Long Term Safety Study of PRALUENT in Patients With Heterozygous Familial Hypercholesterolemia or With Non-Familial Hypercholesterolemia at High and Very High Cardiovascular Risk and Previously Enrolled in the Neurocognitive Function Trial
Phase: PHASE4
Conditions: Heterozygous Familial Hypercholesterolemia, Non-familial Hypercholesterolemia
Sponsor: Regeneron Pharmaceuticals

Regeneron Pharmaceuticals, Inc. 
Page 1 of 57 
CONFIDENTIAL 
EudraCT Number: 2018-002810-11 
IND Number: 105574 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
Long Term Safety Study of PRALUENT in Patients with Heterozygous Familial 
Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High and Very High 
Cardiovascular Risk and Previously Enrolled in the Neurocognitive Function Trial 
Compound: 
PRALUENT 
Study Name: 
Open-Label Extension after the Neurocognitive 
Function Study 
Clinical Phase: 
4 (Phase 3 in South Africa) 
Protocol Number: 
R727-CL-1609 
Protocol Version:  
R727-CL-1609 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page. 
Amendment 1 Date of Issue: 
23 Jul 2018 
Original Date of Issue: 
06 May 2016 
Scientific/Medical Monitor: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
  
 
 
 
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NCT03694197

Clinical Study Protocol 
 
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AMENDMENT HISTORY 
Amendment 2 
The protocol is being amended to add back text that was inadvertently removed in protocol 
amendment 1, and to clarify language for blinding, study discontinuation, treatment compliance, 
adverse event (AE) reporting period, and procedures for reporting serious adverse events (SAEs). 
The table below outlines changes made in this amendment. 
Change 
Sections Changed 
Revised study hypothesis for clarity 
Section 3.1 Hypothesis 
Deleted reference to Company Core Data 
Sheet, as not applicable 
Clinical Study Protocol Synopsis – Study 
Design 
Section 5.1 Study Description and Duration 
Added new section for language concerning a 
Neurocognitive Events Review Committee, to 
match that in the neurocognitive function 
study (R727-CL-1532), and reintroduced 
wording that was inadvertently removed.  
Also clarified language regarding maintaining 
the blind in R727-CL-1532. 
Clinical Study Protocol Synopsis – Study 
Design 
Section 5.1 Study Description and Duration 
Section 5.3 Study Committees (new) 
Section 5.3.1 Neurocognitive Events Review 
Committee (new) 
Deleted language regarding investigational 
product dispensing, as not applicable 
Section 7.1 Investigational and Reference 
Treatments 
Deleted requirement to maintain patients in 
the trial after treatment discontinuation, as the 
objective of this open-label trial is to assess 
the long-term safety based on actual exposure 
to alirocumab 
Section 7.3.2 Study Drug Discontinuation 
Clarified follow-up on pregnancies, to be 
consistent within the protocol 
Section 7.3.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
Revised language to reflect kit assembly; 
previous language was copied from the 
neurocognitive function study (R727-CL-
1532) 
Section 7.5.4 Treatment Compliance 
Clarified schedule of events and applicable 
footnotes for assessments not collected at 
visit 1; clarified footnotes for assessment of 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of 
Events Table 
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gonadal hormones and gonadotropins, and for 
study kit dispensation 
Clarified details on procedures for reporting 
serious adverse events 
Section 9.4.2 Serious Adverse Events 
Added back sub-bullet under “All 
neurocognitive events” from original 
protocol, concerning regular review by an 
independent panel of experts 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Clarified that adverse events of special 
interest (AESI) will be followed until they are 
considered chronic and/or stable 
Section 9.4.6 Follow-up 
Deleted statement on patient disposition, as 
not applicable 
Section 10.4.1 Patient Disposition 
Replaced the ITT and/or mITT populations 
with the Safety Analysis Set 
Section 10.4.3 Efficacy Analyses 
Clarified the definition of the treatment-
emergent adverse event (TEAE) period to 
align with the last dose and the last study visit 
Section 10.4.4.1 Adverse Events 
Made minor editorial and/or formatting 
changes 
Clinical Study Protocol Synopsis – 
Objectives, Study Design, Treatments 
(Background Treatment), Endpoints 
(Primary) 
Section 2.1 Primary Objective 
Section 4.2.1 Primary Endpoint 
Section 5.1 Study Description and Duration 
Section 7.2 Background Treatments 
Section 7.4 Method of Treatment Assignment 
Section 7.6.1 Prohibited Medications 
Section 8.2.4.1 Review of Diet 
Section 11.1 Data Management 
Appendix 1 Factors to Consider in Assessing 
the Relationship of Adverse Events to Study 
Drug and Study Conduct 
 
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Amendment 1 
The protocol is being amended to align with feedback received from the European Medicines 
Agency (EMA), and updated for clarity and consistency with the current R727-CL-1532 
neurocognitive function protocol Amendment 5.  
The table below outlines changes made in this amendment. 
Change 
Sections Changed 
Corrected the EudraCT number and updated 
the study name to better describe the study 
Title Page 
Added evaluation of the effect of Praluent on 
gonadal steroid hormones as a secondary 
objective 
Synopsis (Objectives) 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
Clarified that eligible patients for this study 
must have completed treatment and the end of 
study (EOS) visit in the neurocognitive study  
Synopsis (Study Design) 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 6.2.1 Inclusion Criteria 
Removed the requirement that at least 14 days 
are required between the last dose of study 
drug in the neurocognitive function study and 
the first dose of study drug in the open-label 
extension (OLE) study 
Synopsis (Study Design) 
Section 5.1 Study Description and Duration 
Section 8.1.1 Footnotes for the Schedule of 
Events Table: Footnote #1 
Added the statement that study drug should 
be administered every 2 weeks throughout the 
study 
Section 8.1.1 Footnotes for the Schedule of 
Events Table: Footnote #1 
Amended required measurement of 
low-density lipoprotein cholesterol (LDL-C) 
levels from within 4 to 8 weeks after 
initiating study treatment or dose 
modification, to 8 weeks after initiating study 
treatment or at least 4 weeks after dose 
modification.  
Synopsis (Study Design) 
Section 5.1 Study Description and Duration 
Updated section to reflect dose selection for 
the open label extension study 
Section 3.2.2 Rationale for Dose Selection 
Added new sections from updated protocol 
template 
Section 5.1.1 End of Study Definition 
Section 18 Data Quality Assurance 
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Updated the expected total number of patients Synopsis (Sample Size) 
Section 3.2.1 Rationale for Study Design 
Section 6.1 Number of Patients Planned 
Broadened monitoring of circulating gonadal 
steroid hormones and gonadotropins by 
removing requirement that these assessments 
be performed only in men with baseline 
luteinizing hormone (LH) <15 IU/L, and 
premenopausal women with baseline follicle 
stimulating hormone (FSH) <25 IU/L 
Table 1 Schedule of Events  
Section 8.1.1 Footnotes for the Schedule of 
Events Table: Footnote #7 
Section 8.2.2.3 Laboratory Testing 
Added monitoring of HbA1c, Apo-B, 
Apo A-1, and Lp(a) 
Table 1 Schedule of Events 
Section 8.2.2.3 Laboratory Testing 
Deleted the requirement that blood sampling 
for lipid parameters must be collected in the 
morning following a 10- to 12-hour overnight 
fast while refraining from smoking 
Section 8.2.3.1 Lipid Panel 
Section 8.1.1 Footnotes for the Schedule of 
Events Table: Footnote #6 
Deleted the section referring to anti-drug 
antibody measurements as these will not be 
collected in this study 
Section 8.2.4.1 Anti-Drug Antibody 
Measurements and Samples 
Deleted the statement that events that are not 
a known response to the study drug should be 
considered not related when evaluating 
causality 
Section 9.5.2 Evaluation of Causality 
Added laboratory evaluations (gonadal 
hormones and gonadotropins, liver panel, 
hematology, blood chemistry, urinalysis, and 
Total-C, calculated LDL-C, HDL-C, TG, and 
non-HDL-C) at weeks 24, 72, 120, and 168; 
deleted assessment of vital signs and physical 
examination at weeks 24, 72, 120, and 168, 
and added collection of research samples on 
day 1, and weeks 144 and 192 
Table 1 Schedule of Events 
Removed review of neurocognitive adverse 
events (AEs) by an independent panel of 
experts 
Section 9.4.3 Other Adverse Events that 
Require Accelerated Reporting to Sponsor 
Updated statistical analysis methods to:  add 
that the anticipated number of patients is 
Section 10.2 Justification of Sample Size 
Section 10.4.3 Efficacy Analyses 
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based on the observed drop-out rate in the 
ODYSSEY program, combined the primary 
and secondary efficacy analysis sections and 
updated text, clarified the definition of the 
TEAE period and the definition of AEs, and 
clarified how unscheduled assessments will 
be handled.  
Section 10.4.4.1 Adverse Events 
Section 10.5 Additional Statistical Data 
Handling Conventions 
Made changes for consistency with 
R727-CL-1532 neurocognitive function 
protocol 
Synopsis (Population) 
Section 6.2.2 Exclusion Criteria #6 
Section 8.2.2.3 Laboratory Testing 
Section 12.1 Monitoring of Study Sites 
Section 12.3 Case Report Form Requirements 
Made corrections, minor changes, and edits 
for clarity 
Synopsis (Objectives, Study Design, Study 
Duration, Population, Procedures and 
Assessments) 
List of Abbreviations and Definitions of 
Terms 
Section 2.1 Secondary Objectives 
Section 3.1 Hypothesis 
Section 3.2.1 Rationale for Study Design 
Section 4.1 Demographic and Baseline 
Characteristics 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Section 6.2.1 Inclusion Criteria 
Section 6.2.2 Exclusion Criteria (#2 and #3) 
Section 7.2 Background Treatments 
Section 7.3.1 Dose Modification 
Section 7.4 Method of Treatment Assignment 
Section 7.6 Concomitant Medications 
Section 7.6.2 Permitted Medications 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of 
Events Table (#1 and #4) 
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Section 8.2.1 Procedures Performed Only at 
the Screening/Baseline Visit 
Section 8.2.3.1 Lipid Panel 
Section 8.2.7 Future Biomedical Research 
Section 9.4.1 Adverse Events 
Section 9.5.1 Evaluation of Severity 
Section 10.4.3 Efficacy Analyses 
Section 10.4.4.2 Other Safety 
Section 11.2 Electronic Systems 
Section 12.3 Case Report Form Requirements 
 
