A Multicenter, Randomized, Open-label, Parallel-group Usability Study of the Commercial 1 mL Alirocumab Auto-injector Device (AI) and the New 2 mL Auto-injector Device (SYDNEY) in High or Very High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy
Phase: PHASE3
Conditions: Hypercholesterolaemia
Sponsor: Sanofi

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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
CLINICAL TRIAL PROTOCOL 
COMPOUND: Praluent® (alirocumab)
A multicenter, randomized, open-label, parallel-group usability study of the 
commercial 1 mL alirocumab auto-injector device (AI) and the new 2 mL 
auto-injector device (SYDNEY) in high or very high cardiovascular risk patients 
with hypercholesterolemia not adequately controlled with their lipid-modifying 
therapy 
STUDY NUMBER: MSC14864 
EudraCT  
Not applicable 
IND Number(s) 
105574 
Version Number: 
1 
WHO universal trial number: 
Not applicable 
Date: 
20-Nov-2017 
Total number of pages: 
100 
(electronic 4.0)
Page 1
NCT Number:  NCT03415178

Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail: 
SPONSOR 
Company: 
Address: 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
(electronic 
 
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND: PRALUENT®  (alirocumab)   
STUDY No.: MSC14864  
TITLE 
A multicenter, randomized, open-label, parallel-group usability study 
of the commercial 1 mL alirocumab auto-injector device (AI) and the 
new 2 mL auto-injector device (SYDNEY) in high or very high 
cardiovascular risk patients with hypercholesterolemia not 
adequately controlled with their lipid-modifying therapy 
INVESTIGATOR/TRIAL LOCATION 
Multicenter, USA 
PHASE OF DEVELOPMENT 
Phase 3  
STUDY OBJECTIVE(S) 
Primary objective:  
•
To collect 12 weeks of real-use (usability) data assessing
the robustness and user interaction of the new alirocumab 
auto-injector device (which is referred to as SYDNEY), in 
unsupervised settings on Weeks 4, 8, and 12. 
Secondary objectives: 
Device-related: 
•
To collect real-use (usability) data assessing the
robustness and user interaction of SYDNEY and the
current 1 mL alirocumab auto-injector device (which is
referred to as AI) in supervised settings on Week 0 (Day1).
Pharmacokinetics:  
•
To compare alirocumab pharmacokinetics (PK) 300 mg
every 4 weeks (Q4W) administered using SYDNEY and AI, 
from baseline until Week 4. 
•
To evaluate alirocumab PK 300 mg Q4W administered
using SYDNEY, until Week 16. 
Anti-drug antibodies: 
•
To evaluate the development of anti-drug (alirocumab)
antibodies (ADA).
Efficacy/pharmacodynamics: 
•
To compare the percent and absolute change in LDL-C
from baseline to Week 4 using SYDNEY and AI. 
•
To evaluate the percent and absolute change in LDL-C
from baseline to Weeks 8, 12 and 16, using SYDNEY.  
Safety:
•
To evaluate the safety and tolerability of alirocumab
300 mg Q4W, using both SYDNEY and AI.
STUDY DESIGN 
This is a multicenter, randomized, open-label, 16-week study, with 
2 parallel arms (parallel-arms period) for the first 4 weeks, and then 
only one arm (single-arm period) for the subsequent weeks until 
Week 16.  
Patients will be randomized to receive self-administered alirocumab 
300 mg Q4W via either SYDNEY or AI for the first injection on 
Week 0 (Day 1).  
(electronic 4.0)
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Clinical Trial Protocol  
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SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
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Subsequently, all patients will receive self-administered alirocumab 
300 mg Q4W via SYDNEY for the 2nd, 3rd and 4th injections on 
Week 4 (Day 29), Week 8 (Day 57) and Week 12 (Day 85).   
STUDY POPULATION  
Main selection criteria 
Main Inclusion Criteria: 
•
Patients are in either category A or B (below), and are not
adequately controlled with a stable daily dose of
atorvastatin (20 mg or 40 mg), or rosuvastatin (10 mg or
20 mg) for at least 4 weeks prior to the screening visit
(Week -2), with or without other lipid-modifying therapy
(LMT).
A)
Patients with heterozygous familial
hypercholesterolemia (heFH)**
**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 WHO criteria/Dutch Lipid Clinical Network
criteria with a score >8 points or the Simon Broome
register diagnostic criteria with a criterion for definite
FH.
OR 
B)
Non-FH patients at high or very high cardiovascular
(CV) risk. High and very high cardiovascular risk
patients include patients with coronary heart disease
(CHD), non-CHD cardiovascular disease (CVD), and
other risk factors.
•
Patient willing and able to self-inject for the duration of the
study.
•
Signed Written Informed Consent Form.
Key Exclusion Criteria: 
•
LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit
(Week-2).
•
Currently taking a daily dose of statin that is not
atorvastatin 20 mg or 40 mg, or rosuvastatin 10 mg or
20 mg.
•
Not on a stable dose of LMT (including statin) for at least
4 weeks, prior to the screening visit (Week- 2) and from
screening to randomization.
•
Having previously used any device for the proprotein
convertase subtilisin/kexin type 9 (PCSK9)) inhibitor
administration, or having participated in any clinical trial for
a PCSK9 inhibitor.
•
Fasting serum Triglyceride (TG) >400 mg/dL
(>4.52 mmol/L) at the screening visit (Week-2).
Total expected number of patients 
66 randomized patients : 
•
A group of 33 patients using SYDNEY  in the entire study
treatment period,
•
A group of 33 patients using AI for the first 4 weeks
(parallel-arms period), then switching to SYDNEY (during
the single-arm period).
(electronic 4.0)
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
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STUDY TREATMENT(s) 
Investigational Medicinal Product A (new 
auto-injector device) 
Alirocumab delivered via the new 2 mL auto-injector device 
(SYDNEY).  
Formulation: 
Sterile alirocumab drug product supplied at a concentration of 
150 mg/mL in histidine (6 mM), polysorbate 20 (0.1 mg), sucrose 
(100 mg), and Water for Injection USP, to pH 6.0. 
Route(s) of administration: 
Subcutaneous (SC) in the abdomen or thigh (site of injection to be 
documented). 
Dose regimen: 
300 mg Q4W administered as 1 single injection of 2 mL.  
Self-administration on:  
•
Week 0 (Day 1), at the investigator site, supervised.
•
Week 4 (Day 29) and Week 8 (Day 57) at the investigator
site, or at home , unsupervised.
•
Week 12 (Day 85) at the investigator site, observed only
(also considered unsupervised).
Investigational Medicinal Product B 
(current auto-injector device) 
Alirocumab delivered via the current (commercial) 1 mL auto-injector 
device (AI).  
Formulation: 
Sterile alirocumab drug product supplied at a concentration of 
150 mg/mL in histidine (6 mM), polysorbate 20 (0.1 mg), sucrose 
(100 mg), and Water for Injection USP, to pH 6.0. 
Route(s) of administration: 
Subcutaneous (SC) in the abdomen or thigh (site of injection to be 
documented). 
Dose regimen: 
300 mg Q4W administered as 2 injections of 1 mL.  
Self-administration on:  
•
Week 0 (Day 1), at the investigator site, supervised.
ENDPOINT(S) 
Primary endpoint: 
Number (%) and types of SYDNEY-associated product technical 
complaints* (PTCs) at the unsupervised injections on Weeks 4, 8, 
and 12. 
Secondary endpoints: 
Device-related endpoints: 
•
For both devices:
- 
Number (%) of patients with auto-injector associated 
PTCs (overall and by type) at the supervised 
injections (Week 0, Day 1). 
- 
Injection experience questionnaire. 
•
For SYDNEY only:
- 
Number (%) of patients with a SYDNEY - associated 
PTC (overall and by type) at the unsupervised 
injections on Weeks 4, 8, and 12. 
- 
Patient perspective questionnaire. 
- 
Injection-Treatment Acceptance Questionnaire  
(I-TAQ©). 
Pharmacokinetics: 
•
Alirocumab PK parameters after the first and the last
dosing. 
(electronic 4.0)
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 6 
• 
Free and total PCSK9 levels measured using PK serum 
samples. 
Anti-drug antibodies: 
• 
ADAs assessed throughout the study. 
Efficacy/pharmacodynamics: 
• 
Percent and absolute change from baseline in LDL-C at 
Weeks 4, 8, 12 and 16. 
Safety: 
• 
Adverse events (AEs), including Serious Adverse Events 
(SAEs) and Adverse events of special interest (AESIs), 
laboratory data, vital signs assessed throughout the study.  
 
*PTC Definition: 
All complaints that triggered an investigation by the Device 
Department will be categorized as device-related, patient- related, 
undetermined, or not related to device nor patient. In this study, 
a PTC is defined as any complaint reported on the Patient 
Complaint form that triggered an investigation by the Device 
Department and was categorized as either device-related,  patient- 
related or undetermined,  whether or not associated with an AE. Of 
note, the complaints categorized as not related to device nor patient 
will not be considered as a PTC. This definition will be used for both 
primary and secondary endpoints. 
* In case a PTC is associated with the occurrence of an AE, the AE 
must be documented on an AE page in the electronic case report 
form (e-CRF) and the PTC must be described. In case a PTC is 
associated with the occurrence of a SAE, the SAE must be reported 
to the Monitoring Team in accordance with the SAE reporting 
procedures. 
ASSESSMENT SCHEDULE 
The study will consist of the following visits: 
• 
Visit 1 (between Week -2 and Week 0), screening visit, 
on-site visit. 
• 
Visit 2 (Week 0, D1): randomization, baseline visit, on-site 
visit. 
• 
Visits 3 through 11 (Week 1 through Week 15):  
- 
Visits 3, 4, 5, 9, 10, and 11: PK sampling will be 
collected at these visits. These visits may be 
performed on site or as home-visits. 
- 
Visits 6 and 7 (Weeks 4 and 8): These visits may be 
performed on site or as home-visits. 
• 
Visit 8 (Week 12): end-of-treatment (EOT) Visit, on site  
• 
Visit 12 (Week 16): end-of-study (EOS) Visit, on site.  
 
