Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99. DOI: 10.1056/NEJMoa1501031

1

Supplementary Appendix

Supplement to: Robinson J.G., Farnier F., Krempf M., et al., Efficacy and Safety of

Alirocumab in Reducing Lipids and Cardiovascular Events.

Table of Contents

Investigators, Steering Committee, Data Monitoring Committee and Independent

Physician .................................................................................................................... 4

Principal Investigators ............................................................................................. 4

Steering Committee ................................................................................................ 7

Data Monitoring Committee .................................................................................... 8

Independent Physicians .......................................................................................... 9

Supplemental Methods ............................................................................................. 10

Inclusion Criteria ................................................................................................... 10

Exclusion Criteria .................................................................................................. 13

Randomization ...................................................................................................... 19

Extent of Study Drug Exposure ............................................................................ 19

Adherence to Study Treatment ............................................................................. 19

Additional Statistical Analyses and Secondary Efficacy Endpoints ....................... 20

2

Monitoring and Laboratory Alert Related to Two Consecutive Calculated LDL

cholesterol <25 mg per deciliter (0.65 mmol per liter) ........................................... 25

Prespecified Definitions of Cardiovascular Events................................................ 26

Custom MedDRA Query “Diabetes” ...................................................................... 44

Figure S1. Study Design .......................................................................................... 51

Figure S2. Percent Change in Calculated LDL Cholesterol from Baseline to Week 24

According to HeFH status (A), and Baseline LDL Cholesterol Subgroup (B) (ITT

Analysis) ................................................................................................................... 52

Figure S3. Percent Change in Calculated LDL Cholesterol from Baseline to Week 24

According Baseline PCSK9 Level (A), and Gender (B) ............................................ 54

Figure S4. The Difference in Percentage Change from Baseline to Week 24 in LDL

Cholesterol (Alirocumab vs. Placebo) According to Baseline Subgroup:

Demographics (A), Medical History and PCSK9 levels (B), Lipids (C), and Lipid

Medication (D) (ITT Population). Dotted line represents mean percent LDL

Cholesterol Reduction for All Patients ...................................................................... 56

Figure S5. Post hoc Analysis of a Subgroup of Adjudicated Major Adverse

Cardiovascular Events (ODYSSEY OUTCOMES endpoint). Kaplan-Meier Estimates

for Time to First Positively Adjudicated CV Event During the TEAE Period (A) and

Duration of Follow-Up for the Safety Population Included in the Post hoc Analysis (B)

................................................................................................................................. 60

Table S1. Calculated LDL Cholesterol Availability Over Time - ITT population ........ 62

3

Table S2. Percent Change from Baseline in Measured LDL Cholesterol at Week 24

in the Intention-to-Treat Population* ......................................................................... 63

Table S3. Selected Secondary Efficacy End Points in the On-Treatment Analysis* 64

Table S4. Percent Change From Baseline in Calculated LDL Cholesterol at Week 24

(Pattern-Mixture Model)* .......................................................................................... 66

Table S5. Adverse Events Including Those Occurring in Alirocumab Patients with 2

Consecutive Calculated LDL Cholesterol Values <25 mg per deciliter: Safety

Analysis* .................................................................................................................. 67

Table S6. Neurocognitive TEAEs: Safety Analysis .................................................. 71

Table S7. Detailed Treatment-Emergent General Allergic Serious Adverse Events

and Neurologic Serious Adverse Events .................................................................. 73

Table S8. Additional Parameters Possibly Related to Low LDL Cholesterol ............ 75

4

Investigators, Steering Committee, Data Monitoring Committee

and Independent Physician

Principal Investigators

Argentina: Alberto Caccavo, Oscar Codutti, Elisabeth Gelersztein, Marisa Vico,

Cesar Zaidman, Claudio Majul; Belgium: Yohan Balthazar, Luc Capiau,

Mathias Vrolix, Paul Vermeersch; Bulgaria: Dobromir Gotchev, Georgi Todorov,

Haralin Tumbev, Maria Tzekova, Naydenka Gronkova, Bojidar Dimov,

Antonoaneta Nikolaeva, Tsvetan Devedzhiev, Valentina Mincheva; Canada:

Giuseppe D'Ignazio, Peter Dzongowski, Thomas Elliott, Randy Hart, Gordon Hoag,

Valdemar Martinho, Michael O’Mahony, Guy Tellier, Jean Bergeron,

Shekhar Pandey, Kenneth Heaton, Christian Constance, Denis­Carl Phaneuf,

Daniel Shu; Chile: Nancy Cardenas Narvaez, Claudia Olivares Cañon,

Sergio Potthoff Cardenas, Manuel Salgado Loayza; Colombia:

Dora Molina de Salazar, Rodrigo Botero Lopez, Jaime Ibarra Gomez,

Jose Accini Mendoza, Carlos Cure Cure; Czech Republic: Richard Ceska,

Eva Zidkova, Petr Jansky; Denmark: Kenneth Egstrup, IB Christian Klausen,

Jens Lomholdt, Gunnar Gislason, Christian Torp-Pedersen, Steen Poulsen; Finland:

Matti Kuusela, Sakari Kekki, Sakari Nieminen, Jaakko Tuomilehto; France:

Alain Boye, Eric Bruckert, Didier Cadinot, Michel Farnier, Dominique Lejay,

Gérald Luc, Thierry Revol, Thierry Schaupp, Michel Krempf, Jacques Bonnet,

François Paillard, Philippe Moulin; Germany: Josef Junggeburth, Berend Isermann,

Martin Zühlke, Dirk Züchner, Elisabeth Theis, Janna Stößel, Hans-Joachim König,

Andrea Rinke, Richard Piechatzek, Christel Contzen, Mariola Lappo, Agnes-

5

Anette Himpel-Boenninghoff, Gudrun Meissner, Olga Maus, Elizabeta Degtyareva,

Erik-Delf Schulze, Thomas Horacek, Irmgard Marten; Hungary: Peter Becher,

Andras Matoltsy, Gabor Nyirati, Gyorgy Paragh, Zsolt Zilahi, Karoly Nagy,

Nikosz Kanakaridisz, Eleonora Beke, Janos Biro, Robert Schnabel; Israel:

Mazen Elias, Dov Gavish, Adi Francis, William Nseir, Reuven Zimlichman; Italy:

Maurizio Averna, Claudio Pozzi, Giuseppe Lembo, Marco Bucci, Andrea Mezzetti,

Paolo Rubba, Anna Maria De Pellegrin, Alessandro Salvioni, Nicoletta De Cesare;

Mexico: Ignacio Rodriguez Briones, Pedro Fajardo Campos, Enrique Lopez Rosas,

Efrain Villeda Espinosa, Melchor Alpizar Salazar, Alberto Bazzoni Ruiz,

Luis Carmona Furusho, Israel Olvera; Netherlands: Erik Stroes,

Remco van den Berg, Dick Basart, Vicdan Köse, Susanne Kentgens, Marc Peeters,

Jacqueline Hoogendijk, C Voors-Pette, Irmaina Agous, Wouter van Kempen,

Gloria Rojas Lingan, Adriaan Kooy, Roland Troquay, Johannes Herrman; Norway:

Hans Hoivik, Gisle Langslet, Paal Norheim, Knut Risberg, Hans Olav Høivik,

Sigbjorn Elle; Poland: Tadeusz Derezinski, Pawel Miekus, Michal Ogorek,

Katarzyna Szymkowiak, Marek Cesar, Adam Gawron, Magda Dabrowska,

Elzbieta Blach, Marek Konieczny, Mateusz Sidor; Portugal: Fernando Matias,

Pedro Marques da Silva, Davide Carvalho, Isabel Mendonca; Romania:

Minodora Andor, Laurentia Andrei, Cristian Podoleanu, Calin Pop; Russia:

Petr Chizhov, Galina Chumakova, Boris Goloschekin, Igor Libov, Zhanna Paltsman,

Andrey Strutinskiy, Natalya Koziolova; South Africa: Johannes Breedt,

Iftikhar Ebrahim, Graham Ellis, Muhamed Fulat, Dirkie Janse van Rensburg,

Frederick Raal, Christo van Dyk, Tasneem Vally, Eugene van der Walt,

Hester Kotzé, Clive Landman, Mohammed Tayob; Spain: Assumpta Caixas,

6

Leonardo Reinares García, Arturo Fernandez-Cruz, Blas Gil-Extremera,

Ovidio Muñiz Grijalvo, Nuria Plana, Francisco Fuentes, Pedro Valdivielso,

Belen Fraile; Sweden: Bertil Borgencrantz, Hans Larnefeldt, Bengt-Olov Tengmark,

Mats Eriksson, Åke Olsson-Önerud; Ukraine: Wiliams Amalyan, Olexander Dyadyk,

Olena Koval, Mykola Kushnir, Anatoliy Svintsitskiy, Olexander Kovalyov,

Oleksandr Bondarchuk, Viktor Tashchuk, Olga Barna, Oleksandr Prokhorov,

Oleksandr Karpenko United Kingdom: Daniela Stanciu, Ravi Pawa,

Hiremagalur Balaji, Frank Doig, Peter Harvey, Lakshminarayan Ranganath,

Wojciech Massalski, Hana Hassanin, Helen Timmis, Irina Pavel-Knox,

Essam Abdulhakim, Babatunde Oyesile, Veronika Horvathova, Hugh Donnachie,

Venkata Kondagunta, Hilary Shaw, Hawys Thomas, Honer Kadr, Anthony Gunstone,

Gregory Lip, Adam Ellery, Jerome Kerrane, Anita Sarker, Yuk­ki Wong,

Handrean Soran; United States: Kelli Maw, James Andersen, Loray Blair-Britt,

Cynthia Huffman, Alan Kivitz, Richard Marple, Andres Patron, Martin Schear,

Nancy Allegar, Vivek Awasty, Rene Casanova, Louis Chaykin, Lisa Cohen,

Harry Collins, Gregory Collins, Gary Elkin, Hubert Reyes, Lawrence Feld,

Gene Fuller, Richard Glover, James Greenwald, John Herrod, William Kaye,

Murray Kimmel, Elias Kolettis, Gregory Lakin, Daniel Lorch, Mikhail Palatnik,

Rajesh Patel, Alan Reichman, Jane Rohlf, Gerald Shockey, Kenneth Shore,

David Radin, Odilon Alvarado, Bridget Bellingar, Richard Egelhof, Thomas McKnight,

