Clinical trial NCT03694197
Conditions: Heterozygous Familial Hypercholesterolemia Non-familial Hypercholesterolemia
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-09-28; Completion date: 2020-04-08
Enrollment: 1389 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study was to evaluate the long term safety of PRALUENT in participants with heterozygous familial hypercholesterolemia (heFH) or non-familial hypercholesterolemia (FH) participants at high or very high cardiovascular risk who completed the neurocognitive function study R727-CL-1532 (NCT02957682).

The secondary objectives of the study were:

* 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

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Praluent
Intervention descriptions: intervention 1: Subcutaneous (SC) administration

Protocol documents:
Prot_000.pdf: 
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

SAP_001.pdf: 
Clinical and Regulatory Development 
Biostatistics and Data Management 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Document’s type 
Document Reference 
Effective Date 
Page 
Standard 
BDM-STD-ST4-1.0 
December 15, 2008 
1/56 
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: 
R727-CL-1609 
Investigational Product: 
PRALUENT® (REGN727/SAR236553) 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Statistician: 
 
Clinical Trial Manager: 
 
Clinical Study Director: 
 
Version/Date:  
V1.0 / July 16, 2020   
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NCT03694197


Regeneron Pharmaceuticals, Inc.                                                                                        Protocol: R727-CL-1609 
(PRALUENT) 
Statistical Analysis Plan                                                                                                                          July 16, 2020 
 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting.  
 
 
See appended electronic signature page 
Regeneron Study Biostatistician  
 
(
) 
 
 
See appended electronic signature page 
Regeneron Study Medical Director             (
) 
 
 
See appended electronic signature page 
Regeneron Project Biostatistician 
 
(
) 
 
 
See appended electronic signature page 
Head of BDM or designee                               (
) 
  
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Regeneron Pharmaceuticals, Inc.                                                                                        Protocol: R727-CL-1609 
(PRALUENT) 
Statistical Analysis Plan                                                                                                                          July 16, 2020 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .....................................................6 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary and Exploratory Objectives .......................................................................10 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 2 .......................10 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan ......................................10 
2. 
INVESTIGATING PLAN ..........................................................................................11 
2.1. 
Study Design ...............................................................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS .....................................................................................13 
3.1. 
Safety Analysis Sets ....................................................................................................13 
3.1.1. 
Safety Population ........................................................................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristic Variables ..................................................14 
4.2. 
Medical History and Disease Characteristics .............................................................15 
4.3. 
Prior and Concomitant Medications ...........................................................................19 
4.4. 
Patient Disposition ......................................................................................................19 
4.5. 
Study Treatment Exposure and Compliance Variables ..............................................21 
4.6. 
Primary and Secondary Endpoints ..............................................................................21 
4.6.1. 
Primary Endpoint ........................................................................................................21 
4.6.2. 
Secondary Endpoints ..................................................................................................22 
4.7. 
Safety Variables ..........................................................................................................22 
4.7.1. 
Adverse Events Variables ...........................................................................................22 
4.7.1.1. 
Adverse Events and Serious Adverse Events .............................................................22 
4.7.1.2. 
Adverse Events of Special Interest .............................................................................23 
4.7.1.3. 
Events Causing Death .................................................................................................25 
4.7.2. 
Clinical Laboratory Safety Variables ..........................................................................26 
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4.7.3. 
Vital Sign Variables ....................................................................................................27 
4.8. 
Other Variables ...........................................................................................................27 
4.9. 
Genomics Variables ....................................................................................................27 
5. 
STATISTICAL METHODS .......................................................................................28 
5.1. 
Demographics and Baseline Characteristics ...............................................................28 
5.2. 
Medical History and Disease Characteristics .............................................................28 
5.3. 
Prior and Concomitant Medications ...........................................................................30 
5.4. 
Patient Disposition ......................................................................................................31 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................31 
5.5.1. 
Exposure to Investigational Product ...........................................................................31 
5.5.2. 
Measurement of Compliance ......................................................................................32 
5.6. 
Analyses of Efficacy Variables ...................................................................................32 
5.6.1. 
Analyses of Efficacy Variables ...................................................................................32 
5.6.2. 
Sub-group Analyses ....................................................................................................32 
5.6.3. 
Adjustment for Multiple Comparisons .......................................................................33 
5.7. 
Analysis of Safety Data...............................................................................................33 
5.7.1. 
Analysis of Adverse Events ........................................................................................34 
5.7.1.1. 
Patient Deaths .............................................................................................................37 
5.7.2. 
Analysis of Clinical Laboratory Variables ..................................................................38 
5.7.3. 
Analysis of Vital Sign Variables.................................................................................39 
5.8. 
Analysis of Other Variables ........................................................................................39 
5.9. 
Analysis of Genomics Variables .................................................................................40 
6. 
DATA CONVENTIONS ............................................................................................41 
6.1. 
Definition of Baseline for Efficacy and Safety Variables ...........................................41 
6.2. 
General Data Handling Conventions ..........................................................................41 
6.3. 
General Missing Data Conventions ............................................................................42 
6.4. 
Visit Windows for Time Points ..................................................................................43 
6.5. 
Unscheduled Assessments ..........................................................................................44 
6.6. 
Pooling of Centers for Statistical Analyses ................................................................44 
6.7. 
Statistical Technical Issues .........................................................................................44 
7. 
TIMING OF STATISTICAL ANALYSES ................................................................45 
8. 
SOFTWARE ...............................................................................................................46 
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Regeneron Pharmaceuticals, Inc.                                                                                        Protocol: R727-CL-1609 
(PRALUENT) 
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9. 
REFERENCES ...........................................................................................................47 
10. 
APPENDIX .................................................................................................................48 
10.1. 
Windows for Analysis Time Points ............................................................................48 
10.2. 
Criteria for Potential Clinical Significant Abnormalities (PCSA) .............................49 
10.3. 
List of MedDRA terms for CMQs ..............................................................................54 
 
LIST OF TABLES 
Table 1: 
Analysis Windows Definition .....................................................................................48 
Table 2: 
Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for 
neurologic events ........................................................................................................54 
Table 3: 
CMQ “Neurocognitive disorders – FDA’s recommendation” ....................................55 
Table 4: 
CMQ “Type 1 or Type 2 diabetes” .............................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................12 
 
 
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(PRALUENT) 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACB 
Anticholinergic burden 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
Apo 
Apolipoprotein 
AST 
Aspartate aminotransferase 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CHD 
Coronary heart disease 
CI 
Confidence interval 
CPK 
Creatine phosphokinase 
CRF 
Case report form (paper or electronic) 
CT 
Computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CRO 
Contract research organization 
CVD 
Cardiovascular disease 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated Glomerular Filtration Rate 
FH 
Familial hypercholesterolemia 
GCP 
Good Clinical Practice 
GDS-S 
Geriatric Depression Scale short form 
HbA1c 
Hemoglobin A1c 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
heFH 
Heterozygous familial hypercholesterolemia 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
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(PRALUENT) 
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IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LMT 
Lipid-modifying therapy 
LOCF 
Last observation carried forward 
Lp(a) 
Lipoprotein a 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MMRM 
Mixed-effect model with repeated measures 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic resonance imaging 
NCEP ATP 
National Cholesterol Education Program-Adult Treatment Panel  
Non-HDL-C 
Non-high-density lipoprotein cholesterol 
PAL 
Paired Associates Learning 
PCSA 
Potentially clinically significant abnormal value 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PRN 
Pro re nata 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RTI 
Reaction Time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SOC 
System organ class 
SWM 
Spatial Working Memory 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
Total-C 
Total cholesterol 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
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(PRALUENT) 
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VHP 
Voluntary Harmonization Procedure 
WBC 
White blood cell 
 