STATISTICAL CONSIDERATIONS 
 
Sample size determination 
No formal sample size was calculated for this study: sample size is 
based on empirical considerations.  
Considering a drop-out rate of 10% it is proposed to randomize 
66 patients overall (33 in each group) in order to ensure 
60 evaluable patients overall (30 in each group) resulting in 
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Clinical Trial Protocol  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 7 
180 unsupervised planned injections using SYDNEY. Patients in the 
AI group will switch to SYDNEY group at the time of the second 
injection; therefore, it will ensure to have 60 evaluable patients using 
SYDNEY for the 2nd, 3rd and 4th unsupervised injections. 
With 60 evaluable patients using SYDNEY, a total of 
180 unsupervised injections is expected to be achieved during the 
study. Expecting a maximum of 3 observed PTC over the 
180 injections (observed PTC rate of 1.67%) with SYDNEY, the 
upper bound of the 2-sided 95% confidence interval (CI) calculated 
with the Wilson score method will be no higher than 5.2%. 
Analysis population 
The primary endpoint will be analyzed on the safety population of the 
single-arm period that will consist of all randomized patients who 
continue in the single-arm period (from Week 4, to Week 16), and 
receive at least 1 dose or part of a dose of Investigational Medicinal 
Product (IMP ) during this period.  
Analysis of the primary endpoint 
The primary endpoint (ie, number (%) and type of 
SYDNEY-associated PTCs at the unsupervised injections) will be 
described on the safety population for the single-arm period. The 
number and % of PTCs will be provided with the 95% CI using 
Wilson score method. If applicable, the number of PTCs per patient 
will be described. 
Analysis of secondary endpoints 
All secondary device-related endpoints will be analyzed on the safety 
population using descriptive statistics. In addition, 95% CI for the 
number of PTCs, number and % of patients with any PTCs will be 
provided using Wilson score method.  
Pharmacokinetics 
PK parameters and levels of PCSK9 (total and free) will be 
summarized descriptively by auto-injector device group. 
After the first administration only, for log-transformed maximum 
plasma concentration (Cmax), area under the curve concentration 
versus time curve extrapolated to infinity (AUC0-tau) and trough 
concentration (Ctrough), the difference between auto-injector devices 
will be assessed using a linear fixed effects model. 
Estimate and 90% CI for the ratio of geometric means 
(SYDNEY/current AI) will be computed for Cmax,  
AUC0-tau and Ctrough.   
Anti-drug antibodies 
Results of ADA will be summarized by auto-injector device group 
using descriptive statistics. 
Pharmacodynamics 
Percent and absolute change from baseline in LDL-C will be 
summarized descriptively for each auto-injector device. 
At Week 4 only, statistical analyses will compare auto-injector 
devices using an ANCOVA model to determine the estimates and 
95% confidence intervals for the difference between means of 
percent LDL-C change for AI versus SYDNEY. 
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Clinical Trial Protocol  
20-Nov-2017 
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 8 
Safety and tolerability 
The safety analysis will be based on the review of the individual data 
and descriptive statistics. 
 
Adverse events will be classified using Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred 
term. The number of treatment-emergent adverse events (TEAEs) 
will be tabulated by auto-injector device, as well as treatment-
emergent AESIs (including in particular local injection site reactions 
LISR), treatment-emergent SAEs, TEAEs leading to permanent 
treatment discontinuation. 
For vital signs and laboratory parameters, the number of patients 
with abnormalities and/or potentially clinically significant 
abnormalities (PCSAs) will be summarized by auto-injector device. 
DURATION OF STUDY PERIOD (per 
patient)  
Total study duration (per patient) is expected to be up to 18 weeks: 
• 
Up to 2 weeks of screening period 
• 
16 weeks of study treatment period (auto-injector device 
assessment phase). 
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
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Property of the Sanofi Group - strictly confidential 
Page 9 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
R
D-14 (V1) 
Week-2 
screening
D1 (V2) 
Week 0 
randomization 
D57 (V7) 
Week 8
D29 (V6) 
Week 4 
D85 (V8) 
Week 12 
EOT 
Unsupervised (at home or at 
investigator site) 
Supervised use 
(at investigator site)
screening 
Alirocumab 300 mg SC administration 
    randomization
Current auto-
injector device 
(AI) 
(2 x 1mL 
injections)
n=33 
n=33 
R
Treatment period 16 weeks 
D113 (V12) 
Week 16 
EOS 
Observed use at 
investigator site, 
(“unsupervised”) 
One administration on 
Day 1, then switch to 
modified device on Day 29
All administrations: self-injected 
Training before D1 self-injection
Supervised: guidance provided   Unsupervised:  no guidance provided, patient alone  Observed: no guidance provided, patient on site 
New auto-injector device (SYDNEY)  
(1 x 2mL injection)
Parallel-arm 
      period 
Single-arm period
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1.2 
STUDY FLOW CHART 
Phase 
Screening 
Treatment Phase 
Daya 
D-14 to D-1 
D1 
D8 
(±1) 
D15 
(±1) 
D22 
(±1) 
D29  
(±3) 
D57 
(±3) 
D85 (±3) 
EOT 
D92 
(±1) 
D99 
(±1) 
D106 
(±1) 
D113 (±3) 
EOS 
Week 
Wk-2 to Wk 0 
Wk 0 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 13 
Wk 14 
Wk 15 
Wk 16 
Visit (visit number) 
1 
2 
3b 
4b 
5b 
6b 
7b 
8 
9b 
10b 
11b 
12 
Place where visits may occur 
On-site 
On-site 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Study treatment administrationc  
 
 
 
 
 
 
 
 
 
 
 
 
Training injection with both devices (prior to 
randomization)d 
 
X 
 
 
 
 
 
 
 
 
 
 
alirocumab SC injection using SYDNEY  
 
Xe 
 
 
 
Xf 
Xf 
Xe 
 
 
 
 
alirocumab SC injection using AI 
 
Xe 
 
 
 
 
 
 
 
 
 
 
Dispense/Complete/Review patient diary 
 
X 
 
 
 
Xf 
Xf 
X 
 
 
 
 
Contact IRT 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Dispense alirocumab device 
 
X 
 
 
 
Xf 
Xf 
X 
 
 
 
 
Collect devices post-injection 
 
X 
 
 
 
 
X 
X 
 
 
 
 
Treatment compliance 
 
X 
 
 
 
 
X 
Xg 
 
 
 
 
End user data recording 
 
 
 
 
 
 
 
 
 
 
 
 
Product Technical Complaints 
 
X 
 
 
 
 Xf 
Xf 
X 
 
 
 
 
Patient perspective questionnaireh 
 
 
 
 
 
 
 
X 
 
 
 
 
Injection-Treatment Acceptance Questionnaire 
(I-TAQ©)i 
 
 
 
 
 
 
 
X 
 
 
 
 
 Injection Experience questionnairej 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
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Clinical Trial Protocol  
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Phase 
Screening 
Treatment Phase 
Daya 
D-14 to D-1 
D1 
D8 
(±1) 
D15 
(±1) 
D22 
(±1) 
D29  
(±3) 
D57 
(±3) 
D85 (±3) 
EOT 
D92 
(±1) 
D99 
(±1) 
D106 
(±1) 
D113 (±3) 
EOS 
Week 
Wk-2 to Wk 0 
Wk 0 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 8 
Wk 12 
Wk 13 
Wk 14 
Wk 15 
Wk 16 
Visit (visit number) 
1 
2 
3b 
4b 
5b 
6b 
7b 
8 
9b 
10b 
11b 
12 
Place where visits may occur 
On-site 
On-site 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site 
On-site or 
home 
On-site or 
home 
On-site or 
home 
On-site 
Safety  
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs (Blood Pressurek, Heart Rate) 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Hematologym, biochemistrym (including fasting 
plasma glucose) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Creatine phosphokinase 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Liver function panel (ALT, AST, ALP & total 
bilirubinl) 
X 
X 
 
 
 
X 
X 
X 
 
 
 
X 
Serum pregnancy test  (if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (if applicable) 
 
X 
 
 
 
 
 
 
 
 
 
X 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
alirocumab pharmacokinetic samplesn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA 
 
Xo 
 
 
 
Xo 
 
 
 
 
 
X 
Pharmacodynamics /efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid parameters (LDL-C, total-C, HDL-C, 
triglyceride) 
X 
Xo 
 
 
 
Xo 
Xo 
Xo 
 
 
 