Sanford Plevin, James Pritchard, Rajneesh Reddy, Francisco Velazquez,

Eric Bolster, Robert Broker, David Butuk, Deanna Cheung, Kenneth Cohen,

Gordon Golden, Alexander Murray, Teran Naccarato, Kari Uusinarkaus,

Krishna Pudi, Alan Graff, Vicki Blumberg, Fredrick Dunn, Phillip Toth,

7

Royal Anspach, Rita Chuang, James Meli, Brooke Nevins, Jeffrey Wayne,

Leah Schmidt, Dale Levinsky, John Rubino, Neal Shealy, Diego Torres,

James West, Rajeev Jain, Gil Vardi, Narendra Singh, Stephen Thew, Eric Lo,

John Heitner, Jamie Gerber, Amir Malik, Debra Weinstein, Rakesh Prashad,

Michael Koren, Arnold Ghitis, William David, Gregg Reis, George Kinzfogl,

Herbert Haught, Louis Kantaros, Daniel O'Dea, Daniel Weiss, Safwan Kassas,

John Hunter, Michael Mollod, Nasser Khan, David Henderson, Lionel Gatien,

Rashmi Schramm, Robert Madder, Mahfouz El Shahawy, Stephen Voyce,

Venkatesh Nadar, Mark Stich, Mariananda Kumar, Robert Black, Charles Treasure,

Mark Lebeis, Peter McCullough, Norman Lepor, Patrick Moriarty, Andrew Waxler,

Deepak Talreja, Michael Gen, Suhail Dohad, Cara East, Gary Conrad, Brian Asbill,

Johnathan Roberts, Jennifer Robinson, Stuart Zarich, Brent Davis, Merrill Krolick,

Howard Sherman, Paul Thompson.

Steering Committee

Chairman: Henry Ginsberg, MD (Irving Institute for Clinical and Translational

Research, Columbia University New York, NY, USA). Members: Jennifer G.

Robinson, MD, MPH (The University of Iowa, Iowa City, IA, USA); Daniel J. Rader,

MD (Institute for Translational Medicine and Therapeutics, University of

Pennsylvania School of Medicine Philadelphia, PA, USA); Christopher P. Cannon,

MD (Harvard Clinical Research Institute, Boston, MA, USA); Helen Colhoun, MD,

MFPHM (Clinical Centre, University of Dundee, Ninewells Hospital & Medical

School, Dundee, UK); John J.P. Kastelein, MD (Academic Medical Center University

of Amsterdam, Amsterdam, The Netherlands); Michel Farnier, MD (Le Point Médical,

Département d’Endocrinologie et de Lipidologie, Dijon, France).

8

Data Monitoring Committee

DMC Chairman: Anders Olsson, MD (Bromma, Sweden). Members: David Waters,

MD (Division of Cardiology, San Francisco General Hospital, San Francisco, CA,

USA); Dominique Larrey, MD (Hôpital Saint-Eloi Service d'hépato-gastro-entérologie,

Montpellier, France); Robert S. Rosenson, MD (Director, Cardiometabolic Disorders,

Mount Sinai Heart; Professor of Medicine, Mount Sinai School of Medicine, New

York, NY, USA); Peter A. Patriarca, MD (Biologics Consulting Group, Inc.,

Alexandria, VA, USA); Geert Molenberghs, Biostatistician (Center for Statistics

(CenStat) Universiteit HasseltAgoralaan 1, Diepenbeek, Belgium).

Clinical Events Committee (Reviewers), Duke Clinical Research Institute, Durham,

NC, USA; Pierluigi Tricoci, CEC Principal Investigator, Cardiology; Kenneth W.

Mahaffey, CEC Director, Cardiology; Renato D. Lopes, Cardiology; Bimal R. Shah,

Cardiology; Rajendra H. Mehta, Cardiology; Matthew T. Roe, Cardiology; Zubin

Eapen, Cardiology; Luciana Armaganijan, Cardiology; Adriana Bertolami,

Cardiology; Sergio Leonardi, Cardiology; Bradley J. Kolls, Neurology; J. Dedrick

Jordan, Neurology; Grégory Ducrocq, Cardiology; Etienne Puymirat, Cardiology;

Robin Mathews, Cardiology.

9

Independent Physicians

Independent physicians monitoring two consecutive LDL< 0.65 mmol/L: Karen

Alexander, and Chiara Melloni (Duke Clinical Research Institute, Durham, NC USA).

10

Supplemental Methods

Inclusion Criteria

Patients meeting all of the following criteria will be considered for enrollment into the

study:

I 01. Patients with heterozygous familial hypercholesterolemia (HeFH)* with or

without established coronary heart disease (CHD) or CHD risk equivalents who are

not adequately controlled with a maximally tolerated stable daily dose of statin** for

at least 4 weeks prior to the screening visit (Week -3) with or without other lipid

lowering therapy (LLT);

OR

I 02. Patients with hypercholesterolemia and established CHD or CHD risk

equivalents (see below for definitions) who are not adequately controlled with a

maximally tolerated stable daily dose of statin** for at least 4 weeks prior to the

screening visit (Week -3) with or without LLT.

I 03. Signed written informed consent.

*Diagnosis of HeFH must be made either by genotyping or by clinical criteria. For

those patients not genotyped, the clinical diagnosis may be based on either the

World Health Organisation/Dutch Lipid Clinical Network criteria with a score > 8

points or the Simon Broome register diagnostic criteria with a criterion for definite

FH.

** Definition of maximally tolerated dose (any of the following are acceptable):

11

- Rosuvastatin 20 mg or 40 mg daily

- Atorvastatin 40 mg or 80 mg daily

- Simvastatin 80 mg daily (if already on this dose for >1 year)

- Patients not able to be on any of the above statin doses, should be treated with the

dose of daily atorvastatin, rosuvastatin or simvastatin which is considered

appropriate for the patient as per the investigator's judgment or concerns. Some

examples of acceptable reasons for a patient taking a lower statin dose include, but

are not limited to: adverse effects on higher doses, advanced age, low body mass

index, regional practices, local prescribing information, concomitant medications, co-

morbid conditions such as impaired glucose tolerance/impaired fasting glucose.

A) Documented history of CHD (includes one or more of the following):

i) Acute myocardial infarction (MI).

ii) Silent MI.

iii) Unstable angina.

iv) Coronary revascularization procedure (eg, percutaneous coronary intervention

[PCI] or coronary artery bypass graft surgery [CABG]).

v) Clinically significant CHD diagnosed by invasive or non-invasive testing (such as

coronary angiography, stress test using treadmill, stress echocardiography or

nuclear imaging).

B) CHD risk equivalents (includes one or more of the following 4 criteria):

12

i) Documented peripheral arterial disease (one of the following criteria [a, b, or c]

must be satisfied):

a) Current intermittent claudication (muscle discomfort in the lower limb that is both

reproducible and produced by exercise and relieved by rest within 10 minutes) of

presumed atherosclerotic origin TOGETHER WITH ankle-brachial index ≤ 0.90 in

either leg at rest, OR

b) History of intermittent claudication (muscle discomfort in the lower limb that is both

reproducible and produced by exercise and relieved by rest within 10 minutes)

TOGETHER WITH endovascular procedure or surgical intervention in one or both

legs because of atherosclerotic disease OR

c) History of critical limb ischemia TOGETHER WITH thrombolysis, endovascular

procedure or surgical intervention in one or both legs because of atherosclerotic

disease.

ii) Documented previous ischemic stroke with a focal ischemic neurological deficit

that persisted more than 24 hours, considered as being of atherothrombotic origin.

CT or MRI must have been performed to rule out hemorrhage and non-ischemic

neurological disease.

iii) Documented moderate chronic kidney disease as defined by estimated

glomerular flow rate (eGFR) <60 mL per min per 1.73 m2 for 3 months or more,

including the screening visit

iv) Known history of diabetes mellitus AND 2 or more additional risk factors (as listed

below):

13

a) History of hypertension (established on antihypertensive medication)

b) Documented history of ankle-brachial index ≤0.90

c) Documented history of microalbuminuria or macroalbuminuria OR dipstick

urinalysis at screening visit (Week -3) with >2+ protein.

d) Documented history of pre–proliferative or proliferative retinopathy or laser

treatment for retinopathy

e) Known family history of premature CHD (CHD in father or brother before 55 years

of age; CHD in mother or sister before 65 years of age).

Exclusion Criteria

Patients who have met all the above inclusion criteria will be screened for the

following exclusion criteria which are sorted and numbered in the following three

sub-sections:

Exclusion criteria related to study methodology

E 01. Without established history of CHD or CHD risk equivalents or without a

diagnosis of HeFH based on genotyping or clinical criteria.

E 02. LDL cholesterol <70 mg per deciliter (<1.81 mmol per liter) at the screening

visit (Week -3).

E 03. Not on a stable dose of LLT (including statin) for at least 4 weeks and/or

fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (Week -3)

and from screening to randomization.

14

E 04. Currently taking a statin that is not simvastatin, atorvastatin, or rosuvastatin.

E 05. Simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a

registered dose.

E 06. Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40

mg (except for patients on simvastatin 80 mg for more than one year, who are

eligible).

E 07. Use of fibrates other than fenofibrate within 6 weeks prior to screening visit

(Week -3) or between screening and randomization visits.

E 08. Use of nutraceutical products or over-the-counter therapies that may affect

lipids which have not been at a stable dose for at least 4 weeks prior to the

screening visit (Week -3) or between screening and randomization visits.

E 09. Use of red yeast rice products within 4 weeks of the screening visit (Week-3)

or between screening and randomization visits.

E 10. Patient who has received plasmapheresis treatment within 2 months prior to

the screening visit (Week -3), or has plans to receive it.