 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION ......................................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objectives .................................................................................................19 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................19 
3.1. 
Hypothesis ..................................................................................................................19 
3.2. 
Rationale .....................................................................................................................19 
3.2.1. 
Rationale for Study Design .........................................................................................19 
3.2.2. 
Rationale for Dose Selection ......................................................................................20 
4. 
STUDY VARIABLES................................................................................................20 
4.1. 
Demographic and Baseline Characteristics ................................................................20 
4.2. 
Primary and Secondary Endpoints..............................................................................20 
4.2.1. 
Primary Endpoint ........................................................................................................20 
4.2.2. 
Secondary Endpoints ..................................................................................................20 
4.2.3. 
Other Endpoints ..........................................................................................................21 
5. 
STUDY DESIGN .......................................................................................................21 
5.1. 
Study Description and Duration .................................................................................21 
5.1.1. 
End of Study Definition ..............................................................................................22 
5.2. 
Planned Interim Analysis ............................................................................................22 
5.3. 
Study Committees .......................................................................................................22 
5.3.1. 
Neurocognitive Events Review Committee ................................................................22 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............23 
6.1. 
Number of Patients Planned .......................................................................................23 
6.2. 
Study Population .........................................................................................................23 
6.2.1. 
Inclusion Criteria ........................................................................................................23 
6.2.2. 
Exclusion Criteria .......................................................................................................23 
6.3. 
Premature Withdrawal from the Study .......................................................................24 
6.4. 
Replacement of Patients .............................................................................................24 
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7. 
STUDY TREATMENTS............................................................................................24 
7.1. 
Investigational and Reference Treatments ..................................................................24 
7.2. 
Background Treatments ..............................................................................................25 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................25 
7.3.1. 
Dose Modification ......................................................................................................25 
7.3.2. 
Study Drug Discontinuation .......................................................................................25 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................26 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................26 
7.4. 
Method of Treatment Assignment ..............................................................................26 
7.4.1. 
Blinding ......................................................................................................................27 
7.5. 
Treatment Logistics and Accountability .....................................................................27 
7.5.1. 
Packaging, Labeling, and Storage ..............................................................................27 
7.5.2. 
Supply and Disposition of Treatments .......................................................................27 
7.5.3. 
Treatment Accountability ...........................................................................................27 
7.5.4. 
Treatment Compliance ................................................................................................27 
7.6. 
Concomitant Medications ...........................................................................................28 
7.6.1. 
Prohibited Medications ...............................................................................................28 
7.6.2. 
Permitted Medications ................................................................................................28 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................29 
8.1. 
Schedule of Events .....................................................................................................29 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................32 
8.1.2. 
Early Termination Visit ..............................................................................................32 
8.1.3. 
Unscheduled Visits .....................................................................................................32 
8.2. 
Study Procedures ........................................................................................................32 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................32 
8.2.2. 
Safety Procedures .......................................................................................................33 
8.2.2.1. 
Vital Signs ..................................................................................................................33 
8.2.2.2. 
Physical Examination and Body Weight ....................................................................33 
8.2.2.3. 
Laboratory Testing ......................................................................................................33 
8.2.3. 
Efficacy Procedures ....................................................................................................35 
8.2.3.1. 
Blood Sampling ..........................................................................................................35 
8.2.4. 
Other Assessments ......................................................................................................35 
8.2.4.1. 
Review of Diet ............................................................................................................35 
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8.2.5. 
Research Samples .......................................................................................................35 
8.2.6. 
Biomarker Procedures ................................................................................................35 
8.2.7. 
Future Biomedical Research .......................................................................................35 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................36 
9.1. 
Obligations of Investigator .........................................................................................36 
9.2. 
Obligations of Sponsor ...............................................................................................36 
9.3. 
Definitions ..................................................................................................................36 
9.3.1. 
Adverse Event .............................................................................................................36 
9.3.2. 
Serious Adverse Event ................................................................................................36 
9.3.3. 
Adverse Events of Special Interest .............................................................................37 
9.4. 
Recording and Reporting Adverse Events ..................................................................37 
9.4.1. 
Adverse Events ...........................................................................................................37 
9.4.2. 
Serious Adverse Events ..............................................................................................37 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................38 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................38 
9.4.5. 
Abnormal Laboratory or Vital Signs ..........................................................................39 
9.4.6. 
Follow-up ....................................................................................................................39 
9.5. 
Evaluation of Severity and Causality .........................................................................39 
9.5.1. 
Evaluation of Severity ................................................................................................39 
9.5.2. 
Evaluation of Causality ...............................................................................................40 
9.6. 
Safety Monitoring .......................................................................................................41 
9.7. 
Investigator Alert Notification ....................................................................................41 
10. 
STATISTICAL PLAN................................................................................................41 
10.1. 
Statistical Hypothesis ..................................................................................................42 
10.2. 
Justification of Sample Size........................................................................................42 
10.3. 
Analysis Sets ...............................................................................................................42 
10.3.1. 
Safety Analysis Set .....................................................................................................42 
10.4. 
Statistical Methods ......................................................................................................42 
10.4.1. 
Patient Disposition ......................................................................................................42 
10.4.2. 
Demography and Baseline Characteristics .................................................................42 
10.4.3. 
Efficacy Analyses .......................................................................................................43 
10.4.4. 
Safety Analysis ...........................................................................................................43 
10.4.4.1. 
Adverse Events ...........................................................................................................43 
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10.4.4.2. 
Other Safety ................................................................................................................44 
10.4.4.3. 
Treatment Exposure ....................................................................................................45 
10.4.4.4. 
Treatment Compliance ................................................................................................45 
10.4.5. 
Other Endpoints ..........................................................................................................45 
10.5. 
Additional Statistical Data Handling Conventions .....................................................45 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........46 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................46 
11.1. 
Data Management .......................................................................................................46 
11.2. 
Electronic Systems ......................................................................................................47 
12. 
STUDY MONITORING ............................................................................................47 
12.1. 
Monitoring of Study Sites ...........................................................................................47 
12.2. 
Source Document Requirements ................................................................................47 
12.3. 
Case Report Form Requirements ................................................................................47 
13. 
AUDITS AND INSPECTIONS .................................................................................48 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................48 
14.1. 
Good Clinical Practice Statement ...............................................................................48 
14.2. 
Informed Consent .......................................................................................................48 
14.3. 
Patient Confidentiality and Data Protection ...............................................................49 
14.4. 
Institutional Review Board/Ethics Committee ...........................................................49 
15. 
PROTOCOL AMENDMENTS ..................................................................................50 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................50 
16.1. 
Premature Termination of the Study ...........................................................................50 
16.2. 
Close-out of a Site ......................................................................................................50 
17. 
STUDY DOCUMENTATION ...................................................................................51 
17.1. 
Certification of Accuracy of Data ...............................................................................51 
17.2. 
Retention of Records ..................................................................................................51 
18. 
DATA QUALITY ASSURANCE ..............................................................................51 
19. 
CONFIDENTIALITY ................................................................................................52 
20. 
FINANCING AND INSURANCE .............................................................................52 
21. 
PUBLICATION POLICY ..........................................................................................52 
22. 
REFERENCES ...........................................................................................................52 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................53 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................57 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................30 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................22 
 