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Regeneron Pharmaceuticals, Inc.                                                                                 Protocol: R727-CL-1609 
(PRALUENT) 
Statistical Analysis Plan                                                                                                                   July 16, 2020 
 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study 
results by pre-specifying the statistical approaches for the analysis of study data prior to 
database lock. The SAP is intended to be a comprehensive and detailed description of the 
strategy and statistical methods to be used in the analysis of data collected in the 
R727-CL-1609 study.  
This plan may be revised during the study to accommodate protocol amendments and adapt 
to unexpected issues in study execution that may affect planned analyses. These revisions 
will be based on data review of the study data, and a final plan will be issued prior to the 
database lock.   
1.1. 
Background/Rationale 
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 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). 
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. 
Following a Type II variation for Praluent submitted on 14 August 2019 to modify the EU 
RMP, the missing information “clinical impact of very low LDL-C for extended period of 
time” was removed from the RMP in the CHMP opinion dated Jan. 16,2020. The EMA 
agreed to release the R727-CL-1609 study as there is no expectation that this study can 
further characterize the safety profile of alirocumab beyond what has already been learned 
from other long-term, controlled studies. Therefore, the study was terminated early by 
sponsor on January 31, 2020.  Given this early termination, all analyses will be considered 
descriptive. 
PRALUENT is also referred to as alirocumab, REGN727 or SAR236553. In the context of 
the R727-CL-1609 SAP, it will be referred to as PRALUENT.  
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(PRALUENT) 
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1.2. 
Study Objectives 
1.2.1. 
Primary Objectives 
The primary objective of the study is to describe 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). 
1.2.2. 
Secondary and Exploratory Objectives 
The secondary objectives of the study are: 
• To describe the effect of PRALUENT on low-density lipoprotein cholesterol 
(LDL-C) 
• To describe the effect of PRALUENT on other lipid parameters 
• To describe the effect of PRALUENT on gonadal steroid hormones 
1.2.3. 
Modifications from the Statistical Section of Protocol Amendment 2 
 Because this study was terminated early by the Sponsor, all analyses will be considered 
descriptive. 
1.2.4. 
Modifications from the Approved Statistical Analysis Plan 
This is the first version of the Statistical Analysis Plan (SAP). 
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Regeneron Pharmaceuticals, Inc.                                                                                 Protocol: R727-CL-1609 
(PRALUENT) 
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2. 
INVESTIGATING PLAN 
2.1. 
Study Design 
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). 
2.2. 
Sample Size and Power Considerations 
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.   
2.3. 
Study Plan 
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 
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(PRALUENT) 
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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 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. 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 
 