E 11. Recent (within 3 months prior to the screening visit [Week -3] or between

screening and randomization visits) MI, unstable angina leading to hospitalization,

uncontrolled cardiac arrhythmia, CABG, PCI, carotid surgery or stenting,

cerebrovascular accident, transient ischemic attack, endovascular procedure or

surgical intervention for peripheral vascular disease.

15

E 12. Planned to undergo scheduled PCI, CABG, carotid or peripheral

revascularization during the study.

E 13. History of New York Heart Association Class III or IV heart failure within the

past 12 months.

E 14. Systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg at

screening visit or randomization visit.

E 15. Known history of hemorrhagic stroke.

E 16. Age < 18 years or legal age of majority at the screening visit (Week -3),

whichever is greater.

E 17. Known history of active optic nerve disease.

E 18. Patients not previously instructed on a cholesterol-lowering diet prior to the

screening visit (Week -3).

E 19. Known history of homozygous FH

E 20. Known history of loss of function of PCSK9 (ie, genetic mutation or sequence

variation).

E 21. Use of systemic corticosteroids, unless used as replacement therapy for

pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to

randomization. Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid

therapies are not considered as “systemic” and are allowed.

16

E 22. Use of continuous hormone replacement therapy unless the regimen has been

stable in the past 6 weeks prior to the Screening visit (Week-3) and no plans to

change the regimen during the study.

E 23. History of cancer within the past 5 years, except for adequately treated basal

cell skin cancer, squamous cell skin cancer, or in situ cervical cancer.

E 24. Known history of HIV positivity.

E 25. Conditions/situations such as:

A) Any clinically significant abnormality identified at the time of screening that in the

judgment of the Investigator or any sub-Investigator would preclude safe completion

of the study or constrain endpoints assessment such as major systemic diseases,

patients with short life expectancy.

B) Patients considered by the Investigator or any sub-Investigator as inappropriate

for this study for any reason, e.g.:

i) Those deemed unable to meet specific protocol requirements, such as scheduled

visits.

ii) Those deemed unable to administer or tolerate long-term injections as per the

patient or the investigator.

iii) Investigator or any sub-Investigator, pharmacist, study coordinator, other study

staff or relative thereof directly involved in the conduct of the protocol, etc.

17

iv) Presence of any other conditions (eg, geographic, social….) actual or anticipated,

that the Investigator feels would restrict or limit the patient’s participation for the

duration of the study.

E 26. Patient who has been previously treated with at least one dose of alirocumab

or any other anti-PCSK9 monoclonal antibody in other clinical trials.

E 27. Patient who has taken any investigational drugs other than alirocumab training

placebo kits within 1 month or 5 half-lives, whichever is longer.

E 28. Patient who withdraws consent during the screening period (patient who is not

willing to continue or fails to return).

E 29. Laboratory findings during the screening period (not including randomization

labs):

A) Positive test for Hepatitis B surface antigen and/or Hepatitis C antibody

(confirmed by reflexive testing).

B) Triglycerides (TG) >400 mg per deciliter (>4.52 mmol per liter) (1 repeat lab is

allowed).

C) Positive serum or urine pregnancy test in women of childbearing potential.

D) eGFR <30 mL per min per 1.73 m2 according to 4-variable Modification of Diet in

Renal Disease equation.

E) HbA1c >10%.

F) ALT or AST >3 x ULN (1 repeat lab is allowed).

18

G) CPK >3 x ULN (1 repeat lab is allowed).

Exclusion criteria related to the active comparator and/or mandatory background

therapies:

E 30. All contraindications to the background therapies or warning/precaution of use

(when appropriate) as displayed in the respective National Product Labeling.

Exclusion criteria related to the current knowledge of alirocumab

E 31. Known hypersensitivity to monoclonal antibody therapeutics.

E 32. Pregnant or breast-feeding women.

E 33. Women of childbearing potential not protected by highly-effective method(s) of

birth control (as defined in the informed consent form and/or in a local protocol

addendum) and/or who are unwilling or unable to be tested for pregnancy.

Note: Women of childbearing potential must have a confirmed negative serum

pregnancy test at screening and urine pregnancy test at randomization visit. They

must use effective contraceptive methods throughout the study and agree to repeat

urine pregnancy test at designated visits. The applied methods of contraception have

to meet the criteria for a highly effective method of birth control according to the

“Note for guidance on non-clinical safety studies for the conduct of human clinical

trials for pharmaceuticals (CPMP/ICH/286/95)”

(http://www.ema.europa.eu/pdfs/human/ich/028695en.pdf.). Postmenopausal women

must be amenorrheic for at least 12 months.

19

Randomization

The randomized list of treatment kit numbers was computer generated by Sanofi and

provided to a central allocation system. Study patients, investigators and study site

personnel remained blinded to treatment allocation until after completion of the trial.

Randomization was stratified according to: (1) heterozygous familial

hypercholesterolemia (HeFH) status, (2) prior history of myocardial infarction (MI) or

ischemic stroke, (3) background statin treatment (atorvastatin 40-80 mg per day or

rosuvastatin 20-40 mg per day vs. simvastatin whatever the daily dose, atorvastatin

<40 mg per day or rosuvastatin <20 mg per day), and (4) geographic region.

Active drug and placebo were identically packaged to protect the blind. Injections

could be performed at home by the patient or a designated caregiver. Training for

the person performing the injection was provided during screening.

Extent of Study Drug Exposure

Total exposure was assessed by (1) duration of study drug exposure in weeks,

defined as: (last double-blind injection date +14 day, minus first double-blind injection

date)/7, regardless of unplanned intermittent discontinuations, and (2) the total

number of injections by patient.

Adherence to Study Treatment

The overall adherence (mean and median) for injections is defined for each patient

as: 100 – (% days with under-planned dosing + % days with above-planned dosing).

Under-planned and above-planned dosing is defined by considering that injections

should be performed every 2 weeks (±3 days as per protocol).

20

Laboratory Assessments

Blood samples were obtained after a 10-hour overnight fast (water only). Analysis of

the lipid samples and clinical laboratory safety tests were performed by a central

laboratory (Covance Central Laboratory, Indianapolis, IN, USA, and Geneva,

Switzerland). Total cholesterol, triglycerides, and HDL cholesterol levels in serum

were determined using Centers for Disease Control and Prevention National Heart

Lung Blood Institute Lipid Standardization Program assays. LDL cholesterol was

calculated using the Friedewald formula at all sampling points. LDL cholesterol was

also measured via ultracentrifugation and precipitation (beta-quantification) by the

central laboratory at weeks 0, 12, 24, 52, and 78, and in cases where triglyceride

values were >400 mg per deciliter (4.52 mmol per liter). Apolipoprotein B,

apolipoprotein A1, and lipoprotein(a) levels in serum were determined using

immunonephelometry. Total and free PCSK9 concentrations in serum were

quantified with validated enzyme-linked immunosorbent assay method (Regeneron

Pharmaceuticals Inc., Tarrytown, NY, USA). Investigators remained blind to

laboratory data (except clinical safety tests) throughout the study.

Additional Statistical Analyses and Secondary Efficacy Endpoints

An on-treatment analysis was also performed as a secondary endpoint, including

only LDL cholesterol measurements taken while the patient was receiving study

treatment. A sensitivity analysis based on a pattern mixture model was also

conducted to evaluate the impact of missing data on the primary endpoint; in this

approach, missing calculated LDL cholesterol values during the on-treatment period

21

were multiply imputed using a model assuming “missing at random”; missing

calculated LDL cholesterol values during the post-treatment period were multiply

imputed using random draws from a normal distribution where the mean was equal

to subject’s own baseline value.

Secondary endpoints were tested in a hierarchical order as shown below:

• The percent change in calculated low-density lipoprotein cholesterol (LDL

cholesterol) from baseline to Week 24 in the modified intent-to-treat (mITT)

population, using all LDL cholesterol values at sampling points during the efficacy

treatment period (on-treatment).

• The percent change in calculated LDL cholesterol from baseline to Week 12 (ITT).

• The percent change in calculated LDL cholesterol from baseline to Week 12 (on-

treatment).

• The percent change in measured LDL cholesterol from baseline to Week 24 (ITT).

• The percent change in apolipoprotein B from baseline to Week 24 (ITT).

• The percent change in apolipoprotein B from baseline to Week 24 (on-treatment).

• The percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from

baseline to Week 24 (ITT).

• The percent change in non-HDL-C from baseline to Week 24 (on-treatment).

• The percent change in total-C from baseline to Week 24 (ITT).

22

The percent change in Apo B from baseline to Week 12 (ITT).

• The percent change in non-HDL-C from baseline to Week 12 (ITT).

• The percent change in total-C from baseline to Week 12 (ITT).

• The proportion of very high CV risk patients reaching calculated LDL cholesterol

<70 mg per deciliter (1.81 mmol per liter) or high CV risk patients reaching calculated

LDL cholesterol < 100 mg per deciliter (2.59 mmol per liter) at Week 24 (ITT)

• The proportion of very high CV risk patients reaching calculated LDL cholesterol <

70 mg per deciliter (1.81 mmol per liter) or high CV risk patients reaching calculated

LDL cholesterol < 100 mg per deciliter (2.59 mmol per liter) at Week 24 (on-

treatment).

• The proportion of patients reaching calculated LDL cholesterol < 70 mg per deciliter

(1.81 mmol per liter) at Week 24 (ITT).

• The proportion of patients reaching calculated LDL cholesterol < 70 mg per deciliter

(1.81 mmol per liter) at Week 24 (on-treatment).

• The percent change in lipoprotein (a) [Lp(a)] from baseline to Week 24(ITT).

• The percent change in HDL-C from baseline to Week 24(ITT).

• The percent change in fasting TG from baseline to Week 24 (ITT).

• The percent change in apolipoprotein A1 from baseline to Week 24 (ITT).

• The percent change in Lp (a) from baseline to Week 12 (ITT).

23

• The percent change in HDL-C from baseline to Week 12 (ITT).

• The percent change in fasting triglycerides from baseline to Week 12 (ITT).

• The percent change in apolipoprotein A-1 from baseline to Week 12 (ITT).