LIST OF APPENDICES 
APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE RELATIONSHIP 
OF ADVERSE EVENTS TO STUDY DRUG AND STUDY 
CONDUCT .........................................................................................................54 
APPENDIX 2. SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL .............................55 
APPENDIX 3. ASSESSMENT OF LOCAL INJECTION SITE REACTIONS ........................56 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
Long Term Safety Study of PRALUENT in Patients with Heterozygous 
Familial Hypercholesterolemia or with Non-Familial Hypercholesterolemia 
at High and Very High Cardiovascular Risk and Previously Enrolled in the 
Neurocognitive Function Trial  
Site Locations 
 
 
Principal Investigator 
Site numbers and countries from enrolling sites in the neurocognitive 
function study (R727-CL-1532).  
To be determined 
Objectives 
The primary objective of the study is to evaluate the long-term safety of 
PRALUENT in patients with heterozygous familial hypercholesterolemia 
(heFH) or non-familial hypercholesterolemia (FH) patients at high or very 
high cardiovascular risk who completed the neurocognitive function study 
(R727-CL-1532). 
The secondary objectives of the study are: 
 
To evaluate the effect of PRALUENT on low-density lipoprotein 
cholesterol (LDL-C) 
 
To evaluate the effect of PRALUENT on other lipid parameters 
 
To evaluate the effect of PRALUENT on gonadal steroid 
hormones 
Study Design 
This is a phase 4, open-label extension (OLE), uncontrolled, multicenter, 
long-term safety study to be performed in patients who have completed the 
neurocognitive function study (R727-CL-1532).  The observation period for 
PRALUENT treatment in the OLE study is planned to be approximately 
192 weeks.   
Patients who completed treatment and the end of study (EOS) visit in the 
neurocognitive function study (R727-CL-1532) may enroll in the OLE 
study.  The end of study (EOS) visit of the double-blind neurocognitive 
function study (R727-CL-1532) corresponds to visit 1 (day 1) of the OLE 
study.  The first subcutaneous (SC) injection of PRALUENT will be 
administered in the clinic (day 1, visit 1).  
After visit 1, patients have the option to either self-administer study drug, or 
have another designated person (such as a spouse or caregiver) administer 
study drug for them. 
The starting dose of PRALUENT will be 75 mg administered SC every 
2 weeks (Q2W, regardless of treatment assigned in the neurocognitive 
function study R727-CL-1532), that may be modified to 150 mg 
administered SC Q2W, and can be maintained or modified from 150 mg 
Q2W to 75 mg Q2W.  Low-density lipoprotein cholesterol (LDL-C) levels 
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must be measured at 8 weeks after initiating study treatment, or least 
4 weeks after dose modification, to assess response and to adjust the dose, 
if needed.   
The investigator will be blinded to the treatment received in the 
neurocognitive function study (R727-CL-1532) until that study is completed 
and the database is locked.  Lipid profile values from samples obtained after 
inclusion will be blinded until week 8 in order to prevent any potential 
unblinding of the neurocognitive function study (R727-CL-1532). 
From week 8 in the OLE study, lipid measurements will be collected and 
will be known by the investigator in real time.  The investigator will manage 
the PRALUENT dose at his/her discretion based on LDL-C levels, starting 
at week 12, by either modifying the dose from 75 mg Q2W to 150 mg Q2W, 
maintaining the dose, modifying the dose from 150 mg Q2W to 75 mg 
Q2W, or discontinuing treatment with PRALUENT at any time during the 
treatment period.  If a dose is missed, the patient should administer the 
injection as soon as possible and thereafter resume treatment from the day 
of the missed dose (ie, resume on the next originally planned date).  The 
statin dose should not be modified to adjust the degree of LDL-C lowering. 
Background lipid modifying therapy (LMT) will be prescribed as per 
clinical practice and should remain the same as in the neurocognitive 
function study (R727-CL-1532).  Lipid modifying therapy, including 
statins, should not be changed during the course of the study.  However, if 
clinically necessary, background LMT may be adjusted at the investigator’s 
discretion.  Any adjustment will be documented in the case report form 
(CRF).  Patients not treated with a statin (eg, statin intolerant patients, or 
patients in whom statin treatment was stopped during the neurocognitive 
function study [R727-CL-1532] for a safety reason) may still participate in 
the OLE study. 
The investigator should refer to the label for information on PRALUENT 
and other LMTs. 
Patients should continue on a National Cholesterol Education Program-
Adult Treatment Panel III Therapeutic Lifestyle Changes (NCEP-ATPIII 
TLC) diet or equivalent throughout the entire study duration. 
Visits are planned at weeks 0, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192.  
At each visit, except at the EOS visit at week 192, study drug will be 
dispensed to the patient.  If at any time during the study after the week 8 
visit, the investigator, based on lipid results or safety issues, decides to 
modify the dose of PRALUENT, an unscheduled kit dispensation visit will 
be performed. 
 Study Duration 
The duration of the OLE study for a patient is planned to be approximately 
192 weeks.   
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Population 
 
 
Sample Size: 
Anticipated enrollment will depend on the number of patients who complete 
treatment in the neurocognitive function study (R727-CL-1532) and the 
number of patients who agree to participate (approximately 1600 patients).   
 
Target Population: 
The study population consists of patients with heFH, or non-FH patients at 
high or very high cardiovascular risk, who completed treatment in the 
neurocognitive function study (R727-CL-1532).   
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Sterile PRALUENT drug product will be supplied at a concentration of 
75 mg/mL and 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose, 
both as 1 mL volume in an auto-injector. 
Subcutaneous injections in the abdomen, thigh or outer area of upper arm. 
75 mg Q2W or 150 mg Q2W (dose may be modified from 75 mg Q2W to 
150 mg Q2W, or from 150 mg Q2W to 75 mg Q2W). 
 
Background Treatment 
 
Dose/Route/Schedule: 
Maximally-tolerated registered daily dose of statin received during the 
neurocognitive function study (R727-CL-1532), with or without other LMT. 
The statin dose should not be modified to adjust the degree of LDL-C 
lowering. 
Background LMT, including statins, should not be changed during the 
course of the study.  However, if clinically necessary, background LMT may 
be adjusted at the investigator’s discretion.  Any adjustment will be 
documented in the CRF. 
Endpoints 
 
 
Primary: 
The primary endpoint in the study is the incidence of adverse events (AEs) 
after first administration of study drug through the last dose of study drug 
plus 2 weeks. 
The following adverse events will be described: 
 
AEs/serious adverse events (SAEs) 
 
AEs leading to treatment discontinuation 
 
Adverse events of special interest (AESI) 
 
Secondary: 
Secondary Endpoints: 
 
Calculated LDL-C values and percent changes from baseline 
over time 
 
Values and percent changes from baseline in other lipids and other 
lipoproteins, 
including 
total 
cholesterol 
(Total-C), 
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non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, 
and triglycerides (TGs) over time 
 
Values and percent changes from baseline in gonadal hormones 
and gonadotropins over time 
Procedures and Assessments 
Safety Procedures: 
Vital signs, including sitting blood pressure and pulse will be collected. A 
general physical examination including body weight will be performed. 
Hematology, chemistry, including the liver panel and HbA1c, gonadal 
hormones and gonadotropins, urinalysis, and pregnancy testing samples will 
be analyzed.  
Efficacy Procedures: 
Blood samples for the determination of lipid parameters will be analyzed. 
Statistical Plan 
There is no formal size calculation for this study.  Patients’ eligibility is 
based on the neurocognitive function study (R727-CL-1532).   
Study data will be summarized descriptively for all patients in the safety 
population, as well as by randomized treatment group in the neurocognitive 
function study (R727-CL-1532). 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition of Term 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CHD 
Coronary heart disease 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form (electronic or paper) 
CRO 
Contract research organization 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EOS 
End of study 
FDA 
Food and Drug Administration 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
heFH 
Heterozygous familial hypercholesterolemia 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LH 
Luteinizing hormone 
LMT 
Lipid modifying therapy 
Lp(a) 
Lipoprotein a 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Abbreviation 
Definition of Term 
NCEP-ATPIII TLC 
National Cholesterol Education Program-Adult Treatment Panel III 
Therapeutic Lifestyle Changes 
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
OLE 
Open-label extension 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PCSV 
Potentially clinically significant value 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
Total-C 
Total cholesterol 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
γGT 
γ Glutamyl transferase 
 