X 
Abbreviations:  EOT: end-of-treatment, EOS: end-of-study, SC:  subcutaneous, IRT: Interactive response technology, ADA: anti (alirocumab) - drug antibody,  ALT: Alanine aminotransferase, AST: Aspartate 
aminotransferase, ALP: Alkaline phosphatase  , LDL-C: Low density lipoprotein cholesterol, total-C: Total cholesterol, HDL-C: High density lipoprotein cholesterol, AI: Autoinjector, PCSK9: Proprotein convertase 
subtilisin/kexin type 9, γGT: gamma-glutamyl transferase. 
a Day is expressed in reference to the 1st administration of alirocumab (D1). 
b Visits 3, 4, 5, 6, 7, 9, 10 and 11: PK sample to be collected, these visits can be either done on site or be home-visits. 
c The self-administration on Day 1 only will be done under supervision (guidance provided) on site. Self-administrations on Week 4 (Day 29) and Week 8 (Day 57) will be done at home or on site, unsupervised and 
without any guidance. The self-administration on Week 12 (Day 85) will be done at the site and will be observed (no guidance provided, considered unsupervised). Injection site will be documented. 
d Patients will first receive paper- based training with each device by the site. They will then practice one injection with each device (SYDNEY and AI) into a training pad. 
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e Self-injection at the site on Days 1 (supervised) and 85 (observed, considered unsupervised). Device collected immediately after dosing. 
f 
Self-injection at home or on-site: If self –injection is performed at home, a visiting Nurse will bring supplies for blood draw, diary, and dispensed IMP kit to subject’s home and collect IMP materials post injection.  
The Visiting Nurse will not observe or provide guidance and therefore the injection will be unsupervised. After the completion of the visit the Visiting Nurse will collect all study supplies and return them to the site. 
g Treatment compliance at Week 12 applies for injection done at Week 8 and injection done at Week 12. 
h Patient perspective questionnaire: Completed by the patient after the last injection to record patient experience and satisfaction associated with use of SYDNEY to administer the 300 mg dose. 
i 
Injection-Treatment Acceptance Questionnaire (I-TAQ©): Completed by the patient after the last injection, to measure their acceptance of self-injection treatment. 
j 
Injection Experience questionnaire: Completed by the patient after each self-injection (AI or SYDNEY) addressing specific aspects of using the device. 
k Blood pressure after 5 minutes in seating resting position.  
l 
Total bilirubin (and, in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin). 
m Hematology includes: red blood cell count, hematocrit, hemoglobin, white blood cell count with differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), and platelets. Biochemistry 
includes: sodium, potassium, chloride, plasma glucose, calcium, urea nitrogen, creatinine, total proteins, albumin, γGT. 
n When alirocumab is to be administered, PK samples will be takien prior to alirocumab injection (Includes  assay of total and free PCSK9).    
o Prior to dosing with any IMP. 
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2 
TABLE OF CONTENTS 
 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS...............................................................................................................................9 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................9 
1.2 
STUDY FLOW CHART ..................................................................................................................10 
2 
TABLE OF CONTENTS ................................................................................................................13 
2.1 
LIST OF TABLES...........................................................................................................................19 
2.2 
LIST OF FIGURES.........................................................................................................................19 
3 
LIST OF ABBREVIATIONS ..........................................................................................................20 
4 
INTRODUCTION AND RATIONALE.............................................................................................22 
4.1 
INTRODUCTION............................................................................................................................22 
4.2 
RATIONALE...................................................................................................................................22 
4.2.1 
Study Rationale..............................................................................................................................22 
4.2.2 
Study description and design rationale..........................................................................................23 
5 
STUDY OBJECTIVES ...................................................................................................................24 
5.1 
PRIMARY.......................................................................................................................................24 
5.2 
SECONDARY ................................................................................................................................24 
6 
STUDY DESIGN ............................................................................................................................25 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................25 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................26 
6.2.1 
Duration of study participation for each patient .............................................................................26 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................26 
6.3 
INTERIM ANALYSIS......................................................................................................................26 
6.4 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS .............................26 
7 
SELECTION OF PATIENTS..........................................................................................................27 
7.1 
INCLUSION CRITERIA..................................................................................................................27 
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7.2 
EXCLUSION CRITERIA ................................................................................................................28 
7.2.1 
Exclusion criteria related to study methodology ............................................................................28 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......30 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................30 
8 
STUDY TREATMENTS .................................................................................................................31 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................31 
8.1.1 
Description of the auto-injectors ....................................................................................................31 
8.1.1.1 
Current auto-injector: AI.................................................................................................................31 
8.1.1.2 
New auto-injector: SYDNEY ..........................................................................................................32 
8.1.2 
Route and method of administration..............................................................................................33 
8.1.3 
Timing of administration.................................................................................................................33 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................34 
8.3 
BLINDING PROCEDURES............................................................................................................34 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................34 
8.5 
PACKAGING AND LABELING ......................................................................................................35 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................35 
8.7 
RESPONSIBILITIES ......................................................................................................................36 
8.7.1 
Treatment accountability and compliance......................................................................................36 
8.7.2 
Return and/or destruction of treatments ........................................................................................37 
8.8 
CONCOMITANT MEDICATION.....................................................................................................37 
8.8.1 
Management of background lipid-modifying therapy.....................................................................37 
8.8.2 
Contraception.................................................................................................................................37 
8.8.3 
Prohibited concomitant medications ..............................................................................................38 
8.9 
LIFESTYLE AND DIETARY HABITS.............................................................................................38 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................39 
9.1 
PRIMARY ENDPOINT ...................................................................................................................39 
9.1.1 
Collection of devices ......................................................................................................................39 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................40 
9.2.1 
Device-related endpoints ...............................................................................................................40 
9.2.2 
Pharmacokinetics assessments.....................................................................................................41 
9.2.2.1 
Sampling time ................................................................................................................................41 
9.2.2.2 
Number of pharmacokinetic samples.............................................................................................41 
9.2.2.3 
Pharmacokinetic sample handling procedure................................................................................41 
9.2.2.4 
Bioanalytical method......................................................................................................................42 
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9.2.2.5 
Pharmacokinetics parameters .......................................................................................................42 
9.2.3 
Anti-drug (alirocumab) antibody (ADA) assessments....................................................................43 
9.2.3.1 
Sampling times...............................................................................................................................43 
9.2.3.2 
Number of ADA samples ...............................................................................................................43 
9.2.3.3 
Sample handling procedure ...........................................................................................................43 
9.2.3.4 
Bioanalytical methods ....................................................................................................................44 
9.2.4 
Efficacy/Pharmacodynamics assessments:...................................................................................44 
9.2.4.1 
Pharmacodynamic parameter........................................................................................................44 
9.2.5 
Safety assessments.......................................................................................................................45 
9.2.5.1 
Adverse events ..............................................................................................................................45 
9.2.5.2 
Laboratory safety variables............................................................................................................45 
9.2.5.3 
Vital signs.......................................................................................................................................46 
9.2.5.4 
Physical examination .....................................................................................................................46 
9.3 
SAMPLED BLOOD VOLUME ........................................................................................................46 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................46 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................47 
10 
STUDY PROCEDURES ................................................................................................................48 
10.1 
VISIT SCHEDULE..........................................................................................................................48 
10.1.1 
Visit 1: Screening/Day-14 (Week -2) to Day-1 (Week 0) ...............................................................48 
10.1.2 
Visit 2: Day 1, Week 0....................................................................................................................49 
10.1.3 
Visit 3: Day 8 ± 1 day, Week 1; Visit 4: Day 15 ± 1 day, Week 2; Visit 5: Day 22 ± 1 day, 
Week 3...........................................................................................................................................50 
10.1.4 
Visit 6: Day 29 ± 3 days, Week 4...................................................................................................50 
10.1.5 
Visit 7: Day 57 ± 3 days, Week 8...................................................................................................51 
10.1.6 
Visit 8 (end-of-treatment): Day 85 ± 3 days, Week 12...................................................................52 
10.1.7 
Visit 9: Day 92 ± 1 day, Week 13; Visit 10: Day 99 ± 1 day, Week 14; Visit 11: Day 106 ± 1 
day, Week 15 .................................................................................................................................53 
10.1.8 
Visit 12 (end-of-study): Day 113 ± 3 days, Week 16 .....................................................................54 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................54 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................55 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................55 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................56 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................56 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................56 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................57 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................57 
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10.4.1 
Definitions of adverse events.........................................................................................................57 
10.4.1.1 Adverse event ................................................................................................................................57 
10.4.1.2 Serious adverse event ...................................................................................................................58 
10.4.1.3 Adverse event of special interest...................................................................................................59 
10.4.2 
General guidelines for reporting adverse events ...........................................................................60 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................61 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................62 
10.4.5 
Guidelines for reporting product complaints ..................................................................................62 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................63 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................63 
10.6.1 
Local tolerability (local injection site reactions)..............................................................................63 
10.6.2 
General allergic adverse events ....................................................................................................64 
10.6.2.1 Allergic adverse event with cutaneous involvement ......................................................................64 
10.6.2.2 Acute allergic injection reactions....................................................................................................65 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................65 
11 
STATISTICAL CONSIDERATIONS..............................................................................................66 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................66 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................66 
11.3 
ANALYSIS POPULATIONS...........................................................................................................66 
11.3.1 
Modified intent-to-treat populations................................................................................................66 
11.3.2 
Safety populations..........................................................................................................................67 
11.3.3 
Pharmacokinetic populations .........................................................................................................67 
11.3.4 
Anti-alirocumab antibody population..............................................................................................68 
11.4 
STATISTICAL METHODS .............................................................................................................68 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................68 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................68 
11.4.1.2 Compliance ....................................................................................................................................68 
11.4.2 
Analyses of primary endpoint.........................................................................................................69 
11.4.3 
Analyses of secondary efficacy endpoints.....................................................................................69 
11.4.4 
Analyses of safety data..................................................................................................................69 
11.4.4.1 Analysis of the adverse event data................................................................................................70 
11.4.4.2 Analysis of the laboratory data.......................................................................................................70 
11.4.4.3 Summary of the vital sign data.......................................................................................................71 
11.4.5 
Analyses of pharmacokinetic, pharmacodynamics and anti-alirocumab antibodies variables......71 
11.4.6 
Analyses of efficacy variables........................................................................................................71 
11.5 
INTERIM ANALYSIS......................................................................................................................71 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................72 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................72 
12.2 
INFORMED CONSENT .................................................................................................................72 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................72 
13 
STUDY MONITORING...................................................................................................................74 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................74 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................74 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................75 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................75 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................75 
14 
ADDITIONAL REQUIREMENTS...................................................................................................76 
14.1 
CURRICULUM VITAE....................................................................................................................76 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................76 
14.3 
CONFIDENTIALITY .......................................................................................................................76 
14.4 
PROPERTY RIGHTS.....................................................................................................................77 
14.5 
DATA PROTECTION.....................................................................................................................77 
14.6 
INSURANCE COMPENSATION....................................................................................................77 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................78 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................78 
14.8.1 
By the Sponsor...............................................................................................................................78 
14.8.2 
By the Investigator .........................................................................................................................79 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................79 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................79 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................80 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................81 
17 
APPENDICES................................................................................................................................82 
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APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS.................................................................83 
APPENDIX B 
PROCEDURES FOR HANDLING PATIENT COMPLAINTS WITH IDENTIFICATION 
OF POTENTIAL PRODUCT TECHNICAL COMPLAINTS ............................................................84 
APPENDIX C PATIENT RELATED QUESTIONNAIRES ..........................................................................85 
APPENDIX D DEFINITION OF CARDIOVASCULAR DISEASE RISK CATEGORIES.............................93 
APPENDIX E 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF ALT INCREASE BY SANOFI...........94 
APPENDIX F PROCEDURE FOR COLLECTION, HANDLING, STORAGE AND SHIPMENT OF 
SAR236533, PHARMACOKINETIC, AND ANTI-SAR236553 ANTIBODY SAMPLES .................95 
APPENDIX G 
LOCAL INJECTION SITE REACTIONS ASSESSMENT....................................................98 
APPENDIX H CLINICAL DIAGNOSIS OF HETEROZYGOUS FAMILIAL 
HYPERCHOLESTEROLEMIA (HEFH)..........................................................................................99 
 
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2.1 
LIST OF TABLES 
Table 1 - Number of serum samples.............................................................................................................41 
Table 2 - Summary of handling procedures ..................................................................................................42 
Table 3 - Summary of bioanalytical method..................................................................................................42 
Table 4 - List of pharmacokinetic parameters and definitions.......................................................................43 
Table 5 - Number of serum samples.............................................................................................................43 
Table 6 - Summary of handling procedures ..................................................................................................43 
Table 7 - Summary of bioanalytical method..................................................................................................44 
Table 8 - Sampled blood volume...................................................................................................................46 
Table 9 - Summary of adverse event reporting instructions..........................................................................62 
 