* CV risk categories are defined for the study as high risk and very high risk as

follows:

• Very high CV risk patients are defined as patients with HeFH with CHD or CHD risk

equivalents or non-FH.

• High CV risk patients are defined as HeFH patients without CHD or CHD risk

equivalents.

The other secondary efficacy endpoints (data not reported for all) are:

• The percent change in calculated LDL cholesterol from baseline to Weeks 52 and

78 (ITT).

• The proportion of very high CV risk patients reaching calculated LDL cholesterol <

70 mg per deciliter (1.81mmol per liter) or high CV risk patients reaching calculated

LDL cholesterol < 100 mg per deciliter (2.59 mmol per liter) at Weeks 12, 52, and 78

(ITT).

• The proportion of patients reaching calculated LDL cholesterol < 100 mg per

deciliter (2.59 mmol per liter) at Weeks 12, 24, 52, and 78 (ITT).

• The proportion of patients reaching calculated LDL cholesterol < 70 mg per deciliter

(1.81 mmol per liter) at Weeks 12, 52, and 78 (ITT).

24

• The absolute change in calculated LDL cholesterol (mg per deciliter and mmol per

liter) from baseline to Weeks 12, 24, 52, and 78 (ITT).

• The percent change in measured LDL cholesterol from baseline to Weeks 12, 52,

and 78 (ITT).

• The percent change in apolipoprotein B, non-HDL-C, total cholesterol, Lp(a), HDL-

C, fasting triglycerides, and apolipoprotein A1 from baseline to Weeks 52 and 78

(ITT).

• The absolute change in ratio apolipoprotein B/apolipoprotein A1 from baseline to

Weeks 12, 24, 52, and 78 (ITT).

• The proportion of patients with apolipoprotein B < 80 mg per deciliter (0.8 g/L) at

Weeks 12, 24, 52, and 78 (ITT).

• The proportion of patients with non-HDL-C < 100 mg per deciliter (2.59 mmol per

liter) at Weeks 12, 24, 52, and 78 (ITT).

• The proportion of patients with non-HDL-C < 130 mg per deciliter (3.37 mmol per

liter) at Weeks 12, 24, 52, and 78 (ITT).

• The proportion of very high CV risk patients with calculated LDL cholesterol < 70

mg per deciliter (1.81 mmol per liter) and/or ≥ 50% reduction from baseline in

calculated LDL cholesterol (if calculated LDL cholesterol ≥ 70 mg per deciliter [1.81

mmol per liter]) at Weeks 12, 24, 52, and 78 (ITT).

• The proportion of patients with ≥ 50% reduction from baseline in calculated LDL

cholesterol at Weeks 12, 24, 52, and 78 (ITT).

25

• The absolute change in ratio total cholesterol/HDL-C from baseline to Weeks 12,

24, 52, and 78 (ITT).

• The percent change in total cholesterol from baseline to Week 12 and Week 24

(on-treatment).

• The percent change in apolipoprotein B from baseline to Week 12 (on-treatment).

• The percent change in non-HDL-C from baseline to Week 12 (on-treatment).

• The percent change in Lp(a) from baseline to Week 12 and Week 24 (on-

treatment).

• The proportion of patients reaching calculated LDL cholesterol < 100 mg per

deciliter (2.59 mmol per liter) at Week 24 (on-treatment).

Monitoring and Laboratory Alert Related to Two Consecutive Calculated LDL

cholesterol <25 mg per deciliter (0.65 mmol per liter)

Patients who achieve two consecutive calculated LDL cholesterol values <25 mg per

deciliter (0.65 mmol per liter) during the study were monitored by a dedicated data

monitoring committee (DMC) member and independent physician. At the discretion

of the DMC member following consultation with the independent physician, an alert

was sent to the site (sham alerts also used to preserve the blind), so the investigator

would call the patient about occurrences of adverse events and decide whether the

patient should be requested to rapidly have an unscheduled site visit, or assessment

could be done at the next scheduled visit. At the site visit, the investigator had to

assess whether the patient needed additional work-up, should see a specialist and

whether the study treatment should be temporarily or permanently discontinued.

26

Prespecified Definitions of Cardiovascular Events

Death

All deaths will be categorized as Cardiovascular, non-Cardiovascular or

Undetermined based on the definitions below. In addition, all deaths will also be

categorized as Coronary Heart Disease Death and further sub-typed based on the

specific Cardiovascular and non-Cardiovascular categories defined below.

Cardiovascular Death:

Cardiovascular Death is defined as death resulting from an acute myocardial

infarction, sudden cardiac death, death due to heart failure, death due to stroke,

death due to cardiovascular (CV) procedures, death due to CV hemorrhage, and

death due to other cardiovascular causes. Coronary Heart Disease Death is defined

as the subset of Cardiovascular deaths for which there is a clear relationship to

underlying coronary heart disease, including death secondary to acute MI, sudden

death, heart failure, complication of a coronary revascularization procedure

performed for symptoms, coronary disease progression, or new myocardial ischemia

where the cause of death is clearly related to the procedure, unobserved and

unexpected death, and other death that cannot definitely be attributed to a

nonvascular cause.

1. Death due to Acute Myocardial Infarction:

Death by any mechanism (arrhythmia, heart failure, low output) within 30 days after

a myocardial infarction (MI) related to the immediate consequences of the

myocardial infarction, such as progressive congestive heart failure (CHF),

27

inadequate cardiac output, or refractory arrhythmia. If these events occur after a

“break” (e.g., a CHF and arrhythmia free period of at least a week), they should be

designated by the immediate cause, even though the MI may have increased the risk

of that event (e.g., late arrhythmic death becomes more likely after an acute

myocardial infarction (AMI)). The acute myocardial infarction should be verified to the

extent possible by the diagnostic criteria outlined for acute myocardial infarction or

by autopsy findings showing recent myocardial infarction or recent coronary

thrombus. Sudden cardiac death, if accompanied by symptoms suggestive of

myocardial ischemia, new ST elevation, new LBBB, or evidence of fresh thrombus

by coronary angiography and/or at autopsy should be considered death resulting

from an acute myocardial infarction, even if death occurs before blood samples or

12-lead electrocardiogram (ECG) could be obtained, or at a time before the

appearance of cardiac biomarkers in the blood. Death resulting from a procedure to

treat a myocardial infarction percutaneous coronary intervention (PCI), coronary

artery bypass graft surgery (CABG), or to treat a complication resulting from

myocardial infarction, should also be considered death due to acute MI. Death

resulting from an elective coronary procedure to treat myocardial ischemia (i.e.,

chronic stable angina) or death due to a MI that occurs as a direct consequence of a

CV investigation/procedure/operation should be considered as a death due to a CV

procedure.

2. Sudden Cardiac Death:

Death that occurs unexpectedly, not following an acute AMI, and includes the

following deaths:

28

a. Death witnessed and occurring without new or worsening symptoms.

b. Death witnessed within 60 minutes of the onset of new or worsening

cardiac symptoms, unless documented (i.e. by ECG or other objective) to be

due to acute myocardial infarction.

c. Death witnessed and attributed to an identified arrhythmia (e.g., captured

on an electrocardiographic (ECG) recording, witnessed on a monitor, or

unwitnessed but found on implantable cardioverter-defibrillator review).

d. Death after unsuccessful resuscitation from cardiac arrest.

e. Death after successful resuscitation from cardiac arrest and without

identification of a non-cardiac etiology.

f. Unwitnessed death without other cause of death (information regarding the

patient’s clinical status preceding death should be provided, if available).

General Considerations

A subject seen alive and clinically stable 24 hours prior to being found dead without

any evidence or information of a specific cause of death should be classified as

“sudden cardiac death.”

Typical scenarios include:

Subject well the previous day but found dead in bed the next day

Subject found dead at home on the couch with the television on

29

Deaths for which there is no information beyond “Patient found dead at home” may

be classified as “death due to other cardiovascular causes”.

3. Death due to Heart Failure or Cardiogenic Shock:

Death due to Congestive Heart Failure refers to a death in association with clinically

worsening symptoms and/or signs of heart failure not following an acute MI. Deaths

due to heart failure can have various etiologies, including single or recurrent

myocardial infarctions, ischemic or non-ischemic cardiomyopathy, hypertension, or

valvular disease. Cardiogenic shock not occurring in the context of an acute

myocardial infarction or as the consequence of an arrhythmia occurring in the

absence of worsening heart failure is defined as systolic blood pressure (SBP) < 90

mm Hg for greater than 1 hour, not responsive to fluid resuscitation and/or heart rate

correction, and felt to be secondary to cardiac dysfunction and associated with at

least one of the following signs of hypoperfusion:

Cool, clammy skin or

Oliguria (urine output < 30 mL/hour) or

Altered sensorium or Cardiac index < 2.2 L/min/m²

Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90

mm Hg in less than 1 hour with positive inotropic or vasopressor agents alone

and/or with mechanical support.

30

4. Death due to Stroke refers to death after a stroke that is either a direct

consequence of the stroke or a complication of the stroke. Acute stroke should be

verified to the extent possible by the diagnostic criteria outlined for stroke.

5. Death due to Cardiovascular Procedures refers to death caused by the

immediate complications of a cardiac procedure and excludes death resulting from

procedures to treat an acute MI or the complications resulting from an acute MI.

6. Death due to Cardiovascular Hemorrhage refers to death related to

hemorrhage such as a non-stroke intracranial hemorrhage, non-procedural or non-

traumatic vascular rupture (e.g., aortic aneurysm), or hemorrhage causing cardiac

tamponade.

7. Death due to Other Cardiovascular Causes refers to a cardiovascular death not

included in the above categories (e.g., pulmonary embolism or peripheral arterial

disease).

Non-cardiovascular Death: Non-cardiovascular death is defined as any death that

is not thought to be due to a cardiovascular cause. The following categories may be

collected:

Non-Malignant Causes

Pulmonary

Renal

Gastrointestinal

31

Hepatobiliary

Pancreatic

Infection (includes sepsis)

Non-infectious (e.g., systemic inflammatory response syndrome (SIRS))

Hemorrhage*, excluding hemorrhagic strokes and bleeding in the setting of

coronary revascularization

Non-cardiovascular procedure or surgery

Accidental (e.g., physical accidents or drug overdose) or trauma

Suicide

Prescription Drug Error (e.g., prescribed drug overdose, use of inappropriate

drug, or drug-drug interaction)

Neurological process that is not a stroke or hemorrhage

*Examples: Death due to GI bleeding is not considered a CV death. Death due to

retroperitoneal hematoma following PCI is considered CV death. Death due to

intracerebral hemorrhage is considered CV death.