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1. 
INTRODUCTION 
PRALUENT® is a human monoclonal antibody that binds proprotein convertase subtilisin/kexin 
type 9 (PCSK9) to inhibit its function.  All relevant information concerning the compound is 
available in the latest version of the Investigator’s Brochure.  PRALUENT was approved for the 
treatment of hypercholesterolemia in the United States on July 24, 2015 and in the 
European Union on September 23, 2015.  Approval has also been granted in other countries around 
the world.  Detailed information on the approved indication is available in the respective local 
product information. 
PRALUENT is also referred to as alirocumab, REGN727, or SAR236553.  In the context of the 
R727-CL-1609 clinical study protocol, it will be referred to as PRALUENT. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety of PRALUENT in patients 
with heterozygous familial hypercholesterolemia (heFH) or non-familial hypercholesterolemia 
(FH) patients at high or very high cardiovascular risk who completed the neurocognitive function 
study (R727-CL-1532). 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the effect of PRALUENT on low-density lipoprotein cholesterol 
(LDL-C) 
 To evaluate the effect of PRALUENT on other lipid parameters 
 To evaluate the effect of PRALUENT on gonadal steroid hormones 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
PRALUENT will have an acceptable safety profile with long-term use. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is an open-label extension (OLE) to the neurocognitive function study (R727-CL-1532) 
in which all patients will be treated, in a single arm, with PRALUENT.  The study will be 
conducted on patients who completed treatment and the end of study (EOS) visit in the 
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neurocognitive function study (R727-CL-1532), with no premature discontinuation of study drug 
or placebo.  This will allow for patient exposure to PRALUENT of approximately 6 years.  
At the time of inclusion into the OLE study, knowledge of the treatment arm in the neurocognitive 
function study (R727-CL-1532) will not be available to the investigator or the sponsor.  Patients 
eligible to participate in the OLE study will initiate treatment with PRALUENT at the starting 
dose of 75 mg once every 2 weeks (Q2W), regardless of the treatment group to which they were 
randomized in the neurocognitive function study (R727-CL-1532).  
No formal sample size was calculated for this study.  The anticipated number of patients is based 
on the previously observed drop-out rate in the ODYSSEY program.   
The study duration of approximately 192 weeks, in addition to the 96-week exposure in the 
neurocognitive function study (R727-CL-1532), will enable the assessment of long-term exposure 
to PRALUENT. 
3.2.2. 
Rationale for Dose Selection 
The doses selected for this study was based on the approved doses for PRALUENT that were used 
in the neurocognitive function study (R727-CL-1532).  
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, gender, race, age [years], and 
ethnicity), and medical history.   
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint in the study is the incidence of AEs after first administration of study drug 
through the last dose of study drug plus 2 weeks. 
The following AEs will be described:  
 AEs/serious adverse events (SAEs)  
 AEs leading to treatment discontinuation 
 Adverse events of special interest (AESI) 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are: 
 Calculated LDL-C values and percent changes from baseline over time 
 Values and percent changes from baseline in other lipids and other lipoproteins, 
including total cholesterol (Total-C), non-high-density lipoprotein cholesterol 
(non-HDL-C), HDL-C, and triglycerides (TGs) over time 
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 Values and percent changes from baseline in gonadal hormones and gonadotropins over 
time 
4.2.3. 
Other Endpoints 
The other endpoints of the study will include: 
 Values and changes from baseline in liver tests over time 
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This is a phase 4, OLE, uncontrolled, multi-center, long-term, safety study to be performed in 
patients who have completed the neurocognitive function study (R727-CL-1532).  The observation 
period for PRALUENT treatment in the OLE study is planned to be approximately 192 weeks.   
Patients who completed treatment and the EOS visit in the neurocognitive function study 
(R727-CL-1532) may enroll in the OLE study.  The EOS visit of the double-blind neurocognitive 
function study (R727-CL-1532) corresponds to visit 1 (day 1) of the OLE study.  The first 
SC injection of PRALUENT will be administered in the clinic (day 1, visit 1).  
After visit 1, patients have the option to either self-administer study drug, or have another 
designated person (such as a spouse or caregiver) administer study drug for them. 
The starting dose of PRALUENT will be 75 mg administered SC Q2W (regardless of treatment 
assigned in the neurocognitive function study R727-CL-1532), that may be modified to 150 mg 
administered SC Q2W, and can be maintained or modified from 150 mg Q2W to 75 mg Q2W. 
Low-density lipoprotein cholesterol levels must be measured at 8 weeks after initiating study 
treatment, or at least 4 weeks after dose modification, to assess response and to adjust the dose, if 
needed. 
The investigator will be blinded to the treatment received in the neurocognitive function study 
(R727-CL-1532) until that study is complete and the database is locked.  Lipid profile values from 
samples obtained after inclusion will be blinded until week 8, in order to prevent any potential 
unblinding of the neurocognitive function study (R727-CL-1532). 
From week 8 in the OLE study, lipid measurements will be collected and will be known by the 
investigator in real time.  The investigator will manage the PRALUENT dose at his/her discretion 
based on LDL-C levels, starting at week 12, by either modifying the dose from 75 mg Q2W to 
150 mg Q2W, maintaining the dose, modifying the dose from 150 mg Q2W to 75 mg Q2W, or 
discontinuing treatment with PRALUENT at any time during the treatment period.  If a dose is 
missed, the patient should administer the injection as soon as possible and thereafter resume 
treatment from the day of the missed dose (ie, resume on the next originally planned date).  The 
statin dose should not be modified to adjust the degree of LDL-C lowering.  
Background LMT will be prescribed as per clinical practice and should remain the same as in the 
neurocognitive function study (R727-CL-1532).  Lipid modifying therapy, including statins, 
should not be changed during the course of the study.  However, if clinically necessary, 
background LMT may be adjusted at the investigator’s discretion.  Any adjustment will be 
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documented in the electronic case report form (CRF).  Patients not treated with a statin (eg, statin 
intolerant patients, or patients in whom statin treatment was stopped during the neurocognitive 
function study [R727-CL-1532] for a safety reason) may still participate in the OLE study. 
The investigator should refer to the label for information on PRALUENT and other LMTs. 
Patients should continue a National Cholesterol Education Program-Adult Treatment Panel III 
Therapeutic Lifestyle Changes (NCEP-ATPIII TLC) diet or equivalent throughout the entire study 
duration. 
Visits are planned at weeks 0, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 (Figure 1).  At each 
visit, except at the EOS visit at week 192, study drug will be dispensed to the patient.  If at any 
time during the study after the week 8 visit, the investigator, based on lipid results or safety issues, 
decides to modify the dose of PRALUENT, an unscheduled kit dispensation visit will be 
performed. 
Figure 1: 
Study Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
5.1.1. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last patient.  
5.2. 
Planned Interim Analysis 
No interim analysis is planned. 
5.3. 
Study Committees 
5.3.1. 
Neurocognitive Events Review Committee 
The neurocognitive events review committee is composed of recognized clinical experts in the 
field of cognition, independent from the sponsor and the investigators. This committee will be 
responsible for defining and validating, and classifying AEs of special interest possibly related to 
cognition impairment. 
Open-Label Treatment Period (192 weeks)  
 