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(PRALUENT) 
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3. 
ANALYSIS POPULATIONS  
In accordance with guidance from the International Conference of Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline 
ICH E9 Statistical Principles for Clinical Trials (ICH, 1998), below are the patient 
populations defined for statistical analysis.  
3.1. 
Safety Analysis Sets 
3.1.1. 
Safety Population 
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 in this study.  All safety and efficacy variables will be analyzed using the SAF. 
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Regeneron Pharmaceuticals, Inc.                                                                                 Protocol: R727-CL-1609 
(PRALUENT) 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristic Variables 
The baseline value is generally defined as the baseline value in the neurocognitive function 
study (R727-CL-1532), i.e., the last available value before the first dose of double-blind 
study treatment in that study. 
All baseline safety and efficacy parameters (apart from those listed below) are presented 
along with the summary statistics in the safety and efficacy sections. 
The following variables will be summarized:  
Demographic Characteristics 
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other) 
• Age in years (quantitative and qualitative variable: <45, ≥45 to <65, ≥65 to <75, 
and ≥75 years; and <65, and ≥65 years) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
Baseline Characteristics 
• Baseline Weight (kg) 
• Baseline Height (cm) 
• Baseline Body mass index (BMI) in kg/m² (quantitative and qualitative variable 
defined as <30, ≥30)  
• Tobacco Use (current, past, never) 
• Alcohol Use (current, past, never) 
• LMT at Baseline 
• Female Menopausal Status 
Baseline Disease Characteristics 
• Lipid parameters - quantitative variables for all efficacy parameters  
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• LDL-C: <70, ≥ 70 to <100, ≥100 to <130, ≥130 to <160, ≥160 to <190, ≥190 
mg/dL (<1.81, ≥1.81, <2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 to <4.91, 
≥4.91 mmol/L) 
• HDL-C: <40, ≥40 mg/dL (<1.04, ≥1.04 mmol/L) 
• Fasting TG: <150, ≥150 to <200, ≥200 mg/dL, and category ≥150 mg/dL for 
mixed dyslipidaemia (<1.7, ≥1.7 to <2.3, ≥2.3 mmol/L, and category ≥ 1.7 
mmol/L), 
• Lp(a): <30, ≥30 to <50, ≥50 mg/dL, and category ≥30 mg/dL (<0.3, ≥0.3 to <0.5, 
and ≥0.5 g/L) 
• HbA1c both quantitative variable and qualitative variable defined as: <5.7%, 
≥5.7% to <6.5%, ≥6.5% 
• hs-CRP 
• Hepatitis B surface antigen 
• Hepatitis C antibody 
4.2. 
Medical History and Disease Characteristics  
Medical history is not collected in this study. The medical history data collected in the 
neurocognitive function study (R727-CL-1532) will be used for the patients enrolled in this 
study. 
As applicable, patient medical history, pre-listed or not in the e-CRF, will be dictionary 
coded by primary system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities (MedDRA), specifically the MedDRA version in effect at the time of 
database lock for the analysis.  Medical history of interest will be assessed through 
cardiovascular history and risk factors (dedicated and pre-listed e-CRF variables of acute 
myocardial infarction, silent myocardial infarction, etc., with outcome of occurred/not 
occurred), subject medical allergic history (dedicated and pre-listed e-CRF variables of 
allergic rhinitis, chronic sinusitis,  etc., with outcome of occurred/not occurred), and family 
medical allergic history (dedicated and pre-listed e-CRF variables of allergic rhinitis, chronic 
sinusitis,  etc., with outcome of occurred/not occurred). Additional other medical history (i.e., 
not already collected in the pre-printed e-CRFs) and surgical history will also be coded and 
reported.  
Medical history of specific interest includes: 
• Coronary heart disease (CHD)  
• CHD risk equivalents  
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• Cardiovascular (CV) risk factors other than hypercholesterolemia (hypertension, 
type 2 diabetes, type 1 diabetes, family history of premature CHD). Smoking 
status will be summarized separately. 
• Family history of type 2 diabetes 
• Patient’s allergies (described using all pre-printed terms collected in the medical 
allergic history e-CRF page). 
Further for medical history variables, CHD, CHD risk equivalents, and CV risk factors are 
defined below, and will be based on items or combinations of items pre-listed in the 
dedicated medical history e-CRF page (unless otherwise specified). Patient status for primary 
and secondary CVD prevention is also defined below. 
CHD (regardless if it is ongoing or not) is defined as at least one of the following events: 
• Acute myocardial infarction 
• Silent myocardial infarction 
• Unstable angina 
• Coronary revascularization procedure 
• Other clinically significant CHD diagnosed by invasive or non-invasive testing  
CHD risk equivalent (regardless if it is ongoing or not) is defined as at least one of the 
following events: 
• Peripheral arterial disease: See definition below.  
• Ischemic stroke 
• Chronic kidney disease 
• Known history of diabetes mellitus (type 1 or 2) AND 2 or more additional risk 
factors among: 
− History of ankle-brachial index ≤ 0.90 
− History of hypertension 
− History of microalbuminuria or macroalbuminuria or dipstick urinalysis at 
screening (week-2) with >2+ protein 
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− History of pre–proliferative or proliferative diabetic retinopathy or laser 
treatment for diabetic retinopathy 
− Known family history of premature CHD  
As listed above, “Peripheral arterial disease” history is defined as follows, using 
combinations of the corresponding pre-listed medical history items of the e-CRF page 
“Cardiovascular history and cardiovascular risk factors”: 
• Intermittent claudication (linked to PAD) TOGETHER WITH ankle-brachial 
index ≤ 0.90;  
Or 
• Intermittent claudication (linked to PAD) TOGETHER WITH peripheral 
revascularization procedure (angioplasty, stenting) for PAD or peripheral 
revascularization surgery (arterial bypass) for PAD; 
Or 
• Critical limb ischemia TOGETHER WITH peripheral revascularization procedure 
(angioplasty, stenting) for PAD or thrombolysis for PAD or peripheral 
revascularization surgery (arterial bypass) for PAD. 
Secondary CVD prevention is defined as patients with any of the following history of CVD 
(other patients will be classified as primary CVD prevention): 
• History of CHD (as defined above) 
• History of ischemic stroke 
• History of PAD with severity criteria defined as one of the following events: 
− Intermittent claudication and ankle brachial index ≤ 0.90 
− Peripheral revascularization procedure (angioplasty, stenting) for PAD 
− Thrombolysis for PAD 
− Peripheral revascularization surgery (arterial bypass) for PAD 
− Critical limb ischemia  
CV Risk Factors are defined for this study as high risk and very high risk below. 
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• Very high CV risk patients are defined as patients with CHD or CHD risk 
equivalents (ASCVD). 
• High CV risk patients are defined as all other patients. 
Hyperlipoproteinemia disease history will be assessed through diagnosis of HeFH, time from 
diagnosis to study randomization (years), confirmation of diagnosis (genotyping [Yes/No], 
clinical diagnosis [Yes/No], lipid modifying therapies history and received at randomization 
in the neurocognitive function study (R727-CL-1532) as detailed below.   
• Lipid modifying therapy history, as reported in the “History of 
Hypercholesterolemia/Statin Use” e-CRF page  
− Type of lipid-modifying therapy taken at screening (statin, fibrates, bile acid 
sequestrant, cholesterol absorption inhibitor, nicotinic acid and derivates, 
omega 3 fatty acids ≥1000 mg/day, other). 
− Number of patients at screening on a maximal tolerated dose of stain. For 
those not on not statin or not taking the maximum tolerated dose, reason for 
not statin or not taking a maximum tolerated dose. 
− Number of patients with a history of down-titration of statin dose due to 
tolerability issues 
− Number of patients with a history of changing to a different statin due to 
tolerability issues 
Lipid modifying therapies received at randomization in the neurocognitive function study 
(R727-CL-1532) will be derived from the prior and concomitant medication e-CRF pages by 
selecting medications with the type of lipid lowering medication tick box checked (“Statin” 
or “Other lipid modifying therapy”). 
• Background lipid modifying therapy at randomization as reported in the dedicated 
prior and concomitant medication e-CRF pages  
− Number of patients taking atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg 
daily  
− Atorvastatin daily dose in mg (10, 20, 40, 80, Other) 
− Rosuvastatin daily dose in mg (5, 10, 20, 40, Other) 
− Simvastatin daily dose in mg (10, 20, 40, 80, Other) 
− Other statins 
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− Any LMT other than statins 
− 
Any LMT other than nutraceuticals (by chemical class and drug name) 
− 
Nutraceuticals (Omega 3 fatty acids (<1000mg/day), Phytosterols, 
Psyllium/plantago, Policosanol, Other nutraceuticals) 
Details (i.e. statin names, doses) for patients who had received at least 2 statins the day of 
randomization in the neurocognitive function study (R727-CL-1532) will be listed. 
4.3. 
Prior and Concomitant Medications 
All medications (including statin, non-statin LMT, CV, and Other) taken from the time of 
informed consent to the end of the study, including medications that were started before the 
study and are ongoing during the study, will be reported in the Concomitant Medications 
CRF.  
All medications will be dictionary coded using the World Health Organization-Drug 
Dictionary (WHO-DD) to both an anatomic category and a therapeutic category, with the 
version in effect at the time of the database lock.  Drug names will be matched to respective 
Anatomical-Therapeutic-Chemical (ATC) classification, although a drug can be matched to 
more than one ATC classification (i.e. patients can be counted in several categories for the 
same medication).    
Definitions for deriving prior medications, concomitant and post-treatment medications are 
described below, with the understanding that a given medication can be simultaneously 
classified both as a prior and concomitant medication. 
• Prior medications are any medications the patient used from the time of informed 
consent up to the day before first study treatment administration.  Prior 
medications can be discontinued before first treatment administration or can be 
ongoing during the treatment phase. 
• Concomitant medications are defined as any treatments received by the patient 
concomitantly with the study treatment, specifically from the first day of study 
treatment administration to the last study visit. Concomitant medications do not 
include medications started during the post-treatment period. 
• Post-treatment medications are those medications administered to the patient 
during the time period starting from 1 days after the last study visit, and ending 
when the patient terminates the study. 
4.4. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations. 
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For patient study status, the following milestone categories are defined below.  For all 
categories of patients, percentages will be calculated using the number of enrolled patients as 
the denominator, with two exceptions.  Specifically, the two exceptions are for the screened 
and non-enrolled categories, which will not have associated percentages shown. 
• Enrolled patients: met the inclusion criteria regarding the target indication and 
signed the informed consent form (ICF) 
• Enrolled but not treated patients  
• Enrolled and treated patients  
• Patients complete 192 weeks of open-label treatment period (at least 190 weeks of 
exposure and visit W192 performed) 
• Patients completed the study treatment period (i.e. as collected on the End of 
Open-Label Treatment eCRF) 
• Patients who did not complete the study treatment period and patient’s decision 
for treatment period discontinuation (as per the End of Open-Label Treatment 
eCRF) 
• Patients who discontinued study treatment by main reason for permanent 
treatment discontinuation (as per the End of Open-label Treatment eCRF)  
• Patients completed the study (i.e. as collected on the Study Completion eCRF) 
• Patients who early terminated the study (as per the Study Completion eCRF) 
• Patients who early terminated the study by main reason for early termination (as 
per the Study Completion eCRF) 
• Status at last study contact 
• Subject’s visit impact due to COVID-19 
• Study/Treatment discontinuation due to COVID-19 
As defined in Section 3 of this document, the patient analysis populations are: 
• Safety Population (SAF) 
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4.5. 
Study Treatment Exposure and Compliance Variables 
Study treatment exposure variables are listed below with associated definitions: 
• Patient duration of study treatment exposure in weeks defined as: (last study 
treatment administration date +14 – first study treatment administration date )/7, 
regardless of intermittent discontinuations.  
• The following categories will be used for treatment exposure intervals: ≥1 day and 
<4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks and <12 weeks, ≥12 weeks and <16 
weeks, ≥16 weeks and <20 weeks, ≥20 weeks and <24 weeks, ≥24 weeks and <28 
weeks, ≥28 weeks and <32 weeks, ≥32 weeks and <36 weeks, ≥36 weeks and <40 
weeks, ≥40 weeks and <44 weeks, ≥44 weeks and <48 weeks, …….,  ≥188 weeks 
and <192 weeks,  ≥192 weeks. 
• The total number of study treatment injections by patient.  
In addition, for patients previously exposed to PRALUENT, the combined 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). 
Compliance will be assessed using the following variables with associated definitions: 
• For each patient, the mean injection frequency for study treatment injections will 
be defined as the average number of days between 2 consecutive injections, that 
is: (last injection date – first injection date) / (number of injections - 1) for patients 
receiving at least 2 injections. 
All important and minor protocol deviations randomization and drug-dispensing 
irregularities, as well as other deviations, will be collected and reviewed on an ongoing basis 
throughout the study as described in the Protocol Deviation Plan (PDP).  Both monitoring-
collected and programmatically derived deviations are listed and defined in the PDP. 
4.6. 
Primary and Secondary Endpoints 
4.6.1. 
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:  
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• AEs/serious adverse events (SAEs)  
• AEs leading to treatment discontinuation 
• Adverse events of special interest (AESI) 
4.6.2. 
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 
• Values and percent changes from baseline in gonadal hormones and 
gonadotropins over time: for female patients - estradiol, follicle-stimulating 
hormone (FSH) and luteinizing hormone (LH); for male patients - testosterone, 
FSH and LH; 
4.7. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), 
clinical laboratory data, and vital signs. Unless otherwise noted, the baseline value is defined 
as the last available value before the first dose study treatment. 
4.7.1. 
Adverse Events Variables  
The period of safety observation starts from the time when the patient gives informed consent 
and continues into the following periods: 
• The PRE-TREATMENT period: defined as the time from the signed informed 
consent up to the first study treatment injection. 
• The treatment-emergent adverse event (TEAE) period: defined as the time from 
