Mild: Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe: Inability to work or perform normal daily activity. 
3.3. 
Study Drug Causality 
The relationship of an AE to study treatment will be assessed with consideration to the following 
criteria: 
 Temporal relationship to the initiation of study medication 
 Response of the event to withdrawal of study medication 
 AE profile of concomitant therapies 
 Clinical circumstances during which the AE occurred 
 Subject’s clinical condition and medical history  
Categorization of causality will be designated by the investigator as stated below: 
Reasonable possibility - There are facts (evidence) or arguments to suggest a causal 
relationship between the event and the IMP. 


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No reasonable possibility – There are few to no facts (evidence) or arguments to suggest 
a causal relationship between the event and the IMP 
3.4. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, ie, the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred (it does not include an event that, had it 
occurred in a more severe form, might have caused death), 
 Results in a significant, persistent or permanent change, impairment, damage or 
disruption in the subject's body function/structure, physical activities and/or quality of 
life, 
 Requires in-subject hospitalization or prolongs hospitalization, 
 Is a congenital anomaly/birth defect, or 
 Is another medically significant event that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above (eg, allergic bronchospasm requiring 
intensive treatment in an emergency department or home, blood dyscrasias or 
convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse). 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or 
measure of the intensity of an AE, while the criteria for serious AEs are indications of adverse 
subject outcomes for regulatory reporting purposes. A severe AE need not necessarily be 
considered serious and a serious AE need not be considered severe. For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE. On the other hand, 
an MI that may be considered minor could also be an SAE if it prolonged hospitalization. 
3.5. 
Medication Errors 
Medication error refers to any unintended error in the dosing and administration of the study 
product as per instructions in the protocol. Medication Errors generally fall into four categories 
as follows:  
1. 
wrong medication 
2. 
wrong dose (including dosing regimen, strength, form, concentration, amount); 
3. 
wrong route of administration; 
4. 
wrong subject (ie, not administered to the intended subject) 
Medication Errors include occurrences of underdose of the study product(s). 
Underdose: Unintentional administration of a quantity of the study product given per 
administration. 


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3.6. 
Adverse Events of Special Interest (AESIS) 
An adverse event of special interest (serious or nonserious) is one of scientific and medical 
concern specific to the Sponsor’s product or program, which warrants ongoing monitoring and 
rapid communication by the investigator to the sponsor. The SAE/AESI form should be utilized 
for reporting the AESI even if a serious outcome may not apply. 
In this study, injection site reactions including individual signs or symptoms at the injection site 
reported following study drug administration will be collected as an AESI.  
Signs or symptoms of injection site reaction will be evaluated by the Common Terminology 
Criteria for Adverse Events (CTCAE) criteria of Injection Site Reaction (General disorders and 
administration site conditions) to determine the event’s grade (severity). 
Table 3: 
Common Terminology Criteria for Adverse Events (CTCAE) criteria of 
Injection Site Reaction 
Grade I: 
Tenderness with or without associated symptoms (eg, warmth, erythema, 
itching) 
Grade II: 
Pain; lipodystrophy; edema; phlebitis 
Grade III 
Ulceration or necrosis; severe tissue damage; operative intervention 
indicated 
Grade IV 
Life-threatening consequences; urgent intervention indicated 
Grade V 
Death  
Abbreviations: AE = adverse even 
Reference source: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, Published May 28, 2009 
4. 
MEASURES TO MINIMIZE/AVOID BIAS 
The study will be conducted using a double-blind design, with placebo matched by volume 
within each dose and regimen but not between regimens. Allocation of treatment is not disclosed 
to the study team. Study medication will be prepared by the unblinded hospital pharmacist and 
will be dispensed in a blinded syringe as randomized by the IWRS. Pharmacists will be required 
by signature to keep the study personnel blinded. Blinding is achieved by placing an over label 
on each unique syringe dispensed by the pharmacist. The over label will cover the outside of the 
syringe masking the color of the solution within. 