2.2 
LIST OF FIGURES 
Figure 1 - 1 mL Clinical pre-filled pen/auto-injector – disposable PFP/AI.....................................................31 
Figure 2 - 2 mL Clinical SYDNEY pre-filled pen............................................................................................32 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
anti-drug (alirocumab) antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AI: 
auto-injector, refers to the current 1mL alirocumab auto-injector only 
ALP: 
alkaline phosphatase  
ALT: 
alanine aminotransferase 
ASCVD: 
atherosclerotic cardiovascular disease 
AST: 
aspartate aminotransferase 
AUC0-tau: 
area under the curve concentration versus time curve extrapolated to infinity  
CHD: 
coronary heart disease 
CI: 
confidence interval 
Cmax: 
maximum plasma concentration 
CPK: 
creatinine phosphokinase 
CRF: 
case report form 
Ctrough: 
trough concentration 
CV: 
cadiovascular 
CVD: 
cadiovascular disease 
DRF: 
Discrepancy Resolution Form 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOS: 
end-of-study 
EOT: 
end-of-treatment 
EU: 
European Union 
FH: 
familial hypercholesterolemia 
GCP: 
good clinical practice 
HDL-C: 
high-density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HLT: 
high-level term 
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
I-TAQ: 
Injection-Treatment Acceptance Questionnaire  
LDL-C: 
low-density lipoprotein chlesterol 
LDLR: 
low-density lipoprotein receptor 
LISR: 
local injection site reactions  
LMT: 
lipid modifying therapy 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intent-to-treat 
NIMP: 
noninvestigational medicinal product 
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PCSA: 
potentially clinically significant abnormality(ies)  
PCSK9: 
proprotein convertase subtilisin/kexin type 9  
PD: 
pharmacodynamic 
PFP: 
pre-filled pen 
PK: 
pharmacokinetics 
PTC: 
product technical complaint 
Q4W: 
every 4 weeks 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan  
SOC: 
system organ class 
SYDNEY: 
new alirocumab 2 mL auto-injector  
TEAE: 
treatment-emergent adverse event 
TG: 
triglyceride 
Total-C: 
total cholesterol 
ULN: 
upper limit of normal 
US: 
United States 
WOCBP: 
women of child bearing potential 
γGT: 
gamma-glutamyl transferase 
 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Alirocumab is a fully human monoclonal antibody (mAb) that binds with high affinity to 
proprotein convertase subtilisin kexin type 9 (PCSK9) across several species.  PCSK9 binds to 
low-density lipoprotein receptors (LDLRs) and promotes the internalization and removal of 
LDLR on hepatocytes.  By blocking PCSK9 from binding to LDLR, alirocumab increases the 
number of LDLR available to remove low-density lipoprotein cholesterol (LDL-C) from 
circulation. Hence, alirocumab is an effective treatment to lower LDL-C and may reduce the risk 
for cardiovascular disease (CVD).  
Alirocumab (also referred to as SAR236553 and REGN727) has been developed for the treatment 
of primary hypercholesterolemia or mixed dyslipidemia and is currently being developed for the 
reduction of cardiovascular (CV) events. Alirocumab is approved in many countries, in particular 
in the United States (US) and the European Union (EU).  
More detailed information is provided in the latest version of Investigator’s Brochure. 
4.2 
RATIONALE 
4.2.1 Study Rationale 
The 300 mg every 4 weeks (Q4W) dosing regimen administered as 2 injections of 150 mg has 
been established as an effective, safe dosing regimen for alirocumab. In order to support the 
300 mg Q4W dosing regimen, a new auto-injector device (which is referred to as SYDNEY) with 
a volume of 2 mL has been developed. 
This larger volume device will allow delivering the 300 mg monthly dosing as a single injection 
of 2 mL of the 150 mg/mL alirocumab solution, rather than 2 separate injections of 1 mL of the 
150 mg/mL alirocumab solution with the currently marketed device. In this study, usability and 
acceptability of the large volume 2 mL SYDNEY device will be assessed when used by patients 
in an unsupervised setting. The current 1 mL auto-injector device (which is referred to as AI,) will 
be used as a calibrator for pharmacokinetics (PK), efficacy and safety.  
In order to assess usability and acceptability of this new 2 mL SYDNEY device, any PTC with 
respect to the use of SYDNEY reported by the patients will be collected. In this study, a PTC is 
defined as any complaint reported on the Patient Complaint form  that triggered an investigation 
by the Device Department and was categorized as either device-related, patient- related, or 
undetermined, whether or not associated with an AE.  
PTCs will also be collected for AI. To allow a proper assessment, only self-administration will be 
allowed and therefore patients will be instructed to self-inject in the abdomen or thigh.  
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4.2.2 Study description and design rationale  
The objective of this study is to assess the usability of SYDNEY in high or very high 
cardiovascular risk patients with hypercholesterolemia not adequately controlled with their 
lipid-modifying therapy (LMT).  
Study population should include  patients with either heterozygous familial hypercholesterolemia 
(heFH) or non-FH patients at high or very high cardiovascular risk (including patients with 
coronary heart disease [CHD], non-CHD CVD, and other risk factors) , not adequately controlled 
with a stable daily dose of atorvastatin (20 mg or 40 mg), or rosuvastatin (10 mg or 20 mg)  for at 
least 4 weeks prior to the screening visit, with or without LMT. 
This is a randomized, open-label, 16-week study, after a screening period of up to 2 weeks: 
Treatment periods include: 
• A parallel-arms period with one of the 2  devices (SYDNEY or AI) for the first 4 weeks. 
Patients will be randomized to receive alirocumab 300 mg Q4W, self-administered using 
either SYDNEY or AI  on Week 0 (Day 1) for the first injection, that will be done on site, 
under supervision and guidance of the Investigator or designee.  
• A single-arm period (with SYDNEY only) for the subsequent weeks until Week 16 
All patients will receive alirocumab 300 mg Q4W, self-administered using only 
SYDNEY, for the 2nd, 3rd and 4th injections on Week 4, Week 8 and Week 12 respectively.  
The Week 4 and Week 8 injections will be performed at home or on-site without 
supervision or guidance. The Week 12 injection will be performed at the site and will be 
under observation only; there will be no guidance provided. Therefore the Week 12 
injection is also considered to be unsupervised. 
Patients assigned to the AI will switch to SYDNEY after the first self-injection to allow for the 
maximum use of SYDNEY in this study (ie, a total of 180 unsupervised injections to be 
performed with the new device), for the evaluation of safety, efficacy and ease of use of the 2 mL 
device in all the study participants. 
The proposed design would support bridging the data for the alirocumab 300 mg monthly dosing 
regimen obtained with the currently marketed 1 mL AI to the new 2 mL SYDNEY. 
It also allows for a descriptive comparison of the two devices up to Week 4 only (after the first 
dose) for pharmacokinetic/pharmacodynamic (PK/PD) and safety (including local injection site 
reactions [LISR]).  
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To collect 12 weeks of real-use (usability) data assessing the robustness and user interaction of the 
new alirocumab auto-injector device (which is referred to as SYDNEY), in unsupervised settings 
on Weeks 4, 8, and 12. 
5.2 
SECONDARY  
Device-related: 
• To collect real-use (usability) data assessing the robustness and user interaction of 
SYDNEY and the current 1 mL alirocumab auto-injector device  (which is referred to as 
AI)  in supervised settings on Week 0 (Day 1). 
Pharmacokinetics:  
• To compare alirocumab PK 300 mg Q4W administered using SYDNEY and AI, from 
baseline until Week 4. 
• To evaluate alirocumab PK 300 mg Q4W administered using SYDNEY, until Week 16. 
Anti-drug antibodies: 
• To evaluate the development of anti-drug (alirocumab) antibodies (ADA). 
Efficacy/pharmacodynamics: 
• To compare the percent and absolute change in LDL-C, from baseline to Week 4 using 
SYDNEY and AI. 
• To evaluate the percent and absolute change in LDL-C from baseline to Weeks 8, 12 and 
16, using SYDNEY.  
Safety: 
• To evaluate the safety and tolerability of alirocumab 300 mg Q4W, using both SYDNEY 
and AI. 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a multicenter, randomized, open-label, 16-week study conducted in the US, with 2 parallel 
arms (parallel-arm period) for the first 4 weeks, and then only one arm (single-arm period) for the 
subsequent weeks until Week 16.   
After a screening period of up to 2 weeks, all patients will be trained in self-injection using both 
devices at clinical site on Week 0 (Day 1) before randomization. They will first receive 
paper-based training with each device by the site. They will then practice one injection with each 
device (SYDNEY and AI) into a training pad.  
Randomization will occur when training is completed and considered satisfactory by the site.  
Eligible patients will then be randomly allocated to receive alirocumab 300 mg Q4W, 
self-administered using either SYDNEY or AI for the first injection on Week 0 (Day 1). This 
injection will be performed at the site under supervision and guidance.  
Subsequently, from Week 4 (Day 29), all patients will receive alirocumab 300 mg Q4W 
self-administered using only SYDNEY for the 2nd, 3rd and 4th injections on Week 4 (Day 29), 
Week 8 (Day 57) and Week 12 (Day 85) respectively.  
The Week 4 and Week 8 injections may be performed at home or on site without supervision or 
guidance. The Week 12 injection will be performed at the site and will be under observation only; 
there will be no guidance provided by  the investigator or designee, and is therefore also  
considered unsupervised. This observation will assess whether the self-injection is performed 
adequately with this information recorded in the e-CRF.  
On Week 0 (Day1), Week  1 (Day 8), Week 2 (Day 15), Week 3 (Day 22), Week 4 (Day 29), 
Week 8 (Day 57), Week 12 (Day 85), Week 13 (Day 92), Week 14 (Day 99), and Week 15 
(Day 106), Week 16 (Day 113), PK collection, AE reporting, and concomitant medication 
reporting will be required. At the above mentioned time points, the patient has a choice to 
complete the assessment at the study site or in the patient’s home (home visit).  Should a patient 
prefer that sample collection be done at home instead of at the site, a research nurse will visit the 
patient’s home to complete the required PK blood draw and management prior to the sample 
being shipped to the central lab. The Visiting Nurse will also bring the IMP and supplies 
(including diary) for the patient to administer unsupervised (the nurse will not provide any 
guidance or be in the room while the dose is self administered).  After the completion of the visit 
the Visiting Nurse will collect all study supplies and return them to the site. 
The Week 12 visit will be the end-of-treatment (EOT) visit. The Week 16 visit will be the 
end-of-study (EOS) visit.  
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A possible complaint identified by the investigator following the patient diary review and the 
patient interview, will trigger the completion of the Patient Complaint form by the investigator.  
The completed Patient Complaint form and the corresponding device (both elements referred as 
“complaint sample”) will be sent to the Research & Development (R&D) complaint office, where 
the type of complaint will be determined: whether the complaint is packaging related or 
potentially due to device issue or patient use. All complaint samples which are potentially due to 
device issue or patient use will be sent to Site Frankfurt Devices (SFD)/PTC Center where, after 
an investigation, the complaint will be classified  as device-related, or  patient- related, or 
undetermined (in case it cannot be determined whether the PTC is device or patient related), or 
not related to device nor patient (see Appendix B).  
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The total study duration (per patient) is expected to be up to 18 weeks: 
• Up to 2 weeks of screening period. 
• 16 weeks of study treatment period (auto-injector device assessment phase). 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the last patient last visit/contact as scheduled per 
protocol. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS 
See Section 4.2 and Section 6.1. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
Patients meeting all of the following criteria will be considered for enrollment into the study: 
I 01. Patients are in either category A or B (below), and are not adequately controlled with a 
stable daily dose of atorvastatin (20 mg or 40 mg), or rosuvastatin (10 mg or 20 mg) for at 
least 4 weeks prior to the screening visit (Week-2), with or without other lipid modifying 
therapy (LMT). 
A) Patients with heterozygous familial hypercholesterolemia (heFH)**. 
**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 WHO 
criteria/Dutch (see Appendix H) 
Lipid Clinical Network criteria with a score >8 points or the Simon Broome register 
diagnostic criteria with a criterion for definite FH. 
OR 
B) Non-FH patients with high and very high cardiovascular risk*, include patients with 
coronary heart disease (CHD), non-CHD CVD, and other risk factors. Definitions for 
CHD, non-CHD CVD, and other risk factors are provided below: 
a) A documented history of CHD (includes 1 or more of the following): 
i. 
Acute myocardial infarction. 
ii. 
Silent myocardial infarction. 
iii. 
Unstable angina. 
iv. 
Coronary revascularization procedure (eg, percutaneous coronary 
intervention or coronary artery bypass graft surgery). 
v. 
Clinically significant CHD diagnosed by invasive or non-invasive testing (eg, 
coronary angiography, stress test using treadmill, stress echocardiography or 
nuclear imaging). 
b) Non-CHD CVD (includes 1 or more of the following criteria): 
i. 
Documented previous ischemic stroke with a focal ischemic neurological 
deficit that persisted more than 24 hours, considered as being of 
atherothrombotic origin. Computed tomography (CT) or magnetic resonance 
imaging (MRI) must have been performed to rule out hemorrhage and 
non-ischemic neurological disease. 
ii. 
Peripheral arterial disease. 
iii. 
Abdominal aortic aneurysm. 
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iv. 
Atherosclerotic renal artery stenosis. 
v. 
Carotid artery disease (transient ischemic attacks or >50% obstruction of a 
carotid artery). 
c) Other risk factors 
i. 
Documented moderate chronic kidney disease as defined by 30≤ Estimated 
Glomerular Filtration Rate (eGFR) <60 mL/min/1.73 m² for 3 months or 
more, including the screening visit. 
ii. 
Type 1 or type 2 diabetes mellitus. 
iii. 
A calculated 10-year fatal CVD risk SCORE ≥5% (European Society of 
Cardiology [ESC] and the European Atherosclerosis Society [EAS] 
Guidelines for the management of dyslipidemias [1]). 
* For CVD risk categories, see Appendix D. 
I 02. Patient willing and able to self-inject for the duration of the study. 
I 03. Signed Written Informed Consent Form. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following three sub-sections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit. 
E 02. Currently taking a daily dose of statin that is not atorvastatin 20 mg or 40 mg, or 
rosuvastatin 10 mg or 20 mg.  
E 03. Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening 
visit and from screening to randomization. 
E 04. Use of fibrates, other than fenofibrate within 4 weeks of the screening visit or between 
screening and randomization visits. 
E 05. Use of red yeast rice products within 4 weeks of the screening visit or between screening 
and randomization visits. 
E 06. Patients who have received plasmapheresis treatment within 2 months prior to the 
screening visit, or have plans to receive it. 
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E 07. Patients who are planned to undergo scheduled percutaneous coronary intervention (PCI), 
coronary artery bypass graft (CABG), carotid or peripheral revascularization during the 
study.  
E 08. History of New York Heart Association (NYHA) Class III or IV heart failure within the 
past 12 months. 
E 09. Age <18 years or legal age of majority at the screening visit, whichever is greater. 
E 10. Known history of homozygous FH. 
E 11. Having previously used any device for PCSK9 inhibitor administration, or having 
participated in any clinical trial for a PCSK9 inhibitor. 
E 12. 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, eg: 
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, 
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 13. Patients who have taken any investigational drugs within 1 month or 5 half-lives, 
whichever is longer. 
E 14. Patients who withdraw consent during the screening period (patient who is not willing to 
continue or fails to return).  
E 15. Laboratory findings during the screening period (not including randomization labs) with 
the following values:  
A) Triglycerides (TG) >400 mg/dL (>4.52 mmol/L) at the screening visit (Week-2). Note: 1 
repeat lab is allowed.  
B) Positive serum pregnancy test in women of childbearing potential.  
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C) eGFR <30 mL/min/1.73 m2 according to 4-variable modification of diet in renal disease 
(MDRD) equation. 
D) ALT or AST >3 x upper limit of normal (ULN) (1 repeat lab is allowed). 
E) Creatinine kinas (CK) >3 x ULN (1 repeat lab is allowed). 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 16. All contraindications to the background therapies or warning/precaution of use (when 
appropriate) as displayed in the respective National Product Labeling. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab 
E 17.  History of a serious hypersensitivity reaction to alirocumab (including hypersensitivity 
vasculitis and hypersensitivity reactions requiring hospitalization).  
E 18. Pregnant or breast-feeding women. 
E 19. 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 “International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. M3(R2): Guidance on nonclinical safety 
studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals 
ICH.2009 Jun: 1-25” (2). Please refer to Appendix A. 
Postmenopausal women must be amenorrheic for at least 12 months.  
  