the first dose of study drug to the last study visit. 
•  The POST-TREATMENT period: defined as starting the day after the end of the 
TEAE periods up to the patient’s end of study. 
4.7.1.1. 
Adverse Events and Serious Adverse Events 
Adverse events (including serious adverse events (SAE), AEs causing permanent treatment 
discontinuation, deaths, and AEs of special interest) are recorded from the time of signed 
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informed consent until the end of study. All AEs diagnosed by the Investigator will be 
reported and described. 
All AEs will be dictionary coded by “lowest level term (LLT)”, “preferred term (PT)”, “high 
level term (HLT)”, “high level group term (HLGT)” and associated primary “system organ 
class (SOC)” using the version of MedDRA in effect at the time of database lock for the 
analysis. 
Adverse Event Observation Period  
• Pre-treatment AEs are AEs that developed or worsened or became serious during 
the pre-treatment period. 
• Treatment-emergent adverse events (TEAEs) are AEs that developed or worsened 
or became serious during the TEAE period.  
• Post-treatment AEs are AEs that developed or worsened or became serious during 
the post-treatment period. 
4.7.1.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol.  
In this study, AESI are the following (their complete descriptions are provided in the 
protocol): 
• Local injection site reactions, selected using an e-CRF specific tick box on the AE 
page; 
• General allergic events will be tabulated. Events will be selected using 
standardized MedDRA query (SMQ) “hypersensitivity” (broad and narrow) 
excluding the preferred terms linked to local injection site reactions (i.e. preferred 
terms containing “injection site” or “infusion site”) 
• ALT ≥3 ULN in the case baseline ALT < ULN or ALT ≥2 times the baseline 
value in the case baseline ALT ≥ ULN, selected using laboratory data. Baseline to 
be considered is the baseline of the present OLE study. 
• Neurologic events selected using SMQs “demyelination” (broad and narrow), 
“peripheral neuropathy” (broad and narrow), and “Guillain-Barre syndrome” 
(broad and narrow) excluding the following preferred terms: “acute respiratory 
distress syndrome”, “asthenia”, “respiratory arrest” and “respiratory failure” and 
including selected PTs from SMQ "optic nerve disorders" (see Appendix 10.3, 
Table 3 for the list of terms) 
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• Symptomatic overdose with investigational medicine product, selected using HLT 
“Overdose” and the tick box “Symptomatic Overdose” in the e-CRF AE page. 
• Pregnancy of female patient/subject (including male subject’s partner), selected 
using appropriate MedDRA codes (PT “Pregnancy”). 
• Neurocognitive events: 
− Selected using a company MedDRA query (CMQ), based on the following 5 
HLGTs: “deliria (including confusion)”, “cognitive and attention disorders 
and disturbances”, “dementia and amnestic conditions”, “disturbances in 
thinking and perception”, and “mental impairment disorders”. 
− A second grouping of terms for neurocognitive events was defined based on 
Regulatory Agency request (FDA CMQ) (see Appendix 10.3, Table 4 for the 
list of terms) 
• Cataract using HLT “Cataract conditions” 
• New onset of diabetes (NOD) will be assessed in patients without diabetes at 
baseline (defined as patients without diabetes at baseline and during the study in 
the neurocognitive function study (R727-CL-1532)): The definition of new onset 
of diabetes (NOD) will be the following: 
− Type 1 or type 2 diabetes TEAE (grouping of Medical Dictionary for 
Regulatory Activities [MedDRA®] terms in Appendix 10.7 Table 7) 
and/or 
− At least 2 values of HbA1c ≥6.5% during the TEAE period 
NOTE: For patients with only a single measurement available during the 
TEAE period, a single value ≥6.5% will be considered and qualify the patient 
as NOD by default. 
For patients with several HbA1c measurements but only with the last one 
≥6.5%, this single value ≥6.5% will be considered and qualify the patient as 
NOD by default 
and/or 
− At least 2 values of fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L) 
NOTE: For patients with only a single measurement available during the 
TEAE period, a single value ≥126 mg/dL (7.0 mmol/L) will NOT be 
considered and will NOT qualify the patient as NOD 
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For patients with several FPG measurements but only with the last one ≥126 
mg/dL (7.0 mmol/L), this single value ≥ 126 mg/dL (7.0 mmol/L) will NOT 
be considered and will NOT qualify the patient as NOD 
Analyses of NOD events will also be provided using the tick box on the e-CRF AE page as a 
second approach. 
In addition, the following grouping of events will be provided: 
• Hepatic disorder events using SMQ “Hepatic disorder” 
• Diabetes mellitus or diabetic complications using 1/ the HLGT “diabetes 
complications” (including PTs pertaining to the secondary SOC included in the 
HLGT),2/ the HLT “diabetes mellitus”, 3/ the HLT “carbohydrate tolerance 
analyses (incl diabetes)” excluding PTs “blood glucose decreased” and 
“Glycosylated haemoglobin decreased” and 4/ from the HLT "Hyperglyceamic 
conditions NEC" only the following PTs “hyperglycaemia”, “Hyperglycaemic 
unconsciousness” and “Hyperglycaemic seizure”  
Neurocognitive Events of Special Interest 
Neurocognitive events are defined in this study as AESI, specifically, neurocognitive AEs 
(serious or nonserious) required to be monitored, documented, and managed in a pre-
specified manner as described in this protocol. The neurocognitive events will be adjudicated 
by the neurocognitive events review committee which is composed of experts in the field of 
cognition, independent from the sponsor and the investigators. This committee will be 
responsible for defining, validating, and classifying AEs of interest possibly related to 
cognition impairment. A charter and an operational manual will specify the procedures and 
criteria used for review of these events.  
The committee will adjudicate whether a neurocognitive event identified by investigator or 
the CMQs is indeed a neurocognitive event (Yes/No). 
The committee will also adjudicate whether possible etiology of the neurocognitive event is 
identified. 
• Yes: means that there is a clear alternative explanation for the neurocognitive 
event. 
• No: means that there is no clear alternative explanation for the neurocognitive 
event, and it might be study related. 
4.7.1.3. 
Events Causing Death 
The observation periods for patient deaths are per the observation periods defined above.  
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• Death on-treatment:  deaths occurring during the TEAE period, 
• Death post-treatment:  deaths occurring during the post-treatment period. 
4.7.2. 
Clinical Laboratory Safety Variables 
Clinical laboratory tests will consist of blood analyses (including hematology and clinical 
chemistry) and urinalysis. Clinical laboratory values will be converted and analyzed in 
international units, including associated normal ranges provided by the central laboratory. 
International units will be used in all listings and tables. Clinical laboratory values in 
conventional (US) units will also be available in the database, with associated normal ranges 
(analyses can be provided upon request). Both actual test values and “change from baseline” 
values (defined as the post-baseline value minus the baseline value) will be used in the result 
summaries.  Potentially clinically significant abnormalities (PCSA) ranges will be applied to 
the laboratory test values as applicable (see Appendix 10.2 for PCSA definitions). 
Unless otherwise specified below, blood samples for clinical laboratories will be collected at 
the protocol scheduled visits, and visits will be assigned to the Analysis Windows 
(See Appendix 10.1). The laboratory parameters (excluding those considered as efficacy 
parameters) will be classified as follows: 
• Hematology: 
− Red blood cells and platelets:  hemoglobin, hematocrit, erythrocytes count, 
platelets count, reticulocyte count, ery. mean corpuscular Hemoglobin (MCH), 
ery. mean corpuscular HGB concentration (MCHC), ery. mean corpuscular 
volume (MCV) 
− White blood cells: white blood cell count, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils 
• Clinical chemistry: 
− Metabolism:  glucose, total protein, albumin, creatine phosphokinase 
− Electrolytes:  sodium, potassium, chloride, calcium, phosphorus, bicarbonate 
− Renal function:  creatinine, creatinine clearance, blood urea nitrogen (BUN), 
uric acid 
− Liver function:  alanine Aminotransferase (ALT), aspartate aminotransferases 
(AST), alkaline phosphatase (ALP), GGT, bilirubin, LDH 
• Hepatitis screen:  anti-hepatitis-C antibody and hepatitis B surface antigen 
collected at day 1 and week 192. 
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4.7.3. 
Vital Sign Variables 
Vital signs parameters will include height (cm), weight (kg), heart rate (bpm), systolic and 
diastolic blood pressure (mmHg) after resting at least five minutes. Both actual test values 
and “change from baseline” values (defined as the post-baseline value minus the baseline 
value) will be provided for protocol specified visits and visits will be assigned to the Analysis 
Windows (See Appendix 10.1). Potentially clinically significant Abnormalities (PCSA) 
ranges will be applied to the vital sign parameter values as applicable (see Appendix 10.2 for 
PCSA definitions).  
4.8. 
Other Variables 
The other endpoints of the study will include: 
• The percent change in hs-CRP from baseline to protocol specified visits. Hs-CRP 
values greater or equal to 10 mg/L will be excluded from analyses in a second 
approach, since these are suggestive of concurrent infection(1). PCSA (potentially 
clinically significant abnormalities) criteria for hs-CRP are listed in 
Appendix 10.2. 
• The absolute change in HbA1c (%) from baseline to protocol specified visits.  
PCSA criteria for HbA1c are listed in Appendix 10.2. 
• The proportion of patients with two consecutives results, separated by at least 21 
days, of calculated LDL-C <25 mg/dL (<0.65 mmol/L) (and again for calculated 
LDL-C <15 mg/dL [< 0.39 mmol/L]) during the treatment period. 
• For the patients with two consecutive results as described above, the time to the 
first calculated LDL-C <25 mg/dL (<0.65 mmol/L) (and again for calculated 
LDL-C <15 mg/dL [< 0.39 mmol/L]) during the treatment period. 
Protocol schedule visits will be assigned to the Analysis Windows (See Appendix 10.1).   
4.9. 
Genomics Variables 
Plans for analysis of genomics data will be provided in a separate SAP.  
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5. 
STATISTICAL METHODS 
There will be no formal testing for safety variables. For the secondary efficacy endpoints, no 
formal statistical hypothesis will be tested.  
Study data will be summarized descriptively for the following patient groups: 
• The placebo treatment group (as-treated) in the neurocognitive function study 
(R727-CL-1532); 
• The Praluent treatment group (as-treated) in the neurocognitive function study 
(R727-CL-1532); 
• Overall: All patients in the safety population; 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively for the safety 
population.  Parameters described in Section 4.1 will be summarized for the safety 
population.  
The baseline value is generally defined as the baseline value in the neurocognitive function 
study (R727-CL-1532), i.e., the last available value before the first dose of double-blind 
study treatment in that study. 
Continuous data will be summarized using the number of patients with data, mean, SD, 
median, minimum and maximum for each patient group. First quartile (Q1) and third quartile 
(Q3) will be also provided for baseline lipid parameters, HbA1c and hs-CRP. Categorical and 
ordinal data will be summarized using the number and percentage of patients in each patient 
group. 
As applicable, other safety baseline data is presented collectively in the descriptive statistics 
summary tables containing respective post-baseline data. 
5.2. 
Medical History and Disease Characteristics 
Medical history and disease characteristics will be descriptively summarized. The medical 
history was not collected in this study. The medical history data from the neurocognitive 
function study (R727-CL-1532) will be used.  
All reported patient’s medical history and surgical history will be presented by primary SOC 
and HLT.  The tables will be sorted by SOC internationally agreed order and decreasing 
patient frequency of HLT based on the overall incidence in the study.  In addition, all medical 
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history of specific interest, as described in Section 4.2, will be summarized by patient 
incidence and percentage. 
For the patients with primary CVD prevention status (see definition in Section 4.2), the 
number (and percentage) of patients with the following comorbidities/risk factors will be 
tabulated: 
• Diabetes mellitus with target organ damage (renal damage (microalbuminuria, or 
macroalbuminuria, moderate CKD) and/or retinopathy (pre-proliferative or 
proliferative diabetic retinopathy and/or laser treatment for diabetic retinopathy)), 
• Diabetes mellitus with 2 or more risk factors (see Section 4.2), 
• Family History of premature CHD 
• Hypertension, 
• Moderate CKD 
• Current smoker 
• At least 2 of the above comorbidities/risk factors 
In addition, smoking status will be summarized in patients with primary CVD prevention 
status. 
For the patients with a secondary prevention status, the CVD history will be described using 
the number (%) of patients with: 
• History of CHD (see Section 4.2) 
• History of ischemic stroke 
• History of PAD with severity criteria 
− Intermittent claudication and ankle brachial index ≤ 0.90 
− Peripheral revascularization procedure (angioplasty, stenting) for PAD 
− Thrombolysis for PAD 
− Peripheral revascularization surgery (arterial bypass) for PAD 
− Critical limb ischemia 
Additionally: 
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• The number (%) of patients with a secondary prevention status with 1 or more 
associated comorbidity among hypertension, diabetes mellitus, and/or moderate 
CKD will be summarized.  
• The number (%) of patients with history of CHD and 1 or more associated 
comorbidity among hypertension, diabetes mellitus, moderate CKD and/or other 
CVD (ischemic stroke, PAD) will be summarized. 
For patient disease characteristics, as described in Section 4.2, continuous data will be 
summarized using the number of patients with data, mean, SD, median, minimum and 
maximum for the study and for each of the strata. Categorical and ordinal data will be 
summarized using the number and percentage of patients in the study.   
5.3. 
Prior and Concomitant Medications 
All prior medications, dictionary coded by WHO-DD, will be descriptively summarized for 
patients in the safety population. Summaries will present patient counts (and percentages) for 
all prior medications, by decreasing frequency of the overall incidence of ATC followed by 
therapeutic class.  In case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication, but may be counted several times for the 
same medication.   
All concomitant medications during the treatment period, dictionary coded by WHO-DD, 
will be descriptively summarized for patients in the safety population. Summaries will 
present patient counts (and percentages) for the concomitant medication groups described in 
Section 4.3 for all concomitant medications (including statin, non-statin LMT, CV), by 
decreasing frequency of the PRALUENT group incidence of ATC followed by therapeutic 
class.  In case of equal frequency across anatomic or therapeutic categories, alphabetical 