Malignant Causes

Death results directly from the cancer;

OR

32

Death results from a complication of the cancer (e.g. infection, complication of

surgery / chemotherapy / radiotherapy);

OR

Death results from withdrawal of other therapies because of concerns relating

to the poor prognosis associated with the cancer

Cancer deaths may arise from cancers that were present prior to randomization or

which developed subsequently should be further classified (worsening prior

malignancy; new malignancy).

Undetermined Cause of Death refers to a death not attributable to one of the above

categories of cardiovascular death or to a non-cardiovascular cause, due to absence

of any information (e.g., the only available information is “patient died”). The use of

this category of death is discouraged and should apply to a minimal number of cases

when no information at all on the circumstances of death are available (i.e. found on

obituary of local newspaper). In all circumstances the reviewer will use all available

information to attribute to one of the categories based on best clinical judgment.

MYOCARDIAL INFARCTION (MI)

Acute Myocardial Infarction - The term acute myocardial infarction (MI) refers to

evidence of myocardial necrosis in a clinical setting consistent with acute myocardial

ischemia. Under these conditions any one of the following criteria meets the

diagnosis for MI:

33

1. Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac

troponin (cTn)] with at least one value above the upper reference limit (URL) and

with at least one of the following:

Symptoms of ischemia.

New or presumed new significant ST-segment–T wave (ST–T) changes or new

left bundle branch block (LBBB). Development of pathological Q waves in the

ECG.

Imaging evidence of new loss of viable myocardium or new regional wall motion

abnormality.

Identification of an intracoronary thrombus by angiography or autopsy.

2. Cardiac death with symptoms suggestive of myocardial ischaemia and

presumed new ischaemic ECG changes or new LBBB, but death occurred before

cardiac biomarkers were obtained, or before cardiac biomarker values would be

increased.

3. Percutaneous coronary intervention (PCI) related MI is defined by elevation of

cTn values (>5 x URL) occurring within 48h of the procedure in patients with

normal baseline values (≤URL) or a rise of cTn values >20% if the baseline values

are elevated and are stable or falling. In addition, at least one of the following is

required

symptoms suggestive of myocardial ischaemia

new ischaemic ECG changes

34

angiographic findings consistent with a procedural complication

imaging demonstration of new loss of viable myocardium or new regional wall

motion abnormality

4. Stent thrombosis associated with MI when detected by coronary angiography or

autopsy in the setting of evidence of myocardial ischaemia and with a rise and/or

fall cardiac biomarker values with at least one value above the Upper Reference

Limit (URL).

5. Coronary artery bypass grafting (CABG) related MI is defined by elevation of

troponin values (>10 x URL) occurring within 48h of the procedure in patients with

normal baseline cTn values (≤URL). In addition at least one of the following is

required

new pathological Q waves or new LBBB

angiographic documented new graft or new native coronary artery occlusion

imaging evidence of new loss of viable myocardium or new regional wall motion

abnormality.

Cardiac troponin is the preferred biomarker for diagnosis of MI. In absence of

troponin, CK-MB will be used.

Silent Myocardial Infarction

Asymptomatic patients who develop new pathologic Q wave criteria for MI detected

during routine ECG follow-up, or reveal evidence of MI by cardiac imaging, that

35

cannot be directly attributed to a coronary revascularization procedure, are termed

‘silent MI”. Any one of the following criteria meets the diagnosis:

• Pathological Q waves with or without symptoms in the absence of non-ischemic

causes.

• Imaging evidence of a region of loss of viable myocardium that is thinned and fails

to contract, in the absence of a non-ischaemic cause.

• Pathological findings of a prior MI All MI events will be classified by Universal MI

definition subtypes as follows:

Type 1

Spontaneous myocardial infarction related to atherosclerotic plaque rupture,

ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus

in one or more of the coronary arteries leading to decreased myocardial blood

flow or distal platelet emboli with ensuing myocyte necrosis. The patient may

have underlying severe CAD but on occasion non-obstructive or no CAD

Type 2

In instances of myocardial injury with necrosis where a condition other than

CAD contributes to an imbalance between myocardial oxygen supply and/or

demand, e.g. coronary endothelial dysfunction, coronary artery spasm,

coronary embolism, tachy/brady-arrhythmias, anemia, respiratory failure,

hypotension, and hypertension with or without LVH.

Type 3

36

Cardiac death with symptoms suggestive of myocardial ischemia and

presumed new ischemic ECG changes or new LBBB, but death occurring

before blood samples could be obtained, before cardiac biomarker could rise,

or in rare cases cardiac biomarkers were not collected.

Type 4a

Myocardial infarction associated with PCI

Type 4b

Myocardial infarction associated with stent thrombosis

Type 4c

Myocardial infarction associated with restenosis (restenosis is the only

angiographic explanation)

Type 5

Myocardial infarction associated with CABG

All MI events will be sub-classified into STEMI vs. NSTEMI as follows:

STEMI

New ST elevation at the J point in two contiguous leads with the cut-points: ≥0.1

mV in all leads other than leads V2–V3 where the following cut points apply: ≥0.2

mV in men ≥40 years; ≥0.25 mV in men <40 years, or ≥0.15 mV in women

If ECG does not meet STEMI criteria will be classified as NSTEMI

37

If ECGs are unavailable or uninterpretable the MI will be classified as unknown

All MI events will be sub-classified into Q wave vs. Non Q wave MI as follows:

Criteria for abnormal Q-waves are any one of:

Any Q wave in leadsV2–V3 ≥0.02 sec or QS complex in leadsV2 andV3.

Q wave ≥0.03 sec and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF or

V4–V6 in any two leads of a contiguous lead grouping (I, aVL; V1–V6; II, III, aVF).

a. The same criteria are used for supplemental leads V7-V9.

R wave ≥0.04 sec in V1–V2 and R/S ≥1 with a concordant positive T wave in

absence of conduction defect

If Q-waves criteria are not met, MI is classified as non-Q-wave MI

If ECGs are unavailable or uninterpretable the MI will be classified as unknown

Unstable angina (UA) Requiring Hospitalization

A diagnosis of an unstable angina (new ACS event without elevation in cardiac

biomarkers) that meets the primary endpoint requires the following:

• Admission to hospital or emergency room (until at least next calendar day) with

symptoms presumed to be caused by myocardial ischemia with an accelerating

tempo in the prior 48 hrs and/or prolonged (at least 20 min) rest chest discomfort

AND

38

• New high-risk ECG findings consistent with ischemia (or presumed new if no prior

ECG available), as defined below:

a) New or presumed new ST depression >0.5mm in 2 contiguous leads or T wave

inversion >1mm in leads with prominent R wave or R/S >1 in 2 contiguous leads.

b) New or presumed new ST elevation at the J point in > 2 contiguous leads >0.2mV

in V2 or V3 in men or >0.15 mV in women in V2 or V3 or >0.1mV in other leads.

c) LBBB (new or presumed new).

AND

• Definite contemporary* evidence of angiographically significant coronary disease

as demonstrated by:

- Need for coronary revascularization procedure (PCI or CABG) excluding those

performed to treat only restenosis lesion(s) at previous PCI site(s)

OR

- Angiographic evidence of at least one significant (> 70%) epicardial coronary

stenosis not due to restenosis at previous PCI site.

*The coronary revascularization procedure or the diagnostic angiography must have

been performed during the hospitalization for that event.

Stroke

39

Stroke is defined as an acute episode of focal or global neurological dysfunction

caused by central nervous system (CNS) vascular injury as a result of hemorrhage

or infarction. CNS includes brain, spinal cord and retina.

Classification:

1. Ischemic Stroke

Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal

dysfunction caused by CNS infarction. Evidence of infarction is defined as

A. Pathological, imaging, or other objective evidence of acute cerebral, spinal

cord, or retinal focal ischemic injury in a defined vascular distribution; or

B. In absence of the above (i.e. imaging or autopsy unavailable), clinical

evidence of cerebral, spinal cord, or retinal focal ischemic injury is based on

symptoms persisting ≥24 hours or until death, and other etiologies excluded.

C. Note, Hemorrhagic infarction, defined as a parenchymal hemorrhage after

CNS infarction, is considered an ischemic stroke.

D. Ischemic strokes may be further classified according to most likely etiology

(example large artery atherosclerosis, cardio-embolic, etc.)

2. Cerebral Hemorrhage

Hemorrhages in the CNS are classified as stroke if they are nontraumatic caused by

a vascular event, and result in injury to the CNS. In contrast, traumatic hemorrhages

will not be characterized as stroke. Subdural hematoma will not be classified as a

40

stroke. The diagnoses included in this section are intracerebral hemorrhage

(intraparenchymal and intraventricular) and subarachnoid hemorrhage (both

aneurysmal and nonaneurysmal).

A. Stroke caused by intracerebral hemorrhage

Rapidly developing clinical signs of neurological dysfunction (focal or global)

attributable to a focal collection of blood within the brain parenchyma or

ventricular system that is not caused by trauma.

B. Stroke caused by subarachnoid hemorrhage

Rapidly developing signs of neurological dysfunction (focal or global) and/or

headache because of bleeding into the subarachnoid space (the space

between the arachnoid membrane and the pia mater of the brain or spinal

cord), which is not caused by trauma.

C. Hemorrhages may be further classified according to location (example,

supratentorial, subtentorial etc.)

3. Stroke not otherwise specified

An episode of acute neurological dysfunction presumed to be caused by ischemia or

hemorrhage, persisting ≥24 hours or until death, but without sufficient evidence to be

classified as one of the above.