Alirocumab 75 mg or 150 mg every two weeks** 
Stable diet (NCEP-ATPIII TLC or equivalent diet) and statin/other LMT daily 
*The end of study visit in the neurocognitive function study (R727-CL-1532) will correspond to visit 1 (day 1) of this study. 
**Starting dose is 75 mg Q2W. The first LDL-C assessment is at week 8. At any time after week 8, the investigator will be responsible to 
manage the PRALUENT dose by either modifying from 75 mg Q2W to 150 mg Q2W, maintain the dose, modifying from 150 mg Q2W to
75 mg Q2W or discontinuing the treatment with PRALUENT at any time during the treatment period. 
W192 
Neurocognitive Function Study 
Double-Blind Treatment Period 
W168 
W144 
W120 
W96 
W72 
W0 W8 W12 
W48 
W24 
Visit 1 (Day 1) 
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A charter and an operational manual will specify the procedures and criteria used for review of 
these events. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
No formal sample size was calculated for this study.  The anticipated number of patients is based 
on the previously observed drop-out rate in the ODYSSEY program.  The expected total number 
of patients is approximately 1600.   
6.2. 
Study Population 
The study population consists of patients with heFH or non-FH patients at high or very high 
cardiovascular risk.  Patients must have had a history of coronary heart disease (CHD) without 
adequate control of their hypercholesterolemia with LDL-C ≥70 mg/dL, or with LDL-C 
≥100 mg/dL with no history of CHD, and be on a maximally-tolerated dose of statin (unless they 
are statin-intolerant). 
6.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Patients having been randomized into the neurocognitive function study (R727-CL-1532) 
who completed treatment and the EOS visit with no premature or permanent 
discontinuation of study drug. 
2. Willing and able to comply with clinic visits and study-related procedures 
3. Provide signed informed consent 
6.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Significant protocol deviation in the parent study (neurocognitive function study, 
R727-CL-1532) based on the investigator's or sponsor's judgment, such as noncompliance 
by the patient 
2. Any patient who experienced an AE leading to permanent discontinuation from the 
neurocognitive function study, (R727-CL-1532). 
3. Any new condition or worsening of an existing condition which, in the opinion of the 
investigator or per the PRALUENT local label, would make the patient unsuitable for 
enrollment or could interfere with the patient participating in or completing the OLE study 
4. Known hypersensitivity to monoclonal antibody or any component of the drug product 
5. Pregnant or breastfeeding women  
6. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
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at least 6 months after the last dose. Highly effective contraceptive measures include stable 
use of combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, 
implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles 
prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
bilateral tubal ligation; vasectomized partner; and or sexual abstinence**†.   
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential.  Pregnancy testing and contraception are not required 
for women with documented hysterectomy or tubal ligation. 
**Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
†Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be used 
together.   
6.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients 
Patients prematurely discontinued from the OLE study/study drug will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Sterile PRALUENT drug product will be supplied at a concentration of 75 mg/mL and 150 mg/mL 
in histidine, pH 6.0, polysorbate 20, and sucrose, both as 1 mL volume in an auto-injector. 
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7.2. 
Background Treatments 
Throughout the treatment period, patients should remain on stable, maximally-tolerated registered 
daily dose of statin received during the neurocognitive function study (R727-CL-1532), with or 
without other LMT.  The statin dose should not be modified to adjust the degree of LDL-C 
lowering. 
Background LMT should not be changed during the course of the study.  However, if clinically 
necessary, background LMT may be adjusted at the investigator’s discretion.  Any adjustment will 
be documented in the CRF.  For adjustments based on LDL-C values, simultaneous adjustments 
in PRALUENT dose and any LMT should be avoided.   
For background LMT, including statins, sites must follow the national product label for the safety 
monitoring and management of patients. 
No lipid profile will be performed until week 8, to avoid any unblinding of the neurocognitive 
function study. 
As background treatment, the following classes of drugs are identified as non-investigational 
medicinal products: 
 Concomitant LMT, including statins 
 Cholesterol absorption inhibitors (ezetimibe) 
 Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam) 
 Nicotinic acid (niacin) 
 Fenofibrate, fenofibric acid 
 Omega-3 fatty acids 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification/reduction is allowed for an individual patient according to the following 
specifications: 
 The starting dose of PRALUENT will be 75 mg administered SC Q2W.  The dose may 
be modified to 150 mg administered SC Q2W, and can be maintained or modified from 
150 mg Q2W to 75 mg Q2W. 
7.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug will be asked to complete early termination 
study assessments, per Section 8.1.2. 
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7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
 Pregnancy, intention for pregnancy, or no longer using effective contraceptive 
method of birth control (females only).  All pregnancies will be followed to their 
outcome. 
 Acute injection reaction of clinical concern 
 SAE (or non-serious but severe in intensity) of hypersensitivity reaction considered 
related to study drug 
 At patient request, ie, withdrawal of the consent for treatment 
 If, in the investigator's opinion, continued administration of study drug would be 
detrimental to the patient's safety or well-being.  Any abnormal laboratory value will 
be immediately rechecked for confirmation before making a decision of permanent 
discontinuation of study drug 
 At the specific request of the sponsor 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary treatment discontinuation may be considered by the investigator because of suspected 
AEs.  Reinitiating of treatment with the study drug will be done under close and appropriate 
clinical/and or laboratory monitoring once the investigator will have considered (according to 
his/her best medical judgement) that the responsibility of the study drug in the occurrence of the 
concerned event was unlikely, and if the selection criteria for the study are still met (see 
Sections 6.2.1 and 6.2.2). 
For all temporary treatment discontinuations, duration should be recorded by the investigator in 
the appropriate screens of the CRF.  
Treatment interruption is defined as 1 or more scheduled injections that are not administered to 
the patient as decided by the investigator. 
7.4. 
Method of Treatment Assignment  
This is an open-label study and every patient will receive PRALUENT.  Treatment kit numbers 
will be allocated via interactive voice response system (IVRS)/interactive web response system 
(IWRS).  Patients will keep the same identification number that they were allocated in the 
neurocognitive function study (R727-CL-1532) or a correspondence table will be set up between 
the neurocognitive function study (R727-CL-1532) and this study numbering. 
From week 8, the investigator will manage the PRALUENT dose at his/her discretion based on 
LDL-C values obtained from the sample at the previous scheduled visit, by either modifying the 
dose from 75 mg Q2W to 150 mg Q2W, maintaining the PRALUENT dose, or discontinuing 
treatment with PRALUENT at any time during the treatment period.  The statin dose should not 
be modified to adjust the degree of LDL-C lowering.  
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An unscheduled kit dispensation visit may be scheduled at any time during the study after the week 
12 visit if the investigator, based on lipid results or safety issues, decides to modify the dose of 
PRALUENT (see Section 8.1).  In this instance, IVRS/IWRS will allocate a new treatment kit 
number and the new study drug kit will be dispensed to the patient.  In specific cases, the new kit 
may be sent directly to the patient’s home. 
7.4.1. 
Blinding 
This is an open-label, uncontrolled study; therefore, no blinding procedures will be implemented. 
7.5. 
Treatment Logistics and Accountability 
7.5.1. 
Packaging, Labeling, and Storage  
Open-label study drug will display the product lot number on the label. 
Study drug will be stored at the site at a temperature of 2°C to 8°C; storage instructions will be 
provided in the study manual. 
7.5.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2°C to 8°C to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee. 
7.5.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.5.4. 
Treatment Compliance 
Patients will complete a dosing log to document compliance with study drug administration.  
Measures taken to ensure and document study drug accountability and compliance are as follows: 
 The investigator or designee will obtain, via IVRS/IWRS, the treatment kit number(s) 
and will dispense the treatment kit(s) to the patient. 
 Accountability is to be verified during study drug kit re-supply visits only.  The used 
and unused kit(s) should be brought to these visits for accountability purposes. 
 All kits, including used and unused kits, are to be returned by the patient at the 
designated visit.  An unused kit contains the unused auto-injector. 
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 All sharps containers should be returned to the site by the patient. 
 The investigator/study coordinator will enter data in the appropriate CRF pages, 
according to data recorded in the treatment log form. 
 The monitor will check the data consistency among CRF pages, treatment log form 
and returned unused kit(s). 
All treatments kits will be retrieved by the sponsor. A detailed treatment log of the returned study 
drug will be established with the investigator or designee and countersigned by the investigator 
and the monitoring team. 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.6. 
Concomitant Medications 
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication.  This includes medications that were started before the study 
and are ongoing during the study.  
Concomitant medications should be kept to a minimum during the study.  However, if considered 
necessary for the patient’s welfare and unlikely to interfere with study drug, a stable dose, when 
possible, may be given at the discretion of the investigator.  
Concomitant medications allowed during the study include: 
Lipid Modifying Therapy 
Throughout the treatment period, patients should stay on a stable maximally-tolerated registered 
daily dose of statin, with or without other LMT, received during the neurocognitive function study 
(R727-CL-1532).  
Lipid modifying therapy, including statins, should not be changed during the course of the study.  
However, if clinically necessary, background LMT may be adjusted at the investigator’s 
discretion.  Any adjustment will be documented in the CRF. 
Contraception 
Women of childbearing potential must use an effective contraceptive method throughout the study 
treatment, and for at least 6 months after the last study drug injection. 
7.6.1. 
Prohibited Medications 
PCSK9 inhibitors, other than PRALUENT, taken from the time of informed consent until the last 
study visit, are prohibited during the study. 
7.6.2. 
Permitted Medications 
Concomitant medications should be kept to a minimum during the study.  However, if these are 
considered necessary for the patient’s welfare and are unlikely to interfere with the study drug, 
they may be given at the discretion of the investigator at a stable dose (when possible).  Besides 
the specific information related to concomitant medications provided in this section, any other 
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concomitant medication(s) will be allowed and are required to be recorded in the CRF and source 
data. 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
 