order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication, hence may be counted several times for the same 
medication.  Additionally, concomitant medications pre-specified as statin, non-statin LMT, 
and CV will be summarized by patient counts (and percentages) by therapeutic class or 
e-CRF pre-specified categories as appropriate and standardized medication name.  
Post-treatment medications will be summarized as described above for all medications.  
LMT (statins and other LMTs) use after enrollment will be summarized over time graphically 
BY? LMTs intensity at enrollment using the following categories: 
• atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily or; 
• atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily or simvastatin 
at any daily dose, or other statins 
• LMT other than statin only, 
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• no LMT.    
The LMTs intensity at baseline is defined as: 
• patients treated at enrollment with atorvastatin 40 to 80 mg daily or rosuvastatin 
20 to 40 mg daily (high intensity statin), 
• patients treated at enrollment with atorvastatin below 40 mg daily or rosuvastatin 
below 20 mg daily or simvastatin at any daily dose (low intensity statin), or other 
statins; 
• non-statin LMT only, 
• no LMT.    
5.4. 
Patient Disposition 
Patient disposition includes the description of patient status at major milestone decisions in 
the study, as well as the patient analysis populations. 
Patient study status will be summarized for the study.  Summaries will provide the frequency 
(and percentage as applicable) of patients that met the criteria for the variables described in 
Section 4.4.  Exception listings will be generated for any subject treated but not enrolled, 
enrolled but not treated. 
Patient analysis populations will be summarized, depicting frequencies (and percentages) of 
patients that met the criteria for each population described in Section 3.  
5.5. 
Extent of Study Treatment Exposure and Compliance 
The extent of study treatment exposure and study compliance parameters for the treatment 
period described in Section 4.5 will be assessed and summarized for patients in the safety 
population.  
5.5.1. 
Exposure to Investigational Product 
Study treatment exposure for the treatment period will be descriptively summarized for the 
treatment duration and total number of injections as described in Section 4.5. Treatment 
duration will be summarized using the number of patients with data, mean, SD, median, 
minimum and maximum. Categorized 4-week intervals of treatment duration will be 
summarized descriptively by counts and percentages. 
The incidence of premature study treatment discontinuation (irrespective of the reason) and 
premature treatment discontinuation due to AEs will be presented graphically in the safety 
population using the Kaplan-Meier method.  
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5.5.2. 
Measurement of Compliance  
Study treatment compliance parameters will be descriptively summarized using the number 
of patients with data, mean, SD, median, minimum and maximum for the variables listed in 
Section 4.5.  According to protocol, cases of overdose are reported in the AE e-CRF pages 
and will be described in the AE analysis. 
Both monitored and derived protocol deviations will be summarized for important deviations 
(counts of deviations), patients (incurring a deviation by count and percentage), and by type 
of important deviation (patient count and percentage).  A patient listing of all important and 
minor protocol deviations will be provided. 
5.6. 
Analyses of Efficacy Variables 
For statistics where international and conventional units do not impact the results (e.g. 
percent changes from baseline, rates of patients below a threshold), derivations will be 
calculated and summaries will be run using conventional units. For other statistics (e.g. 
values at baseline and over time, absolute changes from baseline), derivations will be 
presented in both international and conventional units. 
5.6.1. 
Analyses of Efficacy Variables 
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.        
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.      
Descriptive statistics for calculated LDL-C will also be provided for patients with or without 
any study medication modification, separately.   
Protocol schedule visits will be assigned to the Analysis Windows (See Appendix 10.1).   
5.6.2. 
Sub-group Analyses 
The subgroup analyses will be performed for LDL-C. 
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The following subgroups of interest will be evaluated, assuming there are enough patients in 
each subgroup level to perform the evaluation.  
• The age group (<65, ≥65), 
• Gender (Female, Male),  
• BMI (<30 kg/m2, ≥30 kg/m2), 
• Statins with versus without other LMT at baseline , 
5.6.3. 
Adjustment for Multiple Comparisons 
Adjustments to the alpha level for the purposes of multiple testing are not applicable for this 
safety study.  
5.7. 
Analysis of Safety Data 
The summary of safety results will be presented on the safety population (Section 3.1). No 
formal inferential testing will be performed. Summaries will be descriptive in nature. All 
summaries of safety results described below will be presented for each period respectively, 
unless otherwise noted. 
General common rules 
All safety analyses will be performed, unless otherwise specified, using the following 
common rules: 
• Safety data in patients who do not belong to the safety population (i.e., exposed 
but not enrolled) will be listed separately. 
• 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). 
• PCSA values are defined as abnormal values considered medically important by 
the Sponsor according to predefined criteria/thresholds based on literature review 
and defined by the Sponsor for clinical laboratory tests and vital signs (PCSA 
version dated January 2009 [Appendix 10.3]). Considering that the threshold 
defined in the PCSA list for monocytes and basophils can be below the ULN, the 
following PCSA criterion will be used for the PCSA analysis of monocytes and 
basophils:  
− PCSA criterion for monocytes: >0.7 Giga/L or >ULN (if ULN ≥0.7 Giga/L). 
− PCSA criterion for basophils: >0.1 Giga/L or >ULN (if ULN ≥0.1 Giga/L). 
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• PCSA criteria will determine which patients had at least 1 PCSA during the 
TEAE period, taking into account all evaluations including nonscheduled or 
repeated evaluations. 
• The treatment-emergent PCSA denominator for a given parameter will be based 
on the number of patients assessed for that given parameter at least once during 
the TEAE period. 
• All measurements, scheduled or unscheduled, fasting or not fasting, will be 
assigned to analysis windows defined in Appendix 10.1, Table 1 in order to 
provide an assessment for week 8 to week 96 time points. 
• For quantitative safety parameters including central laboratory measurements and 
vital sign scores, descriptive statistics will be used to summarize results and 
change from baseline values by visit, the last on-treatment value and the worst on-
treatment value. The last on-treatment value is defined as the last post-baseline 
value collected during the respective treatment period (as defined in 
Section 4.7.1). The worst on-treatment value is defined post-baseline as the nadir 
and/or the peak value collected during the respective treatment period, according 
to the direction (minimum or maximum) of the abnormality as defined in the 
PCSA list.   
• Analyses performed according to diabetes status will be done considering diabetic 
patients as patients with either type 1 or type 2 diabetes in the medical history e-
CRF page (regardless of the ongoing status) in the neurocognitive function study 
(R727-CL-1532). 
5.7.1. 
Analysis of Adverse Events  
In general, the primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-
treatment AEs will be provided separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment.  The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine pre-
treatment or post-treatment status.  Details on classification of AEs with missing or partial 
onset dates are provided in Section 6.4. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC, HLGT (when applicable), HLT (when applicable), and PT.  
Multiple occurrences of the same event in the same patient will be counted only once in the 
tables within a treatment phase. For tables presenting severity of events, the worst severity 
will be chosen for patients with multiple instances of the same event. The denominator for 
computation of percentages is the safety population within each patient group. 
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The table of all TEAEs presented by SOC and PT will be sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs (in the PRALUENT group). This 
will define the presentation order for all other tables by SOC and PT, unless otherwise 
specified. The tables of AEs by SOC, HLGT, HLT and PT will be sorted by the SOC 
internationally agreed order and the other levels (HLGT, HLT, PT) will be presented in 
alphabetical order, unless otherwise specified.   
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
• Overview of TEAEs, summarizing number (%) of patients with any 
− TEAE; 
− Serious TEAE; 
− TEAE leading to death; 
− TEAE leading to permanent treatment discontinuation. 
• All TEAEs by primary SOC, HLGT, HLT, and PT 
• Number (%) of patients experiencing common TEAE(s) presented by primary 
SOC, HLT and PT (HLT incidence ≥ 5 % in the total patient group), sorted by 
SOC internationally agreed order and by alphabetic order for the other levels 
(HLT and PT); 
• All TEAEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC (in the PRALUENT 
group).   
• All TEAEs regardless of relationship in one column and, in the same table a 
second column with TEAEs related to alirocumab according to investigator’s 
opinion by primary SOC, HLGT, HLT and PT; 
• All TEAEs by maximal severity (i.e., mild, moderate or severe), presented by 
primary SOC and PT, sorted as defined above; 
• The event rate per patient-year (the number of patients with an event in question 
divided by total patient-years) will be provided for all TEAEs by SOC and PT.  
For a patient with event, patient year is censored at time of first event; for patient 
without event, it corresponds to length of TEAE period; 
• Kaplan-Meier curves will be provided, when appropriate, for time from first dose 
of study treatment to the first occurrence of selected TEAEs as well as incidence 
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rates at 48, 96, 144, and 192 weeks of exposure. Patients without any event will 
be censored at the end of the TEAE period. Selected TEAEs could be AESIs (e.g 
neurocognitive events), or TEAE related to any clinically significant signal that 
needs further characterization; 
• The frequency of selected AEs by SOC and PT over time during the treatment 
period (number of patients experiencing AE and percentage by patient-months) 
will be provided, when appropriate, by time intervals defined as:  ≤48 weeks, >48 
to ≤96 weeks, >96 to ≤144 weeks, >144 to ≤192 weeks, using the PROC 
LIFETEST with the actuarial method.  Only the first event will be counted. 
Analysis of all treatment emergent serious adverse event(s) 
• All serious TEAEs by primary SOC, HLGT, HLT, and PT and by SOC/PT; 
Patient listings of serious TEAEs will be provided for the report appendix. 
• All serious TEAEs regardless of relationship in one column and in the same table 
a second column with TEAEs related to alirocumab according to investigator’s 
opinion, by primary SOC, HLGT, HLT, and PT;  
• The event rate per patient-year will be provided for all serious TEAEs by SOC 
and PT. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to permanent treatment discontinuation, by primary SOC, 
HLGT, HLT, and PT and by SOC/PT; Patient listings of TEAEs leading to 
permanent treatment discontinuation will be provided for the report appendix.  
Analysis of groupings of adverse events including selected adverse events of special 
interest 
• All grouping of TEAEs including adverse events of special interest, as listed in 
Section 4.7.1.2, will be presented by SMQ/CMQ and PT (when selection is based 
on SMQs/CMQs) and by SOC and PT (when selection is based on the e-CRF tick 
box or HLGT/HLT). The summaries will be sorted by decreasing incidence of PT 
within each SOC/SMQ (in the PRALUENT group).  
• Neurocognitive events adjudicated by the neurocognitive events review committee 
will also be summarized by primary SOC and PT. They will also be summarized 
according to the adjudication of possible etiology of the neurocognitive events 
(Yes/No) (Section 4.7.1.2).  
• All TEAEs within diabetes grouping will be analyzed overall and according to the 
diabetic status at baseline. 
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The following variables will also be tabulated for the local injection site reactions TEAEs: 
• Intensity of the event (mild, moderate, severe); 
• Number of events divided by the number of study treatment injections received; 
• Time from first study treatment injection to first injection site reaction; 
• Description of the highest intensity of each symptom recorded in the specific e-
CRF page with table and bar chart.  
Description of symptoms and possible etiologies for General Allergic Reaction TEAE 
reported by investigator (using the tick box), will be presented. 
Post-treatment adverse events  
• All post-treatment AEs by primary SOC and PT, sorted by the internationally 
agreed SOC order and decreasing incidence of PTs (in the PRALUENT group) 
within each SOC; 
• All post-treatment SAEs by primary SOC and PT, sorted by the sorting order 
defined above. 
Subgroup of patients with two consecutive LDL-C <25 mg/dL (<0.65 mmol/L) 
If applicable, similar summaries of TEAEs as those described above will be provided on the 
safety subgroup population of patients with two consecutive results of LDL-C <25 mg/dL (as 
defined in Section 4.8) in both patient groups. Only TEAEs for which it will be confirmed or 
unclear that they occurred, worsened or became serious on the day or after the day the first 
level of LDL-C <25 mg/dL was observed will be considered in this summary.   
In addition, the neurocognitive event rate in patients with 2 consecutive results separated by 
at least 21 days for calculated LDL-C <25 mg/dL, and calculated LDL-C <15 mg/dL, will be 
assessed. 
5.7.1.1. 
Patient Deaths 
The following summaries of deaths will be generated. 
• Number (%) of patients who died by study period (TEAE and post-treatment);  
• Deaths in enrolled but not treated patients; 
• TEAEs leading to death (death as an outcome on the AE CRF page, as reported by 
the Investigator) by (at least) SOC (sorted by internationally agreed order), and PT 
(sorted by decreasing frequency, showing the number (n) and percentage (%) of 
patients) for the safety population. 
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5.7.2. 
Analysis of Clinical Laboratory Variables 
Clinical laboratory parameter actual values (quantitative) and change from baseline values 
will be descriptively summarized at baseline and each post-baseline visit (collected up to the 
day of last dose of study treatment +21 days) by at least patient number, mean, median, Q1, 
Q3, SD, minimum and maximum for each patient group. Additionally, laboratory parameter 
measures for last on-treatment values and worst on-treatment values will be summarized in a 
similar manner. Clinical laboratory parameters mean changes from baseline, with the 
corresponding SE, can be plotted at each visit, in the case results warrant further 
investigation.  These parameters will be presented by the biological functions defined in 
Section 4.7.2.  For glucose, only fasting samples will be included in the summaries. 