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5. 
STATISTICAL PLAN 
5.1. 
Sample Size 
The sample size calculation was performed with the assumption (which was based on the 
observed results from a phase 1 trial) that the difference in change form baseline between the 
active dose groups and the placebo will be no less than 30 mg/dL, with a standard deviation of 
20 mg/dL. Using a Dunnet mult
 for 6 comparisons.  
Assuming about a 15% drop o
 approximately 100 evaluable 
subjects total across the place
 50 subjects in each of six ALN-
PCSSC
roups. This sample size of at least 400 evaluable subjects will provide more 
than 90% power to detect a 30% reduction of LDL-C levels in at least one ALN-PCSSC dose 
group. 
5.2. 
Randomization 
Subjects will be screened and 480 eligible subjects will be randomized by the IWRS system: 60 
subjects per each of six ALN-PCSSC treatment groups plus 120 subjects total across the placebo 
groups (20 subjects each to match each of the six drug groups). Treatment 
tified by 
country and by curre
d-modifying therapies. Each subject will either 
receive either one or two injections on Day 1 only or a single injection on Day 1 and a second 
injection on Day 90 of blinded ALN PCSSC or placebo. 
5.3. 
General Statistical Considerations and Definitions  
5.3.1. 
General Statistical Methods 
All study-collected data will be summarized by treatment group using descriptive statistics, 
graphs, and/or raw data listings. Categorical variables will be summarized using counts and 
percentages. Percentages are based on the number of subjects in the analysis set for whom there 
are non-missing data, unless otherwise specified. Continuous variables, including changes from 
baseline, will be summarized using descriptive statistics (n, mean, standard deviation [SD], 
confidence intervals, median and interquartile range [Q1 and Q3], minimum and maximum).  
The Statistical Analysis Plan (SAP) will be finalized before database lock.  
Statistical analyses will be carried out using SAS statistical analysis software version 9.2 or 
higher (SAS Institute, Inc., Cary, North Carolina, USA). 
5.3.2. 
Analysis Population 
The following populations will be used for data analyses and/or presentation. 
5.3.2.1. 
Intent-to-Treat (ITT) Population  
All subjects randomized into the trial. Treatment classification will be based on the randomized 
treatment. This population will be used to assess the randomness of treatment allocation. 


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5.3.2.2. 
Modified Intent-to-Treat (mITT) Population 
All randomized subjects who receive at least one dose of study drug and have both the baseline 
and the 180 day follow-up LDL C assessment. Treatment classification will be based on the 
randomized treatment. This will be the primary population for analysis of the primary and 
secondary endpoints. 
5.3.2.3. 
Per-Protocol (PP) Population 
All mITT subjects who received all randomized treatments and the 180 day follow-up LDL C 
assessment. The PP population will be finalized during a data review before database lock. This 
will be the supportive population for analysis of the primary and secondary endpoints. 
5.3.2.4. 
Safety Population 
All subjects who received at least one dose of study drug. Treatment classification will be based 
on the actual treatment received. This will be primary population for the safety analyses. 
5.3.3. 
Analysis Windows and Baseline 
The observational period for the study includes screening period (from Day -14 to Day -1) to the 
EOS visit (follow-up Visit 8, Day 210 or withdrawal date). The time at which LDL-C levels have 
returned to >80% of baseline values will be the last observation.  Any lab results collected after 
the last observation will not be included in the planned efficacy analysis. Safety events after the 
last observation, if collected on the eCRF, will not be included in the planned statistical analysis. 
However, all data, including safety events that were reported after the defined observational 
period, will be included in the subject data listings.  
Unless otherwise specified, for evaluations that are collected at multiple occasions prior to 
initiation of study drug, the last evaluation will be considered the "Baseline" evaluation for 
analysis. Two PD samples for lipids and PCSK9 will be taken prior to initiation of study drug. 
The average of the two samples will be used as the baseline evaluation. If only one sample was 
collected, the collected sample will be used as baseline. If more than two samples were taken, 
then the average of the last two will be used as baseline. 
5.3.4. 
Missing data handling 
Unless otherwise specified, missing data will not be imputed and will be excluded from the 
associated analysis. 
5.4. 
Statistical Analyses 
5.4.1. 
Demographic and Background Characteristics 
Subject demographics and baseline characteristics (including medical history) will be 
summarized by treatment group using the ITT, mITT, PP, and safety populations. 
 