Congestive Heart failure (CHF) requiring hospitalization

A Congestive Heart Failure Event requiring hospitalization is defined as:

41

A. An event that meets ALL of the following criteria:

1. The patient is admitted to the hospital or emergency room (until at least the

next calendar day) with a primary diagnosis of CHF

2. The patient exhibits documented new or worsening symptoms due to CHF

on presentation, including at least ONE of the following:

a. Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal

nocturnal dyspnea)

b. Decreased exercise tolerance

c. Fatigue

d. Other symptoms of worsened end-organ perfusion or volume overload.

3. The patient has objective evidence of new or worsening CHF, consisting of

at least TWO physical examination findings OR one physical examination

finding and at least ONE laboratory/imaging/hemodynamic criterion),

including:

a. Physical examination findings considered to be due to heart failure,

including new or worsened:

i. Peripheral edema

ii. Increasing abdominal distention or ascites (in the absence of primary

hepatic disease)

42

iii. Pulmonary rales/crackles/crepitations

iv. Increased jugular venous pressure and/or hepatojugular reflux

v. S3 gallop

vi. Clinically significant or rapid weight gain thought to be related to fluid

retention

b. Laboratory, imaging or hemodynamic evidence of new or worsening CHF,

including:

i. Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP

(NTproBNP) concentrations consistent with decompensation of heart failure.

In patients with chronically elevated natriuretic peptides, a significant increase

should be noted above baseline.

ii. Radiological evidence of pulmonary congestion

iii. Hemodynamic evidence from right heart catheterization (e.g. elevated

pulmonary capillary wedge pressure, elevated central venous pressure, or low

cardiac index) or from left heart catheterization (elevated left ventricular end-

diastolic pressure)

5. The patient receives initiation or intensification of treatment specifically for

CHF, including at least ONE of the following:

a. Significant augmentation in oral diuretic therapy

43

b. Intravenous diuretic, inotrope, or vasodilator therapy

c. Mechanical or surgical intervention, including:

i. Mechanical circulatory support (e.g., intra-aortic balloon pump, ventricular

assist device)

ii. Mechanical fluid removal (e.g., ultrafiltration, hemofiltration, dialysis)

Ischemia-driven Coronary revascularization procedures

‘Coronary revascularization’ includes all coronary revascularization procedures

(PCI/CABG) performed during the study, and driven by new or presumed new

myocardial ischemia since randomization (categories 1 and 2 described below), and

excluding procedures performed only to treat restenosis lesion(s) at prior PCI

sites(s).

Reasons for the PCI/CABG will be collected in the CRF as follows:

(1) driven by acute ischemia (ACS)

(2) driven by new/progressive (i.e. not present at randomization or with

indication of progression since randomization), chronic (i.e. not in context of

ACS) ischemia, evidenced by new/progressive symptoms (angina or

equivalent) or new/progressive functional testing abnormalities (e.g. stress

test, imaging)

(3) other (i.e. not driven by ACS event, or new/progressive chronic ischemia).

44

PCI involves a catheter-based tool (e.g., balloon catheters, cutting balloons,

atherectomy devices, lasers, bare metal stents, and drug-eluting stents) that

improves myocardial blood flow by increasing the luminal area at a site of an

obstructive coronary lesion. Coronary artery bypass grafting (CABG) is an open

surgical procedure designed to improve myocardial blood flow by providing a conduit

(arterial, venous, or synthetic) for blood flow distal to an obstructive coronary lesion.

Insertion of a guidewire through a coronary guide catheter into a coronary vessel or

aortocoronary bypass graft for the purpose of percutaneous coronary intervention

(PCI) is considered as a PCI (since there is an intention to perform a PCI). However,

insertion of a guidewire in order to assess the severity of intermediate lesions with

the use of intravascular ultrasound, Doppler flow velocity, or fractional flow reserve,

will NOT be considered PCI.

Custom MedDRA Query “Diabetes”

The full list of preferred terms included in the Custom MedDRA Query “diabetes” is

as follows:

Blood glucose abnormal

Blood glucose false positive

Blood glucose increased

Carbohydrate tolerance decreased

Cataract diabetic

Diabetes complicating pregnancy

45

Diabetes mellitus

Diabetes mellitus inadequate control

Diabetes with hyperosmolarity

Diabetic amyotrophy

Diabetic arthropathy

Diabetic autonomic neuropathy

Diabetic blindness

Diabetic cardiomyopathy

Diabetic coma

Diabetic end stage renal disease

Diabetic eye disease

Diabetic gangrene

Diabetic gastropathy

Diabetic glaucoma

Diabetic hyperglycaemic coma

Diabetic hyperosmolar coma

Diabetic ketoacidosis

46

Diabetic ketoacidotic hyperglycaemic coma

Diabetic mononeuropathy

Diabetic neuropathic ulcer

Diabetic neuropathy

Diabetic retinal oedema

Diabetic retinopathy

Diabetic uveitis

Fructosamine decreased

Fructosamine increased

Galactose urine abnormal

Galactose urine decreased

Galactose urine increased

Gestational diabetes

Glucose tolerance decreased

Glucose tolerance increased

Glucose tolerance test abnormal

Glycolysis increased

47

Glycosylated haemoglobin decreased

Glycosylated haemoglobin increased

Hyperglycaemia

Increased insulin requirement

Insulin autoimmune syndrome

Insulin resistant diabetes

Intercapillary glomerulosclerosis

Microalbuminuria

Neonatal diabetes mellitus

Pancreatogenous diabetes

Renal papillary necrosis

Retinopathy proliferative

Urine glucose false positive

Blood glucose fluctuation

Diabetes mellitus malnutrition-related

Diabetic gastroparesis

Retinopathy haemorrhagic

48

Somogyi phenomenon

Decreased insulin requirement

Insulin-requiring type 2 diabetes mellitus

Congenital generalised lipodystrophy

Diabetic dermopathy

Diabetic microangiopathy

Retinal neovascularisation

Diabetic ulcer

Lactose tolerance test abnormal

Diabetic enteropathy

Diabetic gastroenteropathy

Necrobiosis lipoidica diabeticorum

Diabetic foetopathy

Diabetic mastopathy

Blood galactose abnormal

Blood galactose increased

Blood galactose decreased

49

Diabetic foot

Mauriac syndrome

Diabetic foot infection

Diabetic complication

Diabetic cystopathy

Diabetic vascular disorder

Diabetic nephropathy

Diabetic bullosis

Fructose decreased

Fructose increased

Diabetic macroangiopathy

Hyperglycaemic hyperosmolar nonketotic syndrome

Diabetic cheiropathy

Stool reducing substances increased

Carbohydrate tolerance increased

Blood 1,5-anhydroglucitol decreased

Cardiac autonomic neuropathy

50

Latent autoimmune diabetes in adults

Diabetic keratopathy

Diabetic encephalopathy

Diabetic ophthalmoplegia

Type 1 diabetes mellitus

Type 2 diabetes mellitus

Cystic fibrosis related diabetes

Emphysematous pyelonephritis

Diabetic dyslipidaemia

Diabetic end organ damage

Diabetic hepatopathy

Fulminant type 1 diabetes mellitus

Type 3 diabetes mellitus

Acute painful neuropathy of rapid glycaemic control

Acquired lipoatrophic diabetes

Small fibre neuropathy

Diabetic metabolic decompensation

51

Figure S1. Study Design

Abbreviations: CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-

density lipoprotein cholesterol; Q2W, every other week; SC, subcutaneous; W, week.

ClinicalTrials.gov identifier: NCT01507831

52

Figure S2. Percent Change in Calculated LDL Cholesterol from Baseline to

Week 24 According to HeFH status (A), and Baseline LDL Cholesterol

Subgroup (B) (ITT Analysis)

A

53

B

HeFH denotes heterozygous familial hypercholesterolemia, ITT intent-to-treat, LDL low-density

lipoprotein, LS, least-squares, SE standard error, Q2W every 2 weeks.

To convert values for cholesterol to mmol per liter, multiply by 0.02586.

54

Figure S3. Percent Change in Calculated LDL Cholesterol from Baseline to

Week 24 According Baseline PCSK9 Level (A), and Gender (B)

A

55

B

Abbreviations: LS, least squares; Q2W, every 2 weeks; SE, standard error.

For panel A, median total PCSK9 levels were 637 and 640 nanograms per milliliter in the alirocumab

and placebo groups, respectively, and median free PCSK9 levels were 290 and 284 nanograms per

milliliter, respectively.

56

Figure S4. The Difference in Percentage Change from Baseline to Week 24 in

LDL Cholesterol (Alirocumab vs. Placebo) According to Baseline Subgroup:

Demographics (A), Medical History and PCSK9 levels (B), Lipids (C), and Lipid

Medication (D) (ITT Population). Dotted line represents mean percent LDL

Cholesterol Reduction for All Patients

A

57

B

58

C

59

D

Abbreviations: BMI, body mass index; CKD, chronic kidney disease; CI, confidence interval; HeFH,

heterozygous familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; ITT, intent-

to-treat; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); LS, least squares; LLT, lipid-

lowering therapy; MI, myocardial infarction; SE, standard error, TGs, triglycerides.

In panel B, median total PCSK9 levels were 637 and 640 ng per mL in the alirocumab and placebo

groups, respectively, and median free PCSK9 levels were 290 and 284 ng per mL, respectively.

In panel C, equivalent values for LDL cholesterol subgroups are <2.59, 2.59 to <3.36, 3.36 to <4.14,

and ≥4.14 mmol per liter. HDL cholesterol value is equivalent to 1.034 mmol per liter. The TG value in

mmol per liter is 1.69.

In panel D, “High-intensity statin” was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg

daily.