Individual patient laboratory parameter measurements will be additionally evaluated by 
PCSA criteria, specifically identifying patients with at least one post-baseline measurement 
that meets the PCSA criteria within the TEAE period.  The following additional project 
specific PCSA criteria will also be evaluated during the TEAE period: 
• Patients with a hemoglobin decrease from baseline ≥ 15 g/L. 
• Patients meeting the ALT increase defined in Section 4.7.1.2. 
• Glucose (quantitative summary and PCSA) will also be analyzed, overall and 
according to the diabetic status at baseline. 
Patients meeting the PCSA criteria at least once will be summarized by patient count (and 
percent) for a post-baseline PCSA measurement while accounting for the baseline PCSA 
status (PSCA normal/missing; PCSA abnormal), for each patient group. For the appendix, 
this laboratory parameter PCSA table will be reproduced with patients meeting the PCSA 
criteria at least once during the TEAE period regardless of baseline PCSA status. These 
laboratory parameters will be presented by the biological functions defined in Section 4.7.2. 
Patient listings of laboratory measurements that meet PCSA criteria will be provided for the 
report appendix.  For those laboratory parameters that don’t have an associated PCSA 
criteria, similar summary tables can be provided based on measurements outside the central 
laboratory normal ranges, if applicable.  
Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin, are used to assess 
possible drug-induced liver toxicity.  The proportion of patients with PCSA values or ALT 
increase as defined as AESI (see Section 4.7.1.2) during TEAE period by baseline status will 
be displayed for each parameter. 
An evaluation of drug-induced serious hepatotoxicity (eDISH) with the graph of distribution 
of peak values of ALT versus peak values of total bilirubin will also be presented using post-
baseline values during TEAE period. Note that the ALT and total bilirubin values are 
presented on a logarithmic scale. The graph will be divided into 4 quadrants with a vertical 
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line corresponding to 3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for 
total bilirubin. 
Listing of possible Hy’s law cases identified (i.e., patients with any elevated ALT>3 x ULN, 
and associated with an increase in bilirubin >2 x ULN, concomitantly or not) with ALT, 
AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be provided. 
The incidence of liver-related TEAEs will be summarized. The selection of PTs will be based 
on SMQ Hepatic disorder (see Section 4.7.1.2).  
5.7.3. 
Analysis of Vital Sign Variables 
The vital sign actual values and change from baseline values obtained while sitting will be 
descriptively summarized at baseline and each post-baseline visit (collected up to the day of 
last dose of study treatment +21 days) by at least patient number, mean, median, Q1, Q3, SD, 
minimum and maximum for each patient group. Additionally, vital sign measures for last on-
treatment value and worst on-treatment value will be summarized in a similar manner. Vital 
sign mean changes from baseline, with the corresponding SE, can be plotted at each visit, in 
the case results warrant further investigation. 
Individual patient vital sign measurements (regardless of sitting position) will be additionally 
evaluated by PCSA criteria, specifically identifying patients with at least one post-baseline 
measurement that meets the PCSA criteria within the TEAE period.  Patients meeting the 
PCSA criteria at least once will be summarized by patient count (and percent) and patient 
group.  Patient listings of vial sign measurements that meet PCSA criteria will be provided 
for the report appendix.   
5.8. 
Analysis of Other Variables 
The summary of other variables will be presented on the safety population. No formal 
inferential testing will be performed for either period. Summaries will be descriptive in 
nature.  
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to 
analysis windows in order to provide an assessment for week 8 to week 96 time points.   
Hs-CRP and HbA1cparameters (Section 4.8) will be summarized for the number of patients 
with data, mean, SD, median, minimum, and maximum (for hs-CRP, Q1 and Q3 will be also 
provided) by analysis visit during the treatment period.  For HbA1c, summaries will also be 
provided according to diabetes mellitus status at baseline.  The time profile will be plotted for 
HbA1c showing the means and the corresponding SEs, while medians (with Q1-Q3) will be 
plotted for hs-CRP.  Applying the PCSA criteria to these variables at any time during the 
TEAE period, the number of patients (and percentages) meeting the criteria will be 
summarized. 
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The gonadal hormone parameters (Section 4.6.2) will be summarized for the number of 
patients with data, mean, SD, median, minimum, and maximum by analysis visit during the 
treatment period. For FSH and LH, the summaries will be performed for all patients, female 
patients, and male patients. Estradiol will be summarized for female patients only, and 
testosterone will be summarized for male patients only. Summary tables will also be provided 
for gonadal hormone parameters based on measurements outside the central laboratory 
normal ranges, if applicable.  When appropriate, for female patients the gonadal-
gonadotrophin in menopausal and non-menopausal women will be summarized separately. 
In order to minimize confounding factors with menopause or exogenous estrogens, the 
summaries of estradiol, FSH, and LH for female patients will be repeated by excluding 
patients who were receiving hormone replacement therapy, were ≥50 years, or had FSH 
levels ≥25 IU/L at baseline. 
For male patients, the summaries of testosterone, FSH, and LH will be repeated by excluding 
patients who were receiving testosterone supplementation or had LH levels ≥15 IU/L at 
baseline. 
Binary endpoints defined in Section 4.8 will be described through patient counts and 
percentages.  Kaplan-Meier curves will be provided for the variables assessing time to first 
occurrence of an event (i.e., calculated LDL-C related outcome).  Patients not meeting the 
event will be censored at the end of the treatment period.  For the analysis of the time to the 
first of the two consecutive LDL-C events, patients without post-baseline LDL-C result or 
with only one post-baseline LDL-C result will not be included in the analysis. 
5.9. 
Analysis of Genomics Variables 
Plans for the analysis of genomics data will be provided in a separate SAP. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis. 
6.1. 
Definition of Baseline for Efficacy and Safety Variables 
Unless otherwise specified, the baseline value is generally defined as the baseline value in the 
neurocognitive function study (R727-CL-1532), i.e., the last available value before the first 
dose of double-blind study treatment in that study. 
In addition to the OLE study database, some data will be recovered from the neurocognitive 
function study (R727-CL-1532) database 
6.2. 
General Data Handling Conventions 
In general, the following formulas will be used for computation of parameters: 
Time from diagnosis 
Time from diagnosis (years) = (Date of informed consent – Date of diagnosis*) / 365.25.  
 (*):In case the month of diagnosis would be missing, it will be put equal to JANUARY if the year of diagnosis 
equals the year of informed consent; it will be put equal to JUNE otherwise. In the case the day is missing, the 
day will be put equal to 1st if the month and year of diagnosis equals the month and year of informed consent; 
otherwise it will be put equal to the 15th of the month. 
Date of last dose of study treatment 
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page, or missing if the last administration date is unknown.  
Renal function formulas  
Estimated GFR will be derived using the Modification of the Diet in Renal Disease (MDRD) 
equation: 
186.3 × (creatinine in µmol/L / 88.4)-1.154 × (age in years)-0.203 (x 0.742 if female, x 1.21 if 
race is "black or African American"). 
Lipids variables, laboratory safety variables, hs-CRP 
For data below the lower limit of quantification (LLOQ) / limit of linearity, half of the lower 
limit value (i.e., LLOQ/2) will be used for quantitative analyses. For data above the upper 
limit of quantification (ULOQ) / limit of linearity, the upper limit value (i.e., ULOQ) will be 
used for quantitative analyses. 
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6.3. 
General Missing Data Conventions 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing 
data is presented. 
Handling of baseline definition if “time” of first study treatment administration or time of 
assessment at week 0 visit is missing 
If the time of the first study treatment administration or the time of assessment at week 0 visit 
is missing, then the baseline value is defined as the last available value obtained before or on 
the day of the first study treatment administration. 
Handling of computation of treatment duration and compliance if study treatment first or 
end of treatment date is missing  
If the last or first injection date is missing, the exposure duration and compliance will be left 
as missing. 
Handling of safety and efficacy analysis periods and survival analysis if end of study 
treatment date is missing  
If the last injection date is missing, then this date is imputed to the earliest between:  
• the last day of the month and year, when applicable or else the 31st of December 
of the year,  
• the date of the end of treatment visit (week 96 visit for completer, early end of 
treatment visit for patients who prematurely discontinued the study treatment), 
• the date of the last contact  
for the purpose of safety and efficacy analysis period start and/or end. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date 
or time is missing or partially missing and it cannot be determined whether it was taken prior 
or concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset, worsening, 
seriousness 
Missing or partial AE dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, 
the AE will be classified as treatment-emergent. These data imputations are for categorization 
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purpose only and will not be used in listings. No imputation is planned for date/time of AE 
resolution. 
Handling of adverse events when date and time of first study treatment administration is 
missing   
When the time of the first study treatment administration is missing, all AEs that occurred on 
the day of the first study treatment administration will be considered as treatment-emergent 
AEs. 
Handling of missing assessment of relationship of adverse events to investigational 
medicinal product  
If the assessment of the relationship to study treatment is missing, then the relationship to 
study treatment has to be assumed as possibly related in the frequency tables, but no 
imputation should be done at the data level.  
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline value he will be grouped in the category “normal/missing 
at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be 
based only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using 
this threshold if the normal range is missing; e.g., for eosinophils the PCSA is >0.5 GIGA/L 
or >ULN if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into 
account in the computation of PCSA values. 
6.4. 
Visit Windows for Time Points 
Visit windows will be programmatically imposed on those efficacy and safety measures 
repeatedly collected over the course of the study. These visit windows are derived from the 
number of days in study, specifically assigning day ranges to mimic the study assessment 
schedule provided in the protocol.  Data analyzed by time point (including efficacy, 
laboratory safety data, vital signs, physical examinations) will be summarized using the 
analysis windows given in Appendix 10.1. These analysis windows will be applicable for all 
analyses, and they are defined to provide more homogeneous data for time point-specific 
analyses. If multiple valid values of a variable exist within an analysis window, the nearest 
from the targeted study day will be selected. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values of a variable exist within a same day, 
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then the first value of the day will be selected when time is available, else the scheduled visit 
will be selected. 
6.5. 
Unscheduled Assessments 
For efficacy, safety laboratory data, vital signs, physical examinations, and ADA, 
unscheduled visit measurements may be used to provide a measurement for a time point, a 
baseline, a last or a worst value, if appropriate according to their definitions. The 
measurements may also be used to determine abnormal values and PCSA. 
6.6. 
Pooling of Centers for Statistical Analyses 
Not Applicable. 
6.7. 
Statistical Technical Issues 
Not Applicable. 
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7. 
TIMING OF STATISTICAL ANALYSES  
There are no interim analyses planned. The statistical analysis will be conducted at the end of 
the study and will consist of the final analysis of primary and secondary endpoints and final 
safety analysis. 
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8. 
SOFTWARE 
All analyses will be generated using SAS Version 9.4 or higher. 
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9. 
REFERENCES 
1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, et 
al. Markers of inflammation and cardiovascular disease:  application to clinical and 
public health practice: A statement for healthcare professionals from the Centers for 
Disease Control and Prevention and the American Heart Association. Circulation. 
2003 Jan 28;107(3):499-511. 
2. Dolan P. Modeling valuations for EuroQol health states. Med Care. 1997 Nov; 
35(11):1095-108. 
3. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012 Oct 
4;367(14):1355-60. doi: 10.1056/NEJMsr1203730. 
4. SAS Institute Inc. 2009. SAS/STAT ® 9.2 User’s Guide, Second Edition. Cary, NC: 
SAS Institute Inc. 
5. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing 
data using multiple imputation in conjunction with robust regression. Biometrics. 
2012 Dec;68(4):1250-9. doi: 10.1111/j.1541-0420.2012.01780.x. 
6. Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not 
affect the type I error rate. Stat Med. 2003; 22(23): 3571-81. 
7. Robert J. Frerichs ∗, Holly A. Tuokko A comparison of methods for measuring 
cognitive change in older adults. Archives of Clinical Neuropsychology 20 (2005) 
321–333. doi:10.1016/j.acn.2004.08.002 
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10. 
APPENDIX 
10.1. 
Windows for Analysis Time Points 
Below are the definitions for the visit windows programmatically imposed on measures 
repeatedly collected over the course of the study.  These visit windows reflect the study 
schedule of assessments as described in the protocol.  The visit windows are constructed 
using ranges applied to the number of days in study (study days) when the measure is 
collected.  Day 1 is defined as the first date of double-blind study treatment administration, 
and is labeled as baseline for most variables. Since the protocol specifies that measurements 
be collected before study treatment is administered on a given day, it is appropriate that 
baseline include Day 1.  
Table 1: 
Analysis Windows Definition 
Time point 
Targeted study day 
Analysis window in study days 
Week 8 
57 
29 to 70 
Week 12 
85 
71 to 126 
Week 24 
169 
127 to 252 
Week 48 
337 
253 to 420 
Week 72 
505 
421 to 588 
Week 96 
673 
589 to 756 
Week 120 
841 
757 to 924 
Week 144 
1009 
925 to 1092 
Week 168 
1177 
1093 to 1260 
Week 192 
1345 
1261 to 1428 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1.  
 