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL in an aqueous 
buffer, pH 6.0, containing sucrose, histidine, and polysorbate 20 as 1 mL or 2 mL volume 
respectively in a current auto-injector or in a new auto-injector. 
8.1.1 Description of the auto-injectors  
In this study protocol, AI refers to the current commercial 1 mL device only, SYDNEY refers to 
the new 2 mL device. 
8.1.1.1 Current auto-injector: AI 
The currently marketed device,  1 mL AI, delivers 2 separate 1 mL injections of the 150 mg/mL 
Praluent® (alirocumab) for the 300 mg Q4W dosing regimen.  
Figure 1 - 1 mL Clinical pre-filled pen/auto-injector – disposable PFP/AI  
 
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8.1.1.2 New auto-injector: SYDNEY 
The new 2 mL AI,  SYDNEY, is a two-step disposable auto-injector designed to deliver 2 mL of 
150 mg/ mL Praluent® (alirocumab) subcutaneously in ≤20 seconds. 
The main features of SYDNEY include: 
• An easy to use buttonless device for the patients  
• A needle safety cover that shields the needle at start of injection and extends to cover the 
needle when the AI is removed from the skin, which helps preventing needle stick injury 
• An inspection window to allow visibility of the medication and provide feedback before 
and after injection (window changes from transparent to purple) 
• Visible and audible cues to signal the start and end of injection 
• A single-use, disposable device 
• Self-disabling feature to prevent re-use 
• An arrow around the inspection window (indicating the direction to push the pen against 
the skin) 
The main functional difference other than the injected volume between the new and the current 
device is that there is one step less for preparation of the injection with the new device, there is no 
longer the need to push a button to start the injection. 
This new 2 mL AI, SYDNEY, is illustrated in Figure 2. 
 
Figure 2 - 2 mL Clinical SYDNEY pre-filled pen 
 
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8.1.2 Route and method of administration 
An Instructions for Use sheet will be provided to patients containing detailed instructions on use.  
The IMP will be administered by self-injection. The used auto-injector will be returned to the site 
for accountability and reconciliation.  
It is recommended that the IMP injections be rotated within an anatomical area (eg, right thigh 
then left thigh or right abdomen then left abdomen).  Patients also have the option to inject in a 
different anatomical area (eg, thigh then abdomen) during the study. Patients should not inject into 
areas where the skin is bruised, tender, hard, red, or hot. 
It should be noted that if patients have problems activating the auto-injector by pressing the 
needle cover against their belly (eg, soft tissue), it is recommended to inject into the thigh, where 
the skin is firmer than the belly. If another concomitant drug is being injected at the same site 
planned for the IMP injection, then the patient should be advised to use an alternate location for 
administration of the IMP. 
Patients will be asked to store the IMP in a refrigerator. Prior to administration, the IMP should be 
set outside in a safe location at room temperature for about 45 minutes. Thereafter, the IMP 
should be administered as soon as possible. 
8.1.3 Timing of administration 
On Day 1, prior to the randomization, all patients will be trained in self-injection using both 
devices at clinical site. They will first receive paper-based training with each device by the 
investigator or designee. They will then practice one injection with each device (current and new 
auto-injector devices) into a training pad. 
Randomization will occur when training is completed and considered satisfactory by the 
investigator or designee.  
Patients will be randomized to receive self-administered alirocumab 300 mg Q4W subcutaneously 
via either SYDNEY or AI for the first injection on Week 0 (Day 1).  
The treatment period will start as soon as possible after the call for randomization using the 
treatment kit number provided by the Interactive Response Technology (IRT). The first injection 
after randomization will be done at the investigational site by the patient under direct site staff 
supervision.  Patients will be monitored at the investigational site for at least 30 minutes after this 
first injection. 
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Subsequently, all patients will receive self-administered alirocumab 300 mg Q4W via SYDNEY 
for the 2nd, 3rd and 4th injections on Week 4 (Day 29), Week 8 (Day 57) and Week 12 (Day 85).   
• The 2nd and 3rd injections will be done unsupervised at home or on site. 
• The 4th injection will be done on site under observation by a caregiver (considered 
unsupervised), as no direction or prompting will be given. This observation will assess 
whether the self-injection is performed adequately with this information recorded in the e-
CRF. 
IMP should ideally be administered subcutaneously at approximately the same time of the day 
Q4W; however it is acceptable to have a window period of ± 3 days. The time of the day is based 
on patient’s preference.  
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as noninvestigational medicinal products (NIMP) 
because the medication is a potential background therapy: 
• Atorvastatin 20 mg or 40 mg, rosuvastatin 10 mg or 20 mg. 
• Cholesterol absorption inhibitors (ezetimibe), 
• Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam), 
• Nicotinic acid, 
• Fenofibrate, 
• Omega-3 fatty acids (≥1000 mg daily). 
8.3 
BLINDING PROCEDURES 
Not applicable, this study is an open-label design. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The randomized treatment kit number list is generated centrally by Sanofi. The IMPs are 
packaged in accordance with this list. 
The trial Supply Operation Manager will provide the randomized list of treatment kit numbers and 
the Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system provider. Then, this centralized treatment allocation system provider will 
generate the patient randomization list according to which it will allocate the treatment kits to the 
patients. 
Patients will be randomized to receive either SYDNEY or AI for the first injection at Week 0 (on 
Day 1) using a ratio 1:1.  
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The treatment kit numbers will be allocated using the centralized treatment allocation system 
(IRT) on randomization visit Week 0 (Day 1), Week 4 (Day 29), Week  8 (Day 57) and Week 12 
(Day 85). 
Before randomizing a patient, the Investigator or designee will have to contact the centralized 
treatment allocation system (IRT). 
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. A 
patient cannot be randomized more than once in the study. If a treatment is used without 
contacting the centralized treatment allocation system (IRT), the patient will be considered as not 
randomized and withdrawn from the study. 
8.5 
PACKAGING AND LABELING 
The treatment kit with AI will be prepared to contain 2 auto-injectors (2 x 1 mL) whereas the 
treatment kit with SYDNEY will be prepared to contain 1 auto-injector (1 x 2 mL).  
In addition to the open-label treatment kits, a dummy kit for practice containing 1 auto-injector 
each will be prepared for the purpose of instructing patients on injection administration which is 
to be performed prior to randomization. These training injections will be performed on site at 
randomization Week 0 (Visit 2, Day1). 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
At the investigational site, stored IMP should be kept in an appropriate locked room, under the 
responsibility of the investigator or designee or other authorized person in accordance with local 
regulations, labeling specifications, policies and procedures. Control of IMP storage conditions, 
especially control of temperature (eg, refrigerated storage between +2°C and +8°C [36°- 46° F] at 
the site) and information on in-use stability and instructions for handling the alirocumab should be 
managed according to the rules provided by the Sponsor (eg, the temperature of the site 
refrigerator should be checked daily and recorded on a log sheet). 
IMP will be either given to the patient for self-administration while on site or the supplies will be 
brought and collected by the Visiting Nurse in an appropriate transport bag at the refrigerated 
temperature.   
The IMP must be administered in accordance with the Instructions for Use. If the storage and in 
use conditions described in the Instructions for Use are not followed, do not administer the IMP.  
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8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Clinical Trial Protocol and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure (see Section 6.1) . 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for the Visiting 
Nurse who has been approved by the Sponsor), allow the IMP to be used other than as directed by 
this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
IMP administration data will be recorded by the Investigator or designee on the e-CRF. 
Measures taken to ensure and document IMP compliance and accountability are described below: 
• The Investigator or designee will obtain via IRT the treatment kit number(s) and he/she 
will dispense the treatment kit(s) to the patient. 
• The Investigator or designee will enter the treatment kit packaging number(s) and the kit 
numbers in the e-CRF, if applicable. 
• The accountability is to be performed at IMP kit re-supply visits only. The used and 
unused kit(s) should be brought back to such visits for accountability purposes. 
• The monitor will check the data consistency between e-CRF pages, treatment log forms 
using patient’s diary, and returned unused IMPs of a corresponding kit. 
The patient will be instructed on the importance to take the study treatment as planned for the 
remainder of the treatment duration, as well as the need to return all used and unused IMP kits at 
each site visit. 
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8.7.2 Return and/or destruction of treatments 
All treatments kits will be retrieved from the site by the Sponsor. A detailed treatment log of the 
returned IMP will be established with the Investigator (or the pharmacist) and countersigned by 
the Investigator and the monitoring team.  
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s) 
during the study. This medication is not provided by the Sponsor. 
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 IMP, they may 
be given at the discretion of the Investigator, with a stable dose (when possible). Besides the 
specific information related to concomitant medications provided in this section, any other 
concomitant medication(s) will be allowed and will have to be recorded in the e-CRF and source 
data. 
8.8.1 Management of background lipid-modifying therapy 
For background LMT, including statins (atorvastatin 20 and 40 mg, rosuvastatin 10 and 20 mg), 
sites must follow the national product label for the safety monitoring and management of patients. 
Patients will be on stable dose of statin therapy with or without other LMT during the study as 
indicated in Section 7. 
From the screening visit until the Week 16 visit, the background LMT should not be changed. No 
dose adjustment, discontinuation or initiation of other statins or other LMT should take place 
during this time, barring exceptional circumstances whereby overriding concerns warrant such 
changes, as per the Investigator’s judgment.  
Should the patient require the introduction of a fibrate during the course of the study (ie, as rescue 
treatment) only fenofibrate will be allowed to be added. 
8.8.2 Contraception 
Women of childbearing potential must use an effective contraceptive method throughout the 
entire duration of the study treatment. It is also recommended to continue using an effective 
contraceptive method for at least 4 weeks after the last injection of IMP. The applied methods of 
contraception have to meet the criteria for a highly effective method of birth control according to 
the “International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. M3(R2): Guidance on nonclinical safety studies for the conduct 
of human clinical trials and marketing authorization for pharmaceuticals. ICH. 2009 Jun: 1-25” 
(2). 
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8.8.3 Prohibited concomitant medications 
The following therapies are not allowed during the study (including the screening period until the 
EOS visit): 
• Red yeast rice products 
• Fibrates, other than fenofibrate 
• Other PCSK9 inhibitors 
Note: while red yeast rice is considered a dietary supplement/nutraceutical, it contains HMG CoA 
reductase inhibitor activity (mechanism of action of statins), along with other active ingredients. 
Because such products lack standardization, varying amounts of the active substance could lead to 
alterations in lipids during the study and potentially confound the LDL-C assessment. 
8.9 
LIFESTYLE AND DIETARY HABITS 
Lifestyle and dietary habits should be maintained if possible throughout the entire study duration, 
as medically feasible, with minimum changes. There shall be no significant changes in nutritional 
composition of the diet or in the quantity/pattern of food consumed. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary endpoint is the number (%) and types of SYDNEY-associated product technical 
complaints (PTCs)* at the unsupervised injections on Weeks 4, 8, and 12. 
* Product technical complaints (PTC)  
In this study, all complaints that triggered an investigation by the Device Department will be 
categorized as device-related, patient- related, undetermined, or not related to device nor patient, 
whether or not associated with an AE. In this study, a PTC is defined as any complaint reported 
on the Patient Complaint form that triggered an investigation by the Device Department and was 
categorized as either device-related,  patient- related or undetermined. The complaints categorized 
as not related to device nor patient will not be considered as a PTC. This definition will be used 
for both primary and secondary endpoints. 
Patient diaries 
Patients will be given diaries to complete after each self-injection they perform using the 
auto-injector device. The diary will include specific questions about the self-injection process. 
At each visit, the Investigator will review the diary with the patient, and confirm more particularly 
whether there were any problems associated with the auto-injector during study treatment 
administration and record the experience in the e-CRF. 
Following interview with the patient, in the event the Patient complaints form is completed by the 
investigator, this form and the corresponding auto-injector device (both elements referred as 
“complaint sample”) will be sent to the Sponsor for identification of as described in Section 6.1. 
In case a PTC is associated with the occurrence of an AE, the AE must be documented on an AE 
page in the e-CRF. In case a PTC is associated with the occurrence of a SAE, the SAE must be 
reported to the Monitoring Team in accordance with the SAE reporting procedures. 
9.1.1 Collection of devices 
All used auto-injector devices will be collected by the site. In case a Patient Complaints form is 
completed, the concerned device will be sent to the Sponsor along with the Patient Complaints 
form. 
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9.2 
SECONDARY ENDPOINTS  
• Secondary endpoints include: Device-related endpoints  
• Pharmacokinetics  
• Anti-drug antibodies 
• Efficacy/pharmacodynamics: 
• Safety:  
- 
Adverse events (AEs), including Serious Adverse Events (SAEs) and Adverse events 
of special interest (AESIs), laboratory data, and vital signs assessed throughout the 
study. 
AESIs and other groupings of interest will include: general allergic reactions (GARs) 
requiring consultation with another physician, LISR requiring consultation with another 
physician, neurologic events that require additional examinations/procedures and/or 
referral to a specialist, neurocognitive events, pregnancy, symptomatic overdose with IMP, 
alanine aminotransferase (ALT) increase: ALT ≥3 x Upper Limit of Normal (ULN) (if 
baseline ALT <ULN) or ALT ≥2 times the baseline value (if baseline ALT ≥ULN). 
9.2.1 Device-related endpoints 
For both devices: 
• Number (%) of patients with current AI- associated PTCs (overall and by type) at the 
supervised injections (Week 0, Day 1). 
• Patient questionnaires (see Appendix C): 
- 
Injection Experience Questionnaire: patients will be given an Injection Experience 
Questionnaire to complete after the self-injection they perform using SYDNEY or AI 
on Week 0 (Day 1). The questionnaire will include questions about specific aspects of 
using the device. 
For SYDNEY only: 
• Number (%) of patients with a SYDNEY- associated PTC (overall and by type) at the 
unsupervised injections on Weeks 4, 8, and 12. 
• Patient questionnaires (see Appendix C): 
- 
Patient Perspective Questionnaire: the aim of the Patient Perspective Questionnaire 
(to be completed by the patient after the last injection) will be to generate data to 
support an understanding of the patient experience and satisfaction associated with use 
of the large volume 2 mL SYDNEY to administer the 300 mg dose. 
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- 
Injection-Treatment Acceptance Questionnaire: the I-TAQ© (to be completed by 
the patient after the last injection) is a 22-item, self-administered questionnaire 
administered to patients in order to measure their acceptance of the injection. The aim 
is to generate data to show patient acceptance of self-injection treatments.   
Assessment schedule  
The assessment timing can be found in the study flow chart (Section 1.2). 
9.2.2 Pharmacokinetics assessments  
Total serum alirocumab concentrations, as well as total and free PCSK9 concentrations will be 
measured: 
• Alirocumab PK parameters after the first and the last dosing. 
• Free and total PCSK9 levels measured using PK serum samples. 
9.2.2.1 Sampling time 
The sampling times for blood collection can be found in the study flow chart (Section 1.2). 
9.2.2.2 Number of pharmacokinetic samples 
Table 1 - Number of serum samples 
 