60

Figure S5. Post hoc Analysis of a Subgroup of Adjudicated Major Adverse

Cardiovascular Events (ODYSSEY OUTCOMES endpoint). Kaplan-Meier

Estimates for Time to First Positively Adjudicated CV Event During the TEAE

Period (A) and Duration of Follow-Up for the Safety Population Included in the

Post hoc Analysis (B)

A

61

B

Duration of follow-up, wks Alirocumab 150 Q2W (N=1550) Placebo (N=788)

Mean (SD) 80.87 (17.33) 80.07 (18.47)

Median (Q1 : Q3) 86.14 (85.86 : 87.00) 86.14 (85.71 : 86.86)

Min : Max 2.4 : 117.9 2.0 : 101.7

Duration of follow-up by time interval, n (%)

< 24 wks 60 (3.9%) 38 (4.8%)

≥ 24 wks and < 52 wks 74 (4.8%) 40 (5.1%)

≥ 52 wks and < 78 wks 46 (3.0%) 19 (2.4%)

≥ 78 wks 1370 (88.4%) 691 (87.7%)

Abbreviations: CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; HR, hazard

ratio; LLT, lipid-lowering therapy, MACE, major adverse cardiac events; MI, myocardial infarction,

wks, Weeks.

Error bars on Panel A indicate 95% CIs.

This is a post hoc analysis not specified in the study protocol and which included the following CV

event categories which also form the endpoint for the ODYSSEY OUTCOMES study: CHD death,

Non-fatal MI, fatal and non-fatal ischemic stroke, and unstable angina requiring hospitalization.8

“Unstable angina requiring hospitalization” is limited to the unstable angina events with definite

evidence of progression of the ischemic condition (strict criteria). Congestive heart failure requiring

hospitalization and ischemia driven coronary revascularization procedure are not included in the post

hoc analysis. Rates of all adjudicated CV events are shown in Table 3. When these two types of

event are counted the number of patients with CV events is 4.6% (n=72) alirocumab vs 5.1% (n=40)

placebo; in this case, no statistically significant difference between groups was observed.

Patients were censored at the end of the treatment-emergent adverse event period (defined as the

time from first to last injection of study treatment + 70 days).

62

Table S1. Calculated LDL Cholesterol Availability Over Time - ITT population

Placebo

(N=780)

Alirocumab 150 Q2W

(N=1530)

Calculated LDL cholesterol, n (%)

On-treatment

value

Post-treatment

value Missing value

On-treatment value

Post-treatment

value Missing value

Week 4 752

(96.4%) 2 (0.3%) 26 (3.3%) 1470

(96.1%) 3 (0.2%) 57 (3.7%)

Week 8 745

(95.5%) 2 (0.3%) 33 (4.2%) 1447

(94.6%) 11 (0.7%) 72 (4.7%)

Week 12 737

(94.5%) 9 (1.2%) 34 (4.4%) 1416

(92.5%) 20 (1.3%) 94 (6.1%)

Week 16 702

(90.0%) 13 (1.7%) 65 (8.3%) 1378

(90.1%) 34 (2.2%) 118 (7.7%)

Week 24 688

(88.2%) 20 (2.6%) 72 (9.2%) 1347

(88.0%) 39 (2.5%) 144 (9.4%)

Week 36 666

(85.4%) 28 (3.6%) 86 (11.0%) 1315

(85.9%) 44 (2.9%) 171 (11.2%)

Week 52 643

(82.4%) 33 (4.2%) 104 (13.3%) 1285

(84.0%) 64 (4.2%) 181 (11.8%)

Week 64 630

(80.8%) 29 (3.7%) 121 (15.5%) 1239

(81.0%) 85 (5.6%) 206 (13.5%)

Week 78 573

(73.5%) 79 (10.1%) 128 (16.4%) 1070

(69.9%) 199 (13.0%) 261 (17.1%)

63

Table S2. Percent Change from Baseline in Measured LDL Cholesterol at Week

24 in the Intention-to-Treat Population*

Alirocumab (N = 1530)

Placebo (N = 780)

Alirocumab vs. placebo

Least-Squares

Mean Difference

95% CI P Value

No. patients with measured LDL cholesterol values available

1278 652

Baseline level – mg/dL

Mean±SD 117.0±38.9 115.3±37.3

Range 30–359 17–303

Absolute level at wk 24 – mg/dL 49.0±0.9 115.8±1.2

Percentage change from baseline to wk 24

–57.8±0.8 3.5±1.1 –61.3±1.4 –64.0

to –58.5 <0.001

*LDL cholesterol measured by beta-quantification. To convert cholesterol to mmol per liter, multiply by

0.02586. CI denotes confidence interval, LDL, low-density lipoprotein, SE, standard error.

64

Table S3. Selected Secondary Efficacy End Points in the On-Treatment

Analysis*

Alirocumab (N = 1523)

Placebo (N = 777)

Alirocumab vs. placebo

Least-Squares

Mean

Difference

95% CI P Value

Percentage change from baseline to wk 24 in calculated LDL cholesterol

–62.8±0.7 0.7±1.0 –63.5±1.2 –65.9

to –61.2 <0.001

Proportion (%) of patients reaching pre-specified calculated LDL cholesterol levels by w24†

<70 mg/dl in patients at very high risk or <100 mg/dl in patients at high risk

82.8 8.5 <0.001

<70 mg/dl regardless of risk 81.2 8.0 <0.001

Percentage change from baseline to wk 78 in calculated LDL cholesterol

–58.0±0.9 3.9±1.2 –61.8±1.5 –64.9 to –58.8 <0.001‡

Percentage change from baseline to wk 24 in secondary lipid variables

Non-HDL cholesterol –53.1±0.6 0.6±0.9 –53.7±1.0

–55.7 to –51.6

<0.001

Apolipoprotein B –54.3±0.7 1.2±0.9 –55.5±1.2 –57.7

to –53.2 <0.001

Total cholesterol –38.8±0.5 –0.4±0.6 –38.4±0.8

–39.9 to –36.9

<0.001

Lipoprotein(a)§ –30.2±0.7 –3.9±1.0 –26.3±1.3

–28.8 to –23.8

<0.001

Triglycerides§ –15.8±0.8 1.4±1.2 –17.2±1.4

–20.0 to –14.4

<0.001

65

HDL cholesterol 4.2±0.4 –0.7±0.5 4.9±0.7 3.6 to 6.1 <0.001

Apolipoprotein A1 4.2±0.4 1.2±0.6 2.9±0.7 1.6 to 4.3 <0.001

* Plus–minus values are least-squares means ±SE, unless otherwise indicated. Only patients who

were receiving study treatment and had an evaluable primary efficacy endpoint during the efficacy

period were included in the on-treatment analysis. Patients were defined as receiving study treatment

during the period from the first dose of study treatment up until 21 days after last dose. The primary

efficacy endpoint was defined as evaluable in a patient when a calculated LDL cholesterol value was

available at both baseline and during the efficacy treatment period within one of the analysis windows

up to Week 24. Least-squares means, SE and p-value taken from mixed-effect model with repeated

measures analysis (except for endpoints noted by footnote symbols below). The p-values are

significant according to the fixed hierarchical approach used to ensure control of the overall type-1

error rate at the 0.05 level. To convert cholesterol to mmol per liter, multiply by 0.02586. CI denotes

confidence interval, HDL, high-density lipoprotein, LDL, low-density lipoprotein, SE, standard error.

‡Multiple imputation followed by logistic regression: combined estimate for proportion of patients is

obtained by averaging out all the imputed proportions of patients reaching the level of interest.

‡P-value not adjusted for multiplicity and provided for descriptive purpose only.

§The percentage change in levels of lipoprotein(a) and triglycerides was analyzed with the use of

multiple imputation, followed by robust regression. A combined estimate for adjusted mean (±SE) is

shown.

66

Table S4. Percent Change From Baseline in Calculated LDL Cholesterol at

Week 24 (Pattern-Mixture Model)*

Alirocumab (N = 1532)

Placebo (N = 780)

Alirocumab vs. placebo

Least-Squares

Mean

Difference

95% CI P Value

Percentage change from baseline to wk 24 in calculated LDL cholesterol

–57.8±0.8 0.7±1.1 –58.5±1.3 –61.1

to –55.8 <0.001

*This sensitivity analysis has been conducted to further evaluate the impact of missing data on the

primary endpoint: in this approach, missing calculated LDL cholesterol values during the “on-

treatment” period were multiply imputed using a model assuming Missing At Random and missing

calculated LDL cholesterol values during the post-treatment period were multiply imputed using

random draws from a normal distribution, with mean equal to subject’s own baseline value. To convert

cholesterol to mmol per liter, multiply by 0.02586. CI denotes confidence interval, LDL, low-density

lipoprotein, SD, standard deviation, SE, standard error.

67

Table S5. Adverse Events Including Those Occurring in Alirocumab Patients

with 2 Consecutive Calculated LDL Cholesterol Values <25 mg per deciliter:

Safety Analysis*

Alirocumab (N = 1550)

Alirocumab with 2 consecutive

LDL cholesterol <25 mg/dL (N = 575)

Placebo (N = 788)

Summary of adverse events — no. of patients (%)

Any adverse event 1255 (81.0) 435 (75.7) 650 (82.5)

Serious adverse event 290 (18.7) 98 (17.0) 154 (19.5)

Adverse event leading to death 8 (0.5) 4 (0.7) 10 (1.3)

Adverse event leading to study-drug discontinuation 111 (7.2) 26 (4.5) 46 (5.8)

Adverse events by System Organ Class occurring in ≥2% of patients in any group — no. of patients (%)

Infections and infestations 748 (48.3) 243 (42.3) 383 (48.6)

Musculoskeletal and connective tissue disorders 467 (30.1) 150 (26.1) 242 (30.7)

Gastrointestinal disorders 318 (20.5) 96 (16.7) 162 (20.6)

Nervous system disorders 289 (18.6) 74 (12.9) 155 (19.7)

General disorders and administration site conditions 250 (16.1) 65 (11.3) 140 (17.8)

Injury, poisoning and procedural complications 241 (15.5) 76 (13.2) 124 (15.7)

Respiratory, thoracic and mediastinal disorders 182 (11.7) 51 (8.9) 99 (12.6)

Cardiac disorders 171 (11.0) 61 (10.6) 102 (12.9)

Metabolism and nutrition disorders 158 (10.2) 55 (9.6) 73 (9.3)

68

Skin and subcutaneous tissue disorders 156 (10.1) 48 (8.3) 74 (9.4)

Vascular disorders 133 (8.6) 31 (5.4) 79 (10.0)

Eye disorders 108 (7.0) 40 (7.0) 49 (6.2)