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Table 1: 
Schedule of Events 
 
 
Treatment Period 
End of 
Treatment/Early 
Termination/ 
End of Study1 
Study Procedure 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 Visit 10 
Visit 11 
Day 
1 
 
 
 
 
 
 
 
 
 
 
Week 
0 
8 
12 
24 
48 
72 
96 
120 
144 
168 
192 
Visit Window (days) 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Prior Medication History 
X 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
Review of Diet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study Drug 
X2 
 
 
 
 
 
 
 
 
 
 
Study Drug Kit 
Dispensation3, 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
Medication5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Drug Log 
Dispensation/Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Physical Examination 
and Body Weight 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
Total-C, LDL-C, HDL-
C, TG, non-HDL-C6 
X7 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Apo B, Apo A-1, Lp(a) 
X7 
 
 
 
X 
 
X 
 
X 
 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
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Treatment Period 
End of 
Treatment/Early 
Termination/ 
End of Study1 
Study Procedure 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 Visit 10 
Visit 11 
Day 
1 
 
 
 
 
 
 
 
 
 
 
Week 
0 
8 
12 
24 
48 
72 
96 
120 
144 
168 
192 
Visit Window (days) 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Blood Chemistry 
X7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
hs-CRP 
X7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Gonadal Hormones & 
Gonadotropins8 
X7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
(for women of 
childbearing potential) 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Testing 
 
 
 
 
 
 
 
 
 
 
 
Research Samples 
(serum/plasma) 
X7 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Patients who prematurely discontinue study treatment: any study treatment discontinuation 
should be initially considered temporary, and the investigator should make every effort to 
resume study drug treatment as early as possible, pending no safety concerns, and to perform 
all study visits and assessments as usual.  When a treatment discontinuation is considered 
‘permanent’, an extra visit (early termination visit) should be performed within 5 days of the 
decision to permanently discontinue study drug.  This visit will be the last visit for the patient.  
2. The end of study (EOS) visit of the double-blind neurocognitive function study 
(R727-CL-1532) corresponds to visit 1 (day 1) of the OLE study.  Patients may enroll in the 
OLE study after completing treatment and the EOS visit in the neurocognitive function study 
(R727-CL-1532).  The first SC injection of PRALUENT will be administered in the clinic 
(day 1, visit 1).  After visit 1, patients have the option to either self-administer study drug, or 
have another designated person (such as a spouse or caregiver) administer study drug for 
them.  Study drug should be administered Q2 weeks throughout the study. 
3. The kit will include study drug and the study drug compliance log. 
4. If at any time during the study after the week 8 visit, the investigator, based on lipid results 
or safety issue, decides to modify the dose of study drug, an unscheduled kit dispensation 
visit will be performed.  During this visit, a call to the IVRS/IWRS will be performed. 
5. Concomitant medication: received concomitantly to the study drug, from the time of 
informed consent to the final study visit. 
6. Alcohol consumption within 48 hours and intense physical exercise within 24 hours prior to 
blood sampling for lipid parameters are discouraged. 
7.  Assessments completed at EOS in the neurocognitive function study (R727-CL-1532). 
8.  For male patients (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and 
testosterone) and for female patients (LH, FSH, and estradiol).  Menstrual cycle data will be 
collected for women of childbearing potential who are not on hormonal contraceptives. 
8.1.2. 
Early Termination Visit 
This visit is only to be done for patients who discontinue the treatment prematurely, whatever the 
reason, and will take place as soon as practically possible (within 1 month after the last injection 
of PRALUENT).  For patients who prematurely permanently discontinue study drug, see 
Section 7.3.2. 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility: 
inclusion/exclusion criteria.   
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8.2.2. 
Safety Procedures 
8.2.2.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse will be collected at time points 
indicated in Table 1. 
8.2.2.2. 
Physical Examination and Body Weight 
A general physical examination including body weight will be performed at time points indicated 
in Table 1. 
If a new clinically significant abnormality or worsening from baseline is detected after informed 
consent, the patient should be considered for further clinical investigation and/or specialist 
consultation at the investigator’s discretion. 
Body weight will be obtained with the patient wearing undergarments or very light clothing and 
no shoes, and with an empty bladder.  The same scale should be used throughout the study. 
Calibrated balance scales should be used to guarantee accuracy of patients’ weight.  Self-reported 
weights are not acceptable, and patients must not read the scales themselves.  
8.2.2.3. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  A liver panel will be forwarded to the central laboratory.  In case of total bilirubin 
values above the normal range, differentiation into conjugated and nonconjugated bilirubin will 
occur automatically.   
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
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Samples for laboratory testing will be collected at visits at time points according to Table 1.  Tests 
will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN) 
Creatine phosphokinase (CPK) 
Carbon dioxide 
AST 
γGT 
Calcium 
ALT 
HbA1c 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
White blood cells (WBCs) 
Monocytes 
Red cell indices 
Basophils 
Platelet count 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Pregnancy testing (urine) will be performed for women of childbearing potential at time points 
according to Table 1. 
Samples for high-sensitivity C-reactive protein (hs-CRP), and gonadal hormones (for female 
patients - estradiol, follicle-stimulating hormone [FSH] and luteinizing hormone [LH]; for male 
patients – testosterone, FSH and LH) will be collected at time points according to Table 1.   
Abnormal Laboratory Values and Laboratory Adverse Events 
 All laboratory values must be reviewed by the investigator or authorized designee. 
 Significantly abnormal test results that occur after start of treatment must be repeated 
to confirm the nature and degree of the abnormality.  When necessary, appropriate 
ancillary investigations should be initiated.  If the abnormality fails to resolve or cannot 
be explained by events or conditions unrelated to the study medication or its 
administration, the medical monitor must be consulted.   
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 The clinical significance of an abnormal test value, within the context of the disease 
under study, must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.3. 
Efficacy Procedures  
8.2.3.1. 
Blood Sampling 
Blood sampling for determination of lipid parameters includes Total-C, LDL-C, HDL-C, TG, 
non-HDL-C, Apo B, Apo A-1, and Lp(a).  Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours prior to the blood sampling are discouraged.   
The blood sampling schedule is described in Table 1. 
8.2.4. 
Other Assessments 
8.2.4.1. 
Review of Diet 
Patients will follow a diet equivalent to the NCEP-ATP III TLC diet at visit 1 (week 0) and will 
be asked to continue the dietary plan until the last study visit.  Patients will be queried about 
compliance with the dietary plan during the treatment period, at time points according to Table 1. 
Details are provided in Appendix 2. 
8.2.5. 
Research Samples 
8.2.6. 
Biomarker Procedures 
Research samples for possible biomarker assessments will be collected at time points listed in 
Table 1.  Biomarker results will be reported separately from the clinical study report. 
8.2.7. 
Future Biomedical Research 
Research samples unused for study-related research, may be utilized for future biomedical 
research.  These samples will be stored for up to 15 years after the final database lock.  After 
15 years, any residual samples will be destroyed.  The results of these future biomedical research 
analyses will not be presented in the CSR.  
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patient.  This includes death from any cause 
and all SAEs related to the use of the study drug.  It is recommended that all SAEs be reported to 
the IRB/EC, regardless of assessed causality. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, ECs/IRBs as appropriate, and to the 
investigators.  
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug to the health authorities, according to local regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and ECs/IRB as appropriate. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is prolonged 
due to the development of a new AE as determined by the investigator or treating 
physician. 
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 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
9.3.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical concern specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate.  Such an event might warrant further investigation in order to 
characterize and understand it.  Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (eg, regulators) might also be warranted (Section 9.4.3).  
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study.   
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, or vital signs are to be 
recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours, as follows:. 
 Complete the SAE form utilizing the AE electronic CRF in the electronic data capture 
(EDC) system and submit within 24 hours of learning of the event 
or 
 Telephone the sponsor (or designee) at the contact information provided in the SAE 
completion guidelines, within 24 hours of learning of the event 
Information not available at the time of the initial report must be documented in a follow-up report.  
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study/early termination visit - the 
SAE will be reported to the sponsor. The investigator should make every effort to 
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obtain follow-up information on the outcome until the event is considered chronic 
and/or stable. 
 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: Accidental or intentional overdose of at least 2 times the 
intended dose of study drug within the intended therapeutic window, if associated with an AE, 
Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the investigator 
to report to the sponsor (or designee), within 24 hours of identification, any pregnancy occurring 
in a female or female partner of a male, during the study or within 180 days of the last dose of 
study drug.  Any complication of pregnancy affecting a female study patient or female partner of 
a male study patient, and/or fetus and/or newborn that meets the SAE criteria must be reported as 
an SAE.  Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: All AESI, serious and nonserious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, per Section 9.4.2.  
Adverse events of special interest for this study include the following:   
 ALT ≥3 upper limit of normal (ULN; if baseline ALT < ULN) or ALT ≥2 times 
the baseline value (if baseline ALT ≥ ULN).  Baseline to be considered is the 
baseline of the present OLE study. 
 Allergic events and/or local injection site reactions that are allergic in nature 
and that require consultation with another physician for further evaluation 
 Neurologic events that require additional examinations/procedures and/or 
referral to a specialist 
 All neurocognitive events 
o Neurocognitive AEs will be reviewed on a regular basis by an independent 
panel of experts (neurologists/specialists of neurocognition) to ensure that 
all the necessary information pertinent to these AESIs is collected 
 Cataracts 
 New onset of diabetes 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
Refer to the study reference manual for the procedures to be followed. 
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9.4.5. 
Abnormal Laboratory or Vital Signs 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event and AESI information will be collected until the event is considered chronic 
and/or stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity  
The severity of AEs (excluding local injection site reactions) will be graded according to the 
following scale: 
 Mild:  Does not interfere in a significant manner with the patient’s normal 
functioning level.  It may be an annoyance.  Prescription drugs are not ordinarily 
needed for relief of symptoms, but may be given because of personality of the patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient’s health.  Treatment for symptom may be given and/or 
patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
 