ALIROCUMAB 
By patient / Total 
11 
Total current auto-injector (AI) arm (33 patients) 
33 * 5 samples  =  165 
Total new auto-injector (SYDNEY) arm (33 patients) 
 
33 * 11 samples =  363 
+ 33 patient * 6 samples = 198 
Total for study  
 165+363+198  =  726 
9.2.2.3 Pharmacokinetic sample handling procedure 
The sample handling procedure is summarized in the below table. 
Special procedures for collection, storage, and shipment will be provided in Appendix F of the 
protocol. 
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Table 2 - Summary of handling procedures 
Blood Sample Volume 
5 mL 
Anticoagulant 
None 
Handling Procedures 
To be described in Appendix F of the protocol 
Serum Aliquot Split 
Two equal aliquots 
Serum Storage Conditions 
-20°C (-68°F) or below 
Serum Shipment Conditions 
Dry ice 
9.2.2.4 Bioanalytical method 
All PK samples will be analyzed by Bioanalytical Sciences group at Regeneron Pharmaceuticals, 
Inc. 
PK samples will be analyzed using a validated enzyme-linked immunosorbent assay (ELISA) to 
determine total concentrations of alirocumab (ie, free SAR236553 and SAR236553 present in 
PCSK9:SAR236553 complexes) in acid-treated human serum as summarized in Table 3. 
Alirocumab PK samples will also be analyzed to determine total and free PCSK9 levels using 
validated ELISA. 
 
Table 3 - Summary of bioanalytical method 
Analyte 
ALIROCUMAB 
Matrix 
Serum 
Analytical Technique 
ELISA 
Lower limit of Quantification 
 
Site of Bioanalysis 
Regeneron Pharmaceuticals, Inc 
Method Reference 
 
 
 
9.2.2.5 Pharmacokinetics parameters 
The pharmacokinetic parameters listed in Table 4 will be calculated, using non-compartmental 
methods for alirocumab serum concentrations after single and multiple doses. The parameters will 
include, but not be limited to the following. 
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Table 4 - List of pharmacokinetic parameters and definitions 
Parameters 
Drug/Analyte 
Matrix 
Definition/Calculation 
Cmax  
SAR236553 
Serum 
Maximum serum concentration observed 
Ctrough  
SAR236553 
Serum 
Serum concentration observed just before treatment administration during 
repeated dosing 
tmax  
SAR236553 
Serum 
Time to reach Cmax  
AUC0-tau 
SAR236553 
Serum 
Area under the serum concentration versus time curve calculated using the 
trapezoidal method during a dosage interval 
9.2.3 Anti-drug (alirocumab) antibody (ADA) assessments 
9.2.3.1 Sampling times 
Anti-drug antibodies will be assessed throughout the study. The sampling times for blood 
collection of ADA samples can be found in the study flow chart (See Section 1.2).  
9.2.3.2 Number of ADA samples 
Table 5 - Number of serum samples 
 
Anti-ALIROCUMAB antibodies 
By patient  
 3 
Number of patients 
66 
Total for study  
       3*66 =   198 
9.2.3.3 Sample handling procedure 
The sample handling procedure is summarized in Table 6. Special procedures for collection 
storage and shipment will be provided in Appendix F of the protocol. 
Table 6 - Summary of handling procedures 
Blood sample volume 
5 mL 
Anticoagulant 
None 
Handling procedures 
Will be provided in Appendix F of the protocol 
Serum aliquot split 
Two equal aliquots 
Serum storage conditions 
-20°C (-68°F) or below 
Serum shipment conditions 
Dry ice 
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9.2.3.4 Bioanalytical methods 
All PK samples will be analyzed by Bioanalytical Sciences group at Regeneron Pharmaceuticals, 
Inc. 
ADA samples will be analyzed using a validated electrochemiluminescence assay for the 
determination of anti- alirocumab antibodies in human serum as summarized in Table 7. 
Table 7 - Summary of bioanalytical method 
Analyte 
Anti-ALIROCUMAB 
Matrix 
Serum 
Analytical technique 
Electrochemiluminescence 
Sensitivity 
approx. 5.6 ng/mL 
Site of bioanalysis 
Regeneron Pharmaceuticals, Inc. 
Method reference 
 