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10.2. 
Criteria for Potential Clinical Significant Abnormalities (PCSA) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and 
TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 
ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever the interval 
between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be 
deleted. 
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Parameter 
PCSA 
Comments 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from 
baseline 
≥100% change from 
baseline 
Benichou C., 1994. 
 
CLcr (mL/min) 
(Estimated creatinine clearance 
based on the Cokcroft-Gault 
equation)  
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild decrease 
in GFR) 
≥ 90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an 
MDRD equation)  
 
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild decrease 
in GFR) 
≥ 90 (normal GFR) 
Use is optional. 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L 
(unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
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Parameter 
PCSA 
Comments 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if 
ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); 
<2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-
Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if 
ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L 
(Female) 
≥185 g/L (Male); ≥165 
g/L (Female) 
 
Decrease from Baseline 
≥20 g/L 
Criteria based upon decrease from baseline are more relevant than 
based on absolute value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 
v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 
v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced blood cytopenias, 
1991. 
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Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
To be applied for all positions (including missing) except 
STANDING. 
SBP 
≤95 mmHg and 
decrease from baseline 
≥20mmHg 
≥160 mmHg and 
increase from baseline 
≥20 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
DBP 
≤45 mmHg and 
decrease from baseline 
≥10 mmHg 
≥110 mmHg and 
increase from baseline 
≥10 mmHg 
To be applied for all positions (including missing) except 
STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from 
baseline  
≥5% decrease from 
baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline ≥20 bpm 
 