 
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Local Injection Site Reactions  
The severity of local injection site reactions will be graded by the investigator using a 4-point scale 
(mild, moderate, severe, or very severe), adapted from the toxicity grading scale table from the 
Food and Drug Administration Draft Guidance for Industry:  Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials dated April 2005.  
Local injection site reactions will be reported in detail as indicated on the CRF and/or SAE form, 
as appropriate. 
The complete severity grading scale for assessing local injection site reactions is provided in 
Appendix 3. 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by the 
study drug 
Related: 
There is a reasonable possibility that the event may have been caused by the study 
drug 
A list of factors to consider when assessing the relationship of AEs to study drug is provided in 
Appendix 1. 
The investigator should justify the causality assessment of each SAE. 
Causality Evaluation Factors 
Factors to consider when determining the relationship of an AE to study drug are included below. 
Not Related: 
 Existence of a clear alternative explanation or nonplausibility (eg, the patient is struck 
by an automobile when there is no indication that the drug caused disorientation, or 
cancer diagnosed a few days after first drug administration) 
 Due to external causes such as other treatment(s) being administered 
 Due to the patient’s disease state or clinical condition 
 Does not follow a reasonable temporal sequence following the time of administration 
of the dose of study drug 
 Does not reappear or worsen when dosing with study drug is resumed (ie, negative 
re-challenge) 
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Related: 
 Could not be explained by other treatment(s) being administered 
 Could not be explained by the patient’s disease state or clinical condition 
 Follows a reasonable temporal sequence following the time of administration of the 
dose of study drug 
 Resolves or improves after discontinuation of study drug 
 Reappears or worsens when dosing with study drug is resumed (ie, positive 
re-challenge) 
 Known to be a response to the study drug based upon preclinical data or prior clinical 
data 
 Known to be strongly associated with drug exposure (eg, angioedema, 
Stevens-Johnson Syndrome) 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The medical monitor will have primary responsibility for 
the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance and Risk Management; Biostatistics and Data Management).  Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the Investigator’s 
Brochure or this protocol, and has a reasonable suspected causal relationship to the 
medicinal/study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP may 
be revised during the study to accommodate amendments to the clinical study protocol and to make 
changes to adapt to unexpected issues in study execution and data that may affect the planned 
analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
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10.1. 
Statistical Hypothesis  
There will be no formal testing for safety variables.  Descriptive statistics will be provided. 
For the secondary efficacy endpoints, no formal statistical hypothesis will be tested. 
10.2. 
Justification of Sample Size 
No formal sample size was calculated for this study.  The anticipated number of patients is based 
on the previously observed drop-out rate in the ODYSSEY program.   
10.3. 
Analysis Sets  
10.3.1. 
Safety Analysis Set 
Since this is a single-arm, open-label study, treatment allocated and the actual treatment received 
will be the same.  Therefore, a single analysis set (ie, the safety analysis set [SAF]) will be used 
for safety and efficacy analyses.  The SAF includes all patients who received any study drug.  All 
safety and efficacy variables will be analyzed using the SAF. 
10.4. 
Statistical Methods  
Study data will be summarized descriptively for all patients in the safety population, as well as by 
the randomized treatment group in the neurocognitive function study (R727-CL-1532). 
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, standard deviation, minimum, and 
maximum.  For continuous efficacy endpoints, the first and third quartiles will also be provided. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of enrolled patients:  met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
 The total number of patients in the safety population 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics (gender, race, age [years], ethnicity, body mass index 
[kg/m2], and region [North America, Western Europe, Eastern Europe, and Rest of World) will be 
summarized descriptively by treatment group in the neurocognitive function study 
(R727-CL-1532), and by all patients combined.   
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The baseline value will generally be defined as the baseline value in the neurocognitive function 
study (R727-CL-1532) (ie, the last available value before the first dose of double-blind study 
treatment in that study). 
10.4.3. 
Efficacy Analyses 
All lipid and special lipid measurements obtained from the central laboratory will be used to 
provide a value for the efficacy variables, if appropriate.  The baseline value will be defined as the 
last available value before the first dose of double-blind study treatment in the neurocognitive 
function study (R727-CL-1532). 
The efficacy variables will be explored through descriptive statistics at each scheduled visit, 
including the assessment prior to the first dose of the open-label study administration.  The 
descriptive summaries will be performed in the Safety Analysis Set (for on-treatment analysis).  
Formal statistical testing is not planned.  While describing the long-term effectiveness of Praluent, 
simple testing can be performed as appropriate.   
Continuous variables will be summarized using the number of patients with data, mean, SD, 
median, first quartile (Q1) and third quartile (Q3), minimum and maximum.   
Categorical variables (including the binary outcome variables) will be described by patient 
frequency of occurrence.  Since these descriptive analyses are exploratory in nature, alpha 
adjustments for multiple testing are not needed. 
Descriptive statistics for calculated LDL-C will also be provided for patients with or without any 
study medication modification, separately.   
Time windows used to allocate a time point to a measurement will be defined in the SAP. 
10.4.4. 
Safety Analysis 
The safety analyses address the primary objective of this study, and all safety analyses will be 
performed on the SAF population.  The safety analyses will be conducted on all safety data 
collected during the study. 
10.4.4.1. Adverse Events 
Definitions 
For safety variables, the following observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
 The TEAE period is defined as the day from first dose of study drug to the last study 
visit. 
Pretreatment AEs are defined as those that developed, worsened, or became serious during the 
pretreatment period  
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period. 
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Post-treatment AEs are defined as those that developed, worsened, or became serious during the 
post-treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a prespecified grouping).  If any 
signal is detected with any AESI which warrants further characterization, the time-to 
event approach (Kaplan-Meier methodology) will be used.  Time from the first dose of 
study drug to the first occurrence of the event will be calculated (only the first event 
will be counted).  Patients without any event will be censored at the end of the TEAE 
period.  Incidence rates at 6, 12, 24, 36, and 48 months of exposure will be presented 
and Kaplan-Meier curves will be provided.  
 Drug-induced liver injury (namely ALT, AST, alkaline phosphatase and total 
bilirubin).  The proportion of patients with potentially clinically significant abnormality 
values at any post-baseline visit by baseline status will be displayed for each parameter.  
A graph of distribution of peak values of ALT versus peak values of total bilirubin will 
also be presented.  The ALT and total bilirubin values will be presented on a 
logarithmic scale.  The graph will be divided into 2 quadrants with a vertical line 
corresponding to 3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for 
total bilirubin. 
Deaths and other SAEs will be listed and summarized by treatment group.  
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, sitting blood pressure, and pulse) will be summarized by baseline and 
change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
time point will be summarized for each clinical laboratory test.  
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Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.4.4.3. Treatment Exposure 
The duration of treatment exposure will be calculated as: 
Date of the last study medication dose – date of the first study medication dose + 14 
In addition, for patients previously exposed to PRALUENT, the duration of treatment will be 
calculated as: 
(Date of the last study medication dose in the neurocognitive function study 
(R727-CL-1532) – date of the first study medication dose in the neurocognitive function 
study (R727-CL-1532) + 14) + (Date of the last study medication dose in R727-CL-1609 
[current study] – date of the first study medication dose in R727-CL-1609 
[current study + 14]) 
The treatment exposures will be summarized. 
The number (n) and percentage (%) of patients with a dose modification of PRALUENT will be 
described. 
10.4.4.4. Treatment Compliance 
Study treatment compliance will be assessed by treatment group using the following parameter:  
 The injection frequency will be defined for each patient as the average number of days 
between 2 injections, that is:  (last dose date minus first dose date)/(number of 
injections minus 1) 
These parameters will be summarized descriptively (N, mean, standard deviation, median, 
minimum and maximum). 
10.4.5. 
Other Endpoints 
The other endpoints described in Section 4.2.3 will be summarized descriptively by the 
randomized treatment group in the neurocognitive function study (R727-CL-1532). 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 The last available value before the first dose in the neurocognitive function study, 
R727-CL-1532.  
 In addition to the OLE study database, some data will be recovered from the 
neurocognitive function study (R727-CL-1532) database  
 