9.2.4 Efficacy/Pharmacodynamics assessments: 
The efficacy secondary endpoint is represented by the percent and absolute change from baseline 
in LDL-C at Weeks 4, 8, 12 and 16. 
At all visits LDL-C will be calculated using the Friedewald formula (3). For the purpose of 
calculating LDL-C through the Friedewald formula, blood sampling will be done for 
determination of  Total-cholesterol (Total-C), high-density lipoprotein cholesterol (HDL-C), and 
TG.  If TG values exceed 400 mg/dL (4.52 mmol/L) then the central lab will reflexively measure 
(via the beta quantification method) the LDL-C rather than calculating it. 
The blood sampling for lipid parameters should be performed in the morning, in fasting condition 
(at least 10 to 12 hours fast and refrain from smoking). Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. The 
sample handling procedure will be provided separately in a Central Lab manual. 
9.2.4.1  Pharmacodynamic parameter 
The pharmacodynamic endpoint will be the percent change in LDL-C value from baseline to 
Week 4 defined as: 100x (LDL-C value at Week 4 - LDL-C value at baseline) / LDL-C value at 
baseline. 
The baseline LDL-C value will be the last LDL-C level obtained before the first injection of IMP. 
The LDL-C at Week 4 will be the LDL-C level obtained within the Week 4 analysis window. 
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All calculated and measured LDL-C values (scheduled or unscheduled, fasting or not fasting) may 
be used in the analyses if appropriate according to above definition and analysis windows used to 
allocate a time point to a measurement. Analysis windows will be defined in the statistical 
analysis plan (SAP). In case both calculated and measured LDL-C are provided for the same 
sampling, the measured LDL-C will be considered. 
Percent and absolute change from baseline in LDL-C will also be calculated at Week 8, 12 and 
16. They will be summarized descriptively. 
9.2.5 Safety assessments 
Adverse events, spontaneously reported by the subject or observed by the Investigator, will be 
monitored at each visit. This includes SAEs, detailed in Section 10.4.1.2, AEs of special interest 
(AESIs) detailed in Section 10.4.1.3, laboratory data, vital signs assessed throughout the study. 
Specific additional forms will be completed for AESI. For any Local Injection Site Reactions 
(LISR), and general allergic AEs, whether or not reported as AESI, special forms on symptoms 
will have to be completed (see Section 10.6). 
Assessment of safety will be based on clinical safety endpoints, laboratory safety variables, vital 
signs, and physical examination.  
9.2.5.1 Adverse events 
Refer to Section 10.4 up to Section 10.7 for details. 
9.2.5.2 Laboratory safety variables 
The clinical laboratory data consist of blood analysis including the following:  
• Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), 
platelets. 
• Biochemistry: sodium, potassium, chloride, calcium, plasma glucose, urea nitrogen, 
creatinine, albumin, total proteins, gamma-glutamyl transferase (γGT). 
• Liver function panel: aspartate aminotransferase (AST), Alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), and total bilirubin (and, in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin). 
• Creatine phosphokinase (CPK).  
• Urine and serum (beta-human chorionic gonadotropin [β-HCG])   pregnancy test for 
women of child bearing potential (WOCBP) only. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables.  
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9.2.5.3 Vital signs 
Vital signs include heart rate, systolic and diastolic blood pressure measured after 5 minutes in 
seating resting position.  
9.2.5.4 Physical examination  
Physical examination, including body weight (kg), height (only at screening visit).  
9.3 
SAMPLED BLOOD VOLUME 
The volume of blood sampled in the study is shown in Table 8. 
Table 8 - Sampled blood volume 
Type 
Volume per sample 
Sample number 
Total 
Hematology 
2 mL 
3 
6 mL 
Biochemistry 
2 mL 
3 
6 mL 
Creatine phosphokinase 
2 mL 
6 
12 mL 
Liver function panel 
1 mL 
6 
6 mL 
Pharmacodynamics 
3 mL 
6 
18 mL 
β-HCG (if applicable) 
5 mL 
1 
5 mL 
Pharmacokinetics alirocumab 
5 mL 
11 
55 mL 
Anti-alirocumab antibody 
5mL 
3 
15 mL 
 
 
 