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5.4.2. 
Study Drug  
For all cohorts including those that receive doses only Day 1 and those that receive a dose on 
Day 1 and a second dose on Day 90, dose regimen, summary of study drug dose given, number 
of syringes given and syringe volume, incidences of study drug not prepared, incidences of mis-
dosing will be provided. 
5.4.3. 
Concomitant Medications  
Summaries of each prior (pre-baseline) medication and concomitant (baseline or later) 
medication will be provided by treatment. Separate summaries will be provided for prior 
medication use. Medications will be coded using the WHO drug dictionary. Subjects will be 
counted only once within each period by medication. 
5.4.4. 
Efficacy Analysis  
The results of efficacy and safety analysis will be used to help determine the dose(s) for future 
phase 3 trial(s). 
5.4.4.1. 
Primary Efficacy Endpoints 
The primary endpoint is the percentage change in LDL-C from baseline to Day 180. 
Two sample t-tests will be performed to test the superiority of any dosing group over placebo. A 
Dunnet multiple t-test procedure will be applied to adjust for multiple comparisons with six 
different dosing regimens. 
5.4.4.2. 
Endpoints 
The secondary endpoints of this trial are: 
 Change from Baseline LDL-C 
 Percentage change in LDL-C from baseline to Day 90  
 Percentage change in LDL-C from baseline to Days 14, 30, 60, 120, 150, and 210  
 Proportion of subjects in each group with LDL-C greater than 80% of the baseline 
value at Day 180 and Day 210 
 Duration of time on treatment for subjects to return to >80% of baseline or greater 
LDL-C or PCSK9 protein (if not resolved by Day 210, subjects will continue to be 
followed  until LDL-C returns to within 80% of baseline.  
 Individual responsiveness defined as the number of subjects reaching on treatment 
LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 90, 
120, and 180  
 Proportion of subjects in each group with greater or equal to 50% LDL C reduction 
from baseline at Days 90, 120, and 180 
 Proportion of subjects in each group who attain global lipid modification targets for 
their level of ASCVD risk 
 


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 Change from Baseline Lipids/Lipoproteins 
Secondary efficacy assessments will include the measure the effects of ALN-PCSSC on levels of 
lipids and lipoproteins including total cholesterol, triglycerides, LDL-C (calculated and BQ) 
HDL-C, non-HDL-C, very low-density lipoprotein (VLDL), Apo-AI, Apo-B, Lp(a), CRP, and 
PCSK9.  
 Percentage change in PCSK9 levels from baseline to Days 14, 30, 60, 90, 120, 150, 
180, and 210 
 Percentage change in other lipids, lipoproteins, apolipoproteins from baseline at each 
subsequent visit to Day 210 
5.4.4.3. 
Exploratory Efficacy Endpoints 
The exploratory endpoints of this trial are: 
 Information on CV events such as CV death, non-fatal MI, major coronary events 
(CHD death, resuscitated cardiac arrest, non-fatal MI), ischemic stroke, and 
hemorrhagic stroke  
 Evaluation of ADA for the investigational product 
5.4.5. 
Safety Analysis 
The safety objectives of this study are to evaluate: 
 The safety and tolerability profile of ALN-PCSSC. 
5.4.5.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for coding 
AEs. An AE (classified as preferred term, and AESI) occurring during the double-blind 
treatment period will be counted as a treatment emergent AE (TEAE) either if it is not present at 
baseline or if it is present at baseline but increased in severity during the treatment period. 
The number (percentage) of subjects reporting TEAEs for each preferred term will be tabulated 
by system-organ class, by system-organ class and severity, and by system-organ class and 
relationship to study drug. If more than one event occurred with the same preferred term for the 
same subject, the subject will be counted only once for that preferred term using the most severe 
or related occurrence for the summary by severity, or relationship to study drug, respectively. 
5.4.5.2. 
Laboratory Tests 
Laboratory values will be summarized by treatment group, including changes and percent 
changes from baseline at each time point. Analyses will also be performed for each lab parameter 
by treatment group for incidence rates of potentially clinical significant values for subjects 
without potentially clinical significant value at baseline. 
5.4.5.3. 
Clinical Laboratory Assessments 
Clinical laboratory endpoints include: 


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Hematology: hemoglobin, hematocrit, erythrocytes, reticulocytes, platelet counts, mean cell 
hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC), white blood cell count, differential blood count. 
Coagulation: prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin (aPTT). Blood samples for determination of coagulation parameters will be 
performed prior to start of study drug injection on Day 1. 
Biochemistry: AST, ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), 
uric acid, TBIL(direct and indirect bilirubin), sodium, creatine phosphokinase, albumin, total 
protein, urea (BUN), creatinine, potassium, chloride, glucose (fasting), inorganic phosphate, 
eGFR, calcium 
Urinalysis: The following parameters will be assessed: Nitrite, protein, glucose, ketone, 
urobilinogen, bilirubin, RBC/erythrocytes, WBC/leukocytes, pH, urine sediment (microscopic 
examination will be only performed in the event of abnormalities) 
5.4.5.4. 
Vital Signs 
Change and percent change from baseline in vital signs will be summarized descriptively at each 
scheduled time point by treatment group. 
5.4.5.5. 
Neurological Examinations 
The percentage of subjects with a treatment-emergent abnormal neurological examination and 
the specific abnormality reported will be summarized by treatment group. 


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6. 
COMPUTER METHODS 
Statistical analyses will be performed using SAS (version 9.2 or later version). 


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7. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
There are no changes to the analyses specified in the protocol. 


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8. 
REFERENCES 
Protocol MDCO-PCS-15-01