PR 
≥220 ms and increase 
from baseline ≥20 ms 
 
QRS 
≥120 ms 
 
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Parameter 
PCSA 
Comments 
QTc 
Borderline 
Prolonged* 
Additional 
 
Absolute values (ms)
 
 
Borderline: 431-450 ms 
(Male); 451-470 ms 
(Female) 
Prolonged: >450 ms 
(Male); >470 ms 
(Female) 
≥500 ms 
 
Increase from baseline 
Borderline: Increase 
from baseline 30-60 ms 
Prolonged:  Increase 
from baseline >60 ms 
To be applied to any kind of QT correction formula.  
 
 
 
*QTc prolonged and QTc>60 ms are the PCSA to be identified in 
individual subjects/patients listings. 
 
 
 
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10.3. 
List of MedDRA terms for CMQs 
Table 2: 
Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for 
neurologic events 
MedDRA Term Label 
Benign neoplasm of optic nerve 
Optic atrophy 
Optic discs blurred 
Optic nerve disorder 
Optic nerve injury 
Optic nerve neoplasm 
Optic nerve operation 
Optic neuropathy 
Papillitis 
Pseudopapilloedema 
Subacute myelo-opticoneuropathy 
Toxic optic neuropathy 
Visual evoked potentials abnormal 
Amaurosis fugax 
Blindness 
Blindness unilateral 
Colour blindness acquired 
Colour vision tests abnormal 
Cranial nerve injury 
Delayed myelination 
Fundoscopy abnormal 
Hemianopia 
Hemianopia heteronymous 
Hemianopia homonymous 
Loss of visual contrast sensitivity 
Neuro-ophthalmological test abnormal 
Night blindness 
Ophthalmological examination abnormal 
Optic pathway injury 
Optical coherence tomography abnormal 
Quadrantanopia 
Visual acuity reduced 
Visual acuity reduced transiently 
Visual acuity tests abnormal 
Visual field defect 
Visual field tests abnormal 
Visual impairment 
Visual pathway disorder 
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Table 3: 
CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Term Label 
PTCD 
Amnesia 
PTCD 
Amnestic disorder 
PTCD 
Anterograde Amnesia 
PTCD 
 Neuropsychiatric symptoms 
PTCD 
Change in sustained attention 
LLTCD 
Cognitive Deterioration 
PTCD 
Cognitive Disorder 
LLTCD 
Confusion 
LLTCD 
Confusion Aggravated 
PTCD 
Confusional State 
PTCD 
Delirium 
PTCD 
Dementia 
PTCD 
Dementia Alzheimer's type 
LLTCD 
Dementia Nos 
LLTCD 
Dementia Nos Aggravated 
LLTCD 
Dementia of the Alzheimer's type NOS 
PTCD 
Dementia with Lewy Bodies 
PTCD 
Disorientation 
PTCD 
Disturbance in attention 
PTCD 
Executive dysfunction 
PTCD 
Frontotemporal Dementia 
LLTCD 
Global Amnesia 
PTCD 
Illogical Thinking 
PTCD 
Impaired reasoning 
PTCD 
Incoherent 
PTCD 
Judgement impaired 
PTCD 
Memory Impairment 
PTCD 
Mental Impairment 
LLTCD 
Mental Impairment Nos 
LLTCD 
Mental State Abnormal Aggravated 
PTCD 
Mental Status Changes 
PTCD 
Mini Mental Status Examination Abnormal 
PTCD 
Presenile Dementia 
PTCD 
Retrograde Amnesia 
PTCD 
Senile Dementia 
LLTCD 
Senile Dementia Nos 
LLTCD 
Short-term Memory Loss 
PTCD 
Thinking Abnormal 
LLTCD 
Thinking Slowed 
PTCD 
Transient Global Amnesia 
PTCD 
Vascular Dementia 
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Table 4: 
CMQ “Type 1 or Type 2 diabetes” 
MedDRA Term Label 
Preferred Term Code 
Diabetes mellitus 
10012601 
Diabetes mellitus inadequate control 
10012607 
Insulin resistant diabetes 
10022491 
Diabetes mellitus malnutrition-related 
10050197 
Diabetes mellitus management 
10051599 
Insulin-requiring type 2 diabetes mellitus 
10053247 
 
Type 1 diabetes mellitus 
10067584 
Type 2 diabetes mellitus 
10067585 
Fulminant type 1 diabetes mellitus 
10072628 
 
 
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