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General rules for handling missing data: 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed.  
 No imputations for missing safety data will be made. 
Visit windows: 
 Assessments taken outside of the analysis windows specified in the SAP will be 
displayed according to the case report form (CRF) assessment recorded by the 
investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory safety data or vital signs associated with nonprotocol 
clinical visits or obtained in the course of investigating or managing AEs) will be 
summarized based on the analysis windows specified in the SAP.  If more than 1 
laboratory value is available for a given visit, the first observation will be used in 
summaries and all observations will be presented in listings. 
 Extra assessment (laboratory safety data or vital signs associated with nonprotocol 
clinical visits or obtained in the course of investigating or managing AEs) will also be 
used in PCSA analyses if within the TEAE period. 
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC tool. 
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11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IVRS/IWRS system –management of study drug supply 
 EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 AWARE, Business Objects XI – pharmacovigilance activities 
12. 
STUDY MONITORING  
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site following enrollment of 
the first patient, and periodically during the study.  In accordance with ICH guidelines, the monitor 
will compare the CRF entries with the appropriate source documents.  Additional review may 
include, but is not limited to, patient ICFs, documentation of patient recruitment and follow-up, 
AEs, SAEs, and concomitant therapy; as well as records of study drug dispensing, compliance, 
and accountability.  A copy of the drug dispensing log must be provided to the sponsor upon 
request. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on CRFs by trained site 
personnel.  A CRF must be completed for every patient enrolled in the study.  After review of the 
clinical data for each patient, the investigator must provide an electronic signature.  A copy of each 
CRF page is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing the corrections, will be available via a system-
generated audit trail.  For corrections made via data queries, a reason for any alteration must be 
provided.   
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13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the International Council for Harmonisation (ICH) 
guidelines for GCP and applicable regulatory requirements. 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
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 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
14.3. 
Patient Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by their initials and a patient identification 
number, only, on CRFs or other documents submitted to the sponsor.  Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
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15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
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17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor.  
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must consult with the sponsor before discarding or 
destroying any essential study documents following study completion or discontinuation.  Records 
must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor and the relevant records will be transferred to a mutually 
agreed-upon destination. 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13).   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1).   
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient/subject final CRF 
(Section 12.3 and Section 17.1).  
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Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.3).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY  
The publication policy is provided as a separate agreement. 
22. 
REFERENCES 
None 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  Long Term Safety Study of PRALUENT in Patients with 
Heterozygous Familial Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High 
and Very High Cardiovascular Risk and Previously Enrolled in the Neurocognitive Function Trial, 
and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
 
 
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APPENDIX 1. FACTORS TO CONSIDER IN ASSESSING THE 
RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
DRUG AND STUDY CONDUCT 
Is there a reasonable possibility that the event may have been caused by the study drug or study 
conduct? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug  
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug is resumed 
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
NOTE:  This list is not exhaustive. 
 
 
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APPENDIX 2. SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL 
 
Total Fat  
25% - 35% total calories*  
Saturated fat*  
<7% total calories  
Polyunsaturated fat  
up to 10% total calories  
Monounsaturated fat  
up to 20% total calories  
Carbohydrates†  
50% - 60% total calories*  
Protein  
~15% total calories  
Cholesterol  
<200 mg/day (5.172 mmol/day) 
Plant Sterols  
2g  
Soluble Fiber such as psyllium  
10g - 25g  
* ATP III allows an increase of total fat to 35 percent of total calories and a reduction in 
carbohydrate to 50 percent for persons with the metabolic syndrome. Any increase in fat intake 
should be in the form of either polyunsaturated or monounsaturated fat. Trans-fatty acids are 
another LDL-raising fat that should be kept at a low intake. 
† Carbohydrate should derive predominantly from foods rich in complex carbohydrates including 
grains—especially whole grains—fruits, and vegetables. 
 
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APPENDIX 3. ASSESSMENT OF LOCAL INJECTION SITE 
REACTIONS 
Reaction to 
Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Very Severe 
(Grade 4) 
Pain 
Does not interfere with 
activity 
Interferes with 
activity or repeated 
use of non-narcotic 
pain reliever 
Prevents daily activity 
or repeated use of 
narcotic pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at 
rest 
ER visit or 
hospitalization 
Erythema / 
Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swelling ** 
2.5 – 5 cm and does 
not interfere with 
activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Itching 
Does not interfere with 
activity 
Interferes with 
activity or repeated 
use of topical or 
systemic treatment 
Prevents daily activity 
or leads to other 
significant dermatologic 
conditions (such as 
infection, scarring, etc.) 
Emergency Room 
(ER) visit or 
hospitalization 
Other (Please 
specify)*** 
No modification of daily 
activities and/or does 
not require 
symptomatic treatment. 
Hinders normal daily 
activities and/or 
requires symptomatic 
treatment. 
Prevents daily activities 
and requires 
symptomatic treatment. 
Emergency Room 
(ER) visit or 
hospitalization 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** 
Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
*** Please specify the other signs or symptoms (for example, hematoma, discoloration, re-activation, etc.). 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials April 2005 
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Clinical Study Protocol 
 
R727-CL-1609 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 57 of 57 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, Regulatory Representative, Biostatistician and Clinical Study 
Team Lead) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: Long Term Safety Study of PRALUENT in Patients with Heterozygous Familial 
Hypercholesterolemia or with Non-Familial Hypercholesterolemia at High and Very 
High Cardiovascular Risk and Previously Enrolled in the Neurocognitive Function 
Trial 
Protocol Number:  R727-CL-1609 
Protocol Version:  R727-CL-1609 Amendment 2 
 
Sponsor’s Responsible Scientific/Medical Monitor: 
See appended electronic signature page 
 
 
Sponsor’s Responsible Regulatory Representative: 
See appended electronic signature page 
 
 
Sponsor’s Responsible Biostatistician: 
See appended electronic signature page 
 
 
Sponsor’s Responsible Clinical Study Team Lead: 
See appended electronic signature page 
 
                                        VV-RIM-00057919-1.0 Approved - 17 Sep 2018 GMT-5:00

Signature Page for VV-RIM-00057919 v1.0
Signature Page for VV-RIM-00057919 v1.0 Approved
Approval
-2018 16:54:38 GMT+0000
Approval
18 17:05:18 GMT+0000
Approval
-2018 18:11:36 GMT+0000
Approval
00
                                        VV-RIM-00057919-1.0 Approved - 17 Sep 2018 GMT-5:00