Psychiatric disorders 101 (6.5) 30 (5.2) 67 (8.5)

Investigations 99 (6.4) 25 (4.3) 43 (5.5)

Renal and urinary disorders 85 (5.5) 27 (4.7) 52 (6.6)

Reproductive system and breast disorders 50 (3.2) 16 (2.8) 27 (3.4)

Neoplasms, benign, malignant and unspecified (including cysts and polyps)

47 (3.0) 22 (3.8) 34 (4.3)

Blood and lymphatic disorders 46 (3.0) 14 (2.4) 29 (3.7)

Ear and labyrinth disorders 37 (2.4) 10 (1.7) 31 (3.9)

Hepatobiliary disorders 27 (1.7) 8 (1.4) 18 (2.3)

Adverse events by Preferred Term occurring in ≥2% of patients in any group - no. of patients (%)

Nasopharyngitis 209 (13.5) 63 (11.0) 103 (13.1)

Upper respiratory tract infection 115 (7.4) 35 (6.1) 68 (8.6)

Injection site reaction 91 (5.9) 22 (3.8) 33 (4.2)

Urinary tract infection 90 (5.8) 35 (6.1) 54 (6.9)

Diarrhea 90 (5.8) 28 (4.9) 45 (5.7)

Influenza 88 (5.7) 26 (4.5) 45 (5.7)

Back pain 85 (5.5) 35 (6.1) 53 (6.7)

Myalgia 84 (5.4) 18 (3.1) 23 (2.9)

Bronchitis 83 (5.4) 31 (5.4) 41 (5.2)

69

Arthralgia 82 (5.3) 22 (3.8) 52 (6.6)

Headache 77 (5.0) 11 (1.9) 45 (5.7)

Muscle spasms 61 (3.9) 19 (3.3) 27 (3.4)

Hypertension 60 (3.9) 13 (2.3) 33 (4.2)

Fall 54 (3.5) 14 (2.4) 37 (4.7)

Cough 52 (3.4) 15 (2.6) 16 (2.0)

Pain in extremity 51 (3.3) 14 (2.4) 36 (4.6)

Dizziness 50 (3.2) 11 (1.9) 32 (4.1)

Lower respiratory tract infection 48 (3.1) 18 (3.1) 27 (3.4)

Fatigue 46 (3.0) 16 (2.8) 32 (4.1)

Sinusitis 44 (2.8) 20 (3.5) 20 (2.5)

Osteoarthritis 41 (2.6) 14 (2.4) 27 (3.4)

Gastroenteritis 40 (2.6) 6 (1.0) 24 (3.0)

Non-cardiac chest pain 40 (2.6) 17 (3.0) 17 (2.2)

Nausea 39 (2.5) 6 (1.0) 24 (3.0)

Musculoskeletal pain 38 (2.5) 9 (1.6) 15 (1.9)

Contusion 37 (2.4) 8 (1.4) 7 (0.9)

Angina unstable† 35 (2.3) 9 (1.6) 9 (1.1)

Angina pectoris 34 (2.2) 12 (2.1) 23 (2.9)

Depression 34 (2.2) 10 (1.7) 26 (3.3)

Constipation 34 (2.2) 11 (1.9) 15 (1.9)

70

Pneumonia 27 (1.7) 7 (1.2) 16 (2.0)

Type 2 diabetes mellitus 27 (1.7) 14 (2.4) 11 (1.4)

Atrial fibrillation 27 (1.7) 12 (2.1) 20 (2.5)

Insomnia 25 (1.6) 7 (1.2) 16 (2.0)

Rhinitis 24 (1.5) 7 (1.2) 17 (2.2)

Influenza-like illness 23 (1.5) 3 (0.5) 16 (2.0)

Vertigo 19 (1.2) 5 (0.9) 16 (2.0)

Dyspnoea 13 (0.8) 3 (0.5) 16 (2.0)

* The “alirocumab” and “placebo” columns include adverse events that developed, worsened, or

became serious after the first injection and up to 10 weeks after the last injection. The “alirocumab

with 2 consecutive LDL cholesterol <25 mg/dL” column includes only those adverse events that

developed, worsened or became serious the day or after the first of the 2 consecutive LDL cholesterol

measurements of <25 mg per deciliter (<0.6 mmol per liter). Values were considered as consecutive if

spaced out by at least 21 days.

†Investigator-reported term and not adjudicated rates.

71

Table S6. Neurocognitive TEAEs: Safety Analysis

Alirocumab (N = 1550)

Alirocumab with 2 consecutive

LDL cholesterol <25 mg/dL (N = 575)

Placebo (N = 788)

Neurocognitive disorders - no. of patients (%)*

18 (1.2) 3 (0.5) 4 (0.5)

Amnesia 5 (0.3) 0 0

Memory impairment 4 (0.3) 0 1 (0.1)

Confusional state 4 (0.3) 1 (0.2) 1 (0.1)

Confusion postoperative 1 (<0.1) 0 0

Dementia 1 (<0.1) 1 (0.2) 1 (0.1)

Disorientation 1 (<0.1) 0 0

Disturbance in attention 1 (<0.1) 0 1 (0.1)

Frontotemporal dementia 1 (<0.1) 1 (0.2) 0

Reading disorder 1 (<0.1) 0 0

Transient global amnesia 1 (<0.1) 0 0

Vascular encephalopathy 1 (<0.1) 0 0

*Neurocognitive events were selected with the use of a custom MedDRA query that was based on the

following five High-Level Group Terms: “deliria (including confusion),” “cognitive and attention

disorders and disturbances,” “dementia and amnestic conditions,” “disturbances in thinking and

perception,” and “mental impairment disorders.” Occurrence of specific events which fall under the

category “neurocognitive events” are shown in the subsequent rows. The “alirocumab” and “placebo”

columns include those adverse events that developed, worsened, or became serious during after the

first injection and up to 10 weeks after the last injection. The “alirocumab with 2 consecutive LDL

cholesterol <25 mg/dL” column includes only those events that developed, worsened or became

serious the day or after the first of the 2 consecutive LDL cholesterol measurements of <25 mg per

72

deciliter (<0.6 mmol per liter). Values were considered as consecutive if spaced out by at least 21

days.

73

Table S7. Detailed Treatment-Emergent General Allergic Serious Adverse

Events and Neurologic Serious Adverse Events

Alirocumab

(N=1550)

Placebo

(N=788)

General allergic adverse events- no. of patients (%)*

Patients with CMQ

8 (0.5%) 3 (0.4%)

Asthma 3 (0.2%) 1 (0.1%)

Angioedema† 1 (<0.1%) 0

Dermatitis allergic 1 (<0.1%) 0

Drug hypersensitivity 1 (<0.1%) 0

Hypersensitivity 1 (<0.1%) 0

Hypersensitivity vasculitis† 1 (<0.1%) 0

Laryngeal oedema‡ 1 (<0.1%) 0

Rash‡ 1 (<0.1%) 0

Acute respiratory failure 0 1 (0.1%)

Cytokine release syndrome 0 1 (0.1%)

Neurologic adverse events- no. of patients (%)§

Patients with CMQ 5 (0.3%)

2 (0.3%)

Ataxia 1 (<0.1%) 0

Demyelination 1 (<0.1%) 0

Dysarthria 1 (<0.1%) 0

Miller Fisher Syndrome 1 (<0.1%) 0

Optic neuritis 1 (<0.1%) 0

Hypoaesthesia 0 2 (0.3%)

*General allergic adverse events were selected based on preferred terms with Standardized MedDRA

Queries: “hypersensitivity” (broad + narrow) excluding the following PTs (“infusion site dermatitis”,

“infusion site hypersensitivity”, “infusion site rash”, “infusion site urticaria”, “injection site dermatitis”,

“injection site hypersensitivity”, “injection site rash”, “injection site urticaria” and “injection site

vasculitis”).

74

†Both hypersensitivity vasculitis and angioedema were reported in the same patient receiving

alirocumab.

‡Both laryngeal oedema and rash were reported in another patient receiving alirocumab.

§Neurologic adverse events were selected based on preferred terms with Standardized MedDRA

Queries: “demyelination” (broad + narrow), “peripheral neuropathy” (broad + narrow) and “Guillain-

Barre syndrome” (broad + narrow) excluding the following PTs (“acute respiratory distress syndrome”,

“asthenia”, “respiratory arrest” and “respiratory failure”)

CMQ, custom MedDRA Query; MedDRA Medical Dictionary for Regulatory Activities.

75

Table S8. Additional Parameters Possibly Related to Low LDL Cholesterol

Alirocumab

(N = 1550)

Placebo

(N = 788)

Laboratory parameter, n/N patients (%)

Cortisol

<LLN 325/1506 (21.6%) 176/767 (22.9%)

<LLN and ACTH >ULN 2/325 (0.6%) 1/176 (0.6%)

<LLN and ACTH >ULN and normal ACTH stimulation test

1/2 (50.0%) 1/1 (100%)

<LLN and ACTH >ULN and abnormal ACTH stimulation test*

1/2 (50.0%) 0/1

Fat soluble vitamins

Vitamin E <LLN regardless of baseline status 43/1463 (2.9%)† 1/738 (0.1%)

Vitamin A <LLN regardless of baseline status 40/1496 (2.7%) 17/762 (2.2%)

Vitamin D <LLN regardless of baseline status 1315/1494 (88.0%) 681/759 (89.7%)

Vitamin K <LLN regardless of baseline status 141/1496 (9.4%) 52/762 (6.8%)

ACTH, adrenocorticotropic hormone; LDL, low-density lipoprotein; LLN, lower limit of normal; ULN,

upper limit of normal.

*Abnormal ACTH stimulation test was defined as cortisol value <18 µg per deciliter (<497 nmol per

liter) at both 30 and 60 minutes after ACTH administration.

†Few alirocumab patients (43 out of 1463, 2.9%) had decreased plasma vitamin E levels below the

lower limit of normal during the period from first injection of study drug and up to 10 weeks after the

last injection; this was observed for one patient out of 738 (0.1%) in the placebo group. However,

when normalized for LDL cholesterol levels, no meaningful changes in vitamin E were observed.