 
Total if male or female post menopausal 
 
 
118 mL 
Total if WOCBP 
 
 
123 mL 
Abbreviations: β-HCG: beta-human chorionic gonadotropin,  WOCBP: Women of childbearing potential 
9.4 
FUTURE USE OF SAMPLES 
Stored samples may be used for safety analysis, even after study completion. Unused or left over 
samples after testing may be used for other research purposes (excluding genetic analysis) related 
to cardiovascular diseases, other than those defined in the present protocol. Information on these 
stored samples will be included in the informed consent form.  
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9.5 
APPROPRIATENESS OF MEASUREMENTS  
The primary endpoint is the number (%) and types of PTCs associated with the use of SYDNEY 
during the 3 unsupervised injections at Week 4, Week 8 and Week 12. This will allow to assess 
the robustness, usability and acceptability of the new 2 mL SYDNEY device. With an estimation 
of 60 evaluable patients using SYDNEY (30 patients in the SYDNEY group since Day 1 and 
30 additional patients from the AI group switching to SYDNEY group after the 1st injection), a  
total of 180 unsupervised injections with SYDNEY will be assessed. 
The data collected will also allow for evaluation of PK, safety, efficacy and use in real world 
setting of the 2 mL SYDNEY device in all study participants, from Week 4 injection. 
Up to Week 4, the parallel arm design will allow for PK, PD and safety (including LISR) to be 
compared between SYDNEY and AI. 
 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
10.1.1 Visit 1: Screening/Day-14 (Week -2) to Day-1 (Week 0)  
The patient will receive complete information about the study both verbally and in writing. 
Written informed consent for the study must be obtained prior to any study procedures. 
The following procedures will then be performed: 
• Contact IRT to assign a patient number 
• Assess eligibility by review of Inclusion/Exclusion Criteria. Patients who fail to meet the 
eligibility criteria based on this preliminary review should not continue the screening 
process and a screen failure  notification should be done through the IRT  
• Interview to collect: 
- 
Patient demography 
- 
Medical/surgical history 
• Record prior/concomitant medications 
• Perform a physical examination including weight (kg) and height (cm) (collected for body 
mass index [BMI] calculation)  
• Record vital signs including systolic and diastolic blood pressure (measured after 
5 minutes in a seated resting position) and heart rate  
• Obtain blood samples in fasting conditions for  
- 
Lipids panel: LDL-C, Total-C, HDL-C, TG 
- 
Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential, platelets  
- 
Biochemistry: sodium, potassium, chloride, calcium, plasma glucose, urea nitrogen, 
creatinine, albumin, total proteins, γGT 
- 
Liver function panel: AST, ALT, ALP, and total bilirubin (and, in case of values above 
the normal range, differentiation in conjugated and non-conjugated bilirubin)  
- 
CPK 
- 
Serum pregnancy test (for WOCBP, only). 
• Record AEs (including SAE and AESI) if any after informed consent signed 
• Schedule a visit within 2 weeks maximum (Visit 2, Week 0, Day 1)  
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• Remind patient to be in fasting conditions (ie overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.2 Visit 2: Day 1, Week 0 
The following procedures will be performed: 
• Confirm eligibility by review of Inclusion/Exclusion Criteria. Patients who fail to meet the 
eligibility criteria based on this preliminary review should not continue the screening 
process and a screen failure  notification should be done in the IRT  
• Record vital signs including systolic and diastolic blood pressure (measured after 
5 minutes in a seated resting position) and heart rate  
• Contact IRT for allocation of a number for training kit, and alirocumab device (SYDNEY 
or AI)  
• Record the kit number allocated in the e-CRF 
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
• Dispense training for both SYDNEY and AI, and perform injection-training as outlined in 
Section 8.1.3. 
• Prior to dosing with IMP, collect blood sample in fasting conditions for: 
- 
Lipids panel  
- 
Hematology  
- 
Biochemistry 
- 
 Liver function panel 
- 
CPK 
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
- 
Detection of anti-alirocumab antibodies. 
• Obtain urine sample for pregnancy test (for WOCBP, only) 
• Dispense patient diary 
• Contact IRT for allocation of a kit number for alirocumab (SYDNEY or AI) 
• Record the kit number allocated in the e-CRF 
• Dispense alirocumab device (SYDNEY or AI) 
• IMP injection using SYDNEY or AI (dependent on randomization) to be performed by the 
patient under staff supervision 
• Collect used auto-injector device (as described in Section 9.1) 
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• Patient to complete diary 
• Patient to complete the injection experience questionnaire 
• Record Patient complaint (including PTC) in the Patient complaints form, if any occurred 
• Record treatment compliance  
• Schedule home-visits or on-site visits according to patient preference for Visit 3 (Week 1), 
Visit 4 (Week 2), and Visit 5 (Week 3)  
• Schedule a visit for Week 4 (Day 29 [± 3 day]; Visit 6) and Week 8 (Day 57 [± 3 days], 
Visit 7) either on site or at home, based on the patient’s preference.  
• Schedule an on-site visit for Week 12 (Day 85 [± 3 days]; Visit 8) and remind patient to be 
in fasting conditions (ie overnight, at least 10 to 12 hours fast and refrain from smoking) 
for the visit. Also, alcohol consumption within 48 hours and intense physical exercise 
within 24 hours preceding the next visit are discouraged 
• Review patient diary and record patient complaint (including PTC) in the Patient 
complaints form (for the Day 1 injection), if any (as described in Section 9.1) 
10.1.3 Visit 3: Day 8 ± 1 day, Week 1; Visit 4: Day 15 ± 1 day, Week 2; Visit 5: 
Day 22 ± 1 day, Week 3  
These visits may be performed on site or as home-visits 
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
• Obtain blood samples for  
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
• Remind patient to be in fasting conditions (ie overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study visit (Visit 6). Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next visit are 
discouraged 
10.1.4 Visit 6: Day 29 ± 3 days, Week 4 
This visit may be performed on site or as a home-visit.  
The following procedures will be performed: 
• Record vital signs including systolic and diastolic blood pressure (measured after  
5 minutes in a seated resting position) and heart rate  
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
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• Obtain fasting blood samples for:  
- 
Lipids panel 
- 
Liver function panel 
- 
CPK 
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
- 
Detection of anti-alirocumab antibodies. 
• Contact IRT for allocation of a kit number for SYDNEY 
• Record the kit number allocated in the e-CRF 
• Dispense the SYDNEY device to the patient if the injection is to be administered on site or 
to the Visiting Nurse, if the injection to be administered at home 
• Dispense patient diary, to be completed after the injection 
• Dispense Injection Experience Questionnaire, to be completed after the injection  
• Collect and return the study supplies and diary (performed by the Visiting Nurse if the 
visit is completed at home)   
• Confirm scheduled visit for Week 8 (Day 57 [± 3 days], Visit 7)  
• Remind patient to be in fasting conditions (ie overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study visit (Vist 7). Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next visit are 
discouraged 
• Review patient diary and record patient complaint (including PTC) in the Patient 
complaints form (for the Week 4 injection), if any (as described in Section 9.1), after 
received from the patient or theVisiting Nurse. 
10.1.5 Visit 7: Day 57 ± 3 days, Week 8 
This visit may be performed on site or as a home-visit.  
The following procedures will be performed: 
• Record vital signs including systolic and diastolic blood pressure (measured after 
5 minutes in a seated resting position) and heart rate  
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
• Obtain fasting blood samples for:  
- 
Lipids panel 
- 
Liver function panel 
- 
CPK 
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- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9. 
• Collect used auto-injector device (as described in Section 9.1) 
• Record treatment compliance 
• Contact IRT for allocation of a kit number for SYDNEY  
• Record the kit number allocated in the e-CRF 
• Dispense the SYDNEY device to the patient if the injection is to be administered on site, 
or to the Visiting Nurse if the injection is to be administered at home 
• Dispense patient diary, to be completed after the injection 
• Dispense Injection Experience Questionnaire, to be completed after the injection 
• Collect and return the study supplies and diary (performed by the Visiting Nurse if the 
visit is completed at home)   
• Dispense the SYDNEY device, injection to be administered at home 
• Confirm scheduled  visit for Week 12 (Day 85 [± 3 days]Visit 8)  
• Remind patient to be in fasting conditions (ie overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next visit are discouraged 
• Review patient diary and record patient complaint (including PTC) in the Patient 
complaints form (for the Week 8 injection), if any (as described in Section 9.1), after 
received from the patient or the Visiting Nurse. 
10.1.6 Visit 8 (end-of-treatment): Day 85 ± 3 days, Week 12 
This visit must be performed on site.  
The following procedures will be performed: 
• Record vital signs including systolic and diastolic blood pressure (measured after 
5 minutes in a seated resting position) and heart rate  
• Record concomitant medications  
• Record AEs (including SAE and AESI) 
• Prior to dosing with IMP, obtain fasting blood samples for: 
- 
Lipids panel  
- 
Liver function panel 
- 
CPK 
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
• Collect used auto-injector device (as described in Section 9.1) 
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• Collect previous diary  
• Collect previous injection experience questionnaire 
• Record treatment compliance 
• Dispense injection experience questionnaire to be completed on site 
• Dispense patient perspective questionnaire to be completed on site 
• Dispense Injection-Treatment Acceptance Questionnaire (I-TAQ©) to be completed on 
site 
• Contact IRT for allocation of a kit number for SYDNEY  
• Record the kit number allocated in the e-CRF 
• Dispense the SYDNEY device, injection to be  administered on site under observation  by 
the site staff, without any guidance (considered unsupervised) 
• Dispense patient diary to be completed on site 
• Record in the appropriate e-CRF page if the self-injection was performed appropriately 
with the full injection done 
• Review patient diary  and record patient complaint (including PTC) in the Patient 
complaints form, if  any reported for this injection (as described in Section 9.1)  
• Schedule home-visits or on-site visits according to patient preference for Visit 9 
(Week 13), Visit 10 (Week 14), and Visit 11 (Week 15) 
• Schedule a visit for Week 16 (Day 113 [± 3 day],Visit 12) 
10.1.7 Visit 9: Day 92 ± 1 day, Week 13; Visit 10: Day 99 ± 1 day, Week 14; Visit 11: 
Day 106 ± 1 day, Week 15 
These visits may be performed on site or as home-visits. 
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
• Obtain blood samples for: 
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
• Remind patient to be in fasting conditions (ie overnight, at least 10 to 12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the next visit are discouraged.  
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10.1.8 Visit 12 (end-of-study): Day 113 ± 3 days, Week 16 
This visit must be performed on site.  
The following procedures will be performed: 
• Perform a physical examination, including body weight 
• Record vital signs including systolic and diastolic blood pressure (measured after 
5 minutes in a seated resting position) and heart rate 
• Record concomitant medications 
• Record AEs (including SAE and AESI) 
• Obtain fasting blood samples for: 
- 
Lipids panel 
- 
Hematology  
- 
Biochemistry 
- 
Liver function panel. 
- 
CPK  
- 
Pharmacokinetics: PK parameters including assay of total and free PCSK9 
- 
Detection of anti-alirocmab antibodies.  
• Obtain urine sample for pregnancy test (for WOCBP, only) 
• Contact IRT to update the patient’s status (study completion). 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
• Agreement, date, and signature of informed consent mentioning the study identification. 
• Patient identification, medical history, associated diseases, and data related to the studied 
pathology. 
• Contraception methods for women of childbearing potential. 
• Previous and concomitant medications (including the LMT). 
• Study identification. 
• Treatment number, dates of administration. 
• Dates of visits and assessments including the examination report. 
• Vital signs, height, body weight. 
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• IRT confirmation (screening, screen failure, training kit allocation, randomization, 
treatment reallocation, discontinuation, EOT, EOS). 
• AEs and follow-up: 
- In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE. 
• Date of premature study discontinuation (if any) and reason 
• Visiting Nurse records. 
Source documentation may be found in the following: 
• Patient’s chart 
• Patient diaries 
• Patient perspective questionnaire 
• Injection experience questionnaire 
• Injection-Treatment Acceptance Questionnaire (I-TAQ©) 
• Central and local laboratory reports. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
• Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met (refer to Section 10.3.3 and  
Section 10.3.4). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF.  
Temporary treatment discontinuation is defined as one or more scheduled injections that are not 
administered to the patient as decided by the Investigator 
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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
Patient withdrawal from the study treatment or study should be avoided as much as possible. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF.  
Patients should discontinue IMP for the following reasons: 
• Pregnancy, intention for pregnancy, or no longer using effective contraceptive method of 
birth control (females only). 
• Acute injection reaction of clinical concern. 
• Serious or severe hypersensitivity reaction considered related to IMP. 
• At patient request, ie, withdrawal of consent for treatment. 
• If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
• Intercurrent condition that requires discontinuation of the IMP. 
• At the specific request of the Sponsor. 
Any abnormal laboratory value will be immediately rechecked for confirmation (after 24 hours) 
before making a decision of permanent discontinuation of the IMP for the concerned patient. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be followed-
up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedures normally planned for the last dosing day with the IMP (this EOT visit should 
take place within 5 days of treatment discontinuation, if possible) including a PK sample, if 
appropriate.  
The patient, at a minimum, should then be followed-up for 4 weeks from the last administration of 
IMP or until recovery or stabilization of any AE as specified in this protocol, whichever comes 
last. A final end of study visit will take place 4 weeks after the premature discontinuation.  
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All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. IRT should be notified when a 
patient prematurely discontinues study treatment. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason without any effect on their care. However, if patients no longer 
wish to take the IMP, they will be encouraged to remain in the study. If possible, the patients are 
assessed using the procedure normally planned for the EOS visit including a PK sample. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented.  
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
Patients who have withdrawn from the study cannot be rerandomized in the study. Their inclusion 
and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
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10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered a medically important event. The list 
is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
• 
Allergic bronchospasm  
• 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
• 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Required Intervention to Prevent Permanent Impairment or Damage (Devices):  
If you believe that the intervention was necessary to preclude permanent impairment of 
a body function, or prevent permanent damage to a body structure, either situation 
suspected to be due to the use of a medical product.  
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10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
Adverse Events of Special Interest (AESI) are AEs (serious or non-serious) that need to be 
monitored, documented, and managed in a pre-specified manner described in the protocol.  
For these AEs, the Sponsor will be informed immediately (ie within 24 hours), as per SAEs 
notification described in Section 10.4.1.2 even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF. 
The following AEs are considered as AESIs in the study: 
• Pregnancy occurring in a female patient entered in the clinical trial or in a female partner 
of a male patient entered in the clinical trial.  
- 
It will be qualified as an SAE only if it fulfills one of the seriousness criteria (see 
Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
- 
The circumstances (ie, accidental or intentional) should be clearly specified in the 
verbatim and symptoms, if any, entered on separate AE forms.  
• Increase in alanine transaminase (ALT): ALT ≥3 x ULN (if baseline ALT <ULN) or 
ALT ≥2 times the baseline value (if baseline ALT ≥ULN) (see the “Increase in ALT” flow 
diagram in Appendix E. 
• General allergic events: 
- 
Any general allergic events regardless of the cause that require consultation with 
another physician for further evaluation of hypersensitivity/allergy as per the 
Investigator’s medical judgment should be reported as an AESI.  
- 
All general allergic events require completion of the specific e-CRF screen. 
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• Local injection site reactions:   
- 
 Local injection site reactions that require consultation with another physician for 
further evaluation of hypersensitivity/allergy as per the Investigator’s medical 
judgment should be reported as an AESI.  
All LISR require completion of the specific e-CRF screen. 
Note:  
- 
Other LISR are non-AESIs. Please see Section 10.6 for details. 
- 
The safety instructions on allergic events and LISR are detailed in Section 10.6. 
• Neurologic events: neurologic events that require additional examinations/procedures 
and/or referral to a specialist should be reported as an AESI. If the event does not require 
additional examinations/procedures and/or referral to a specialist, it should be reported as 
a standard AE. 
• Neurocognitive events:  All neurocognitive events will be considered as AESI. 
10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
Patients who experience an ongoing SAE or an AESI, at the prespecified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected.  
• When treatment is prematurely discontinued, the patient, at a minimum, should then be 
followed-up for 4 Weeks from the last administration of IMP or until recovery or 
stabilization of any AE as specified in this protocol, whichever comes last. A final end of 
study visit will take place 4 weeks after the premature discontinuation. 
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• Laboratory and vital signs abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
Instructions for AE reporting are summarized in Table 9. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. If the e-CRF system does not work, the investigator must 
report an SAE to the Sanofi representative within 24 hours, and the Sanofi representative 
must report the SAE to Global Pharmacovigilance & Epidemiology (GPE) within 
1 working day. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 9. 
Table 9 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, non-
AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited 
(within 24 hours) 
Acute hypersensitivity/ anaphylaxis 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT increase as defined in the protocol 
Yes 
Yes 
Yes 
 
 
General allergic event requiring 
consultation with another physician 
Yes 
Yes 
Yes  
 
 
 
Local injection site reactions requiring 
consultation with another physician 
Yes 
Yes 
Yes  
 
 
 
Neurologic events that require additional 
examinations/procedures and/or referral 
to a specialist  
Yes 
Yes 
Yes 
 
 
Neurocognitive events (any)  
Yes 
Yes 
Yes 
 
10.4.5 Guidelines for reporting product complaints 
Any patient complaint related to the device (SYDNEY or AI)/ injection process must be reported 
in the Patient complaints form as soon as possible by the Investigator.  
Appropriate information in addition to the device (eg, labels or documents like pictures or 
photocopies) related to product identification and to the potential deficiencies may need to be 
gathered.  
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The completed Patient Complaints form and the corresponding device (both elements referred as 
“complaint sample”) will be sent to the R&D complaint office. 
The Investigator will assess whether or not the quality issue has to be reported together with an 
AE or SAE. 
10.5 
OBLIGATIONS OF THE 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 IMP (SUSAR), to 
the regulatory authorities, Independent Ethics Committee (IECs)/Institutional Review 
Boards (IRBs) as appropriate and to the Investigators.   
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Adverse events that are considered expected will be specified by the reference safety information 
(Investigator’s brochure). 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Local tolerability (local injection site reactions) 
In case the Investigator or the patient recognizes any signs of local intolerability, then this should 
be treated and followed-up as per the Investigator’s medical judgment. Specific e-CRF screens are 
to be filled in. Information on classifying the reaction is provided in Section 10.4, and on 
reporting these reactions is given in Appendix G. 
Local injection site reactions that are related to the alirocumab injection, as opposed to another 
injectable agent, should be further characterized by evaluating the related symptoms that comprise 
an injection site reaction such as but not limited to redness, pain, etc. If the patient experiences a 
local injection site reaction with no signs or symptoms except for erythema/redness, and/or 
swelling, and the diameter of the erythema/ redness, or swelling measure <2.5 cm, no AE for local 
injection site reaction needs to be reported as this is not typically considered a clinically important 
finding. However, if the patient has a reaction of swelling with a diameter <2.5 cm that interferes 
with activity, then it should be considered as a clinically relevant finding and should be reported 
as an AE with a corresponding grade of moderate or severe, in accordance with Appendix G. 
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10.6.2 General allergic adverse events 
Specific e-CRF screens are to be filled in to assess allergic AEs or allergic-like AE that may occur 
during the clinical studies conducted with alirocumab. Sometimes transient injection site 
reactions, irritant in nature, may occur, requiring no intervention and being of dubious 
significance. These reactions would not be considered to be allergic reactions. Adverse events that 
may constitute an allergic reaction (eg, generalized itch, nasal itch, swelling at injection site, 
flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, difficulty to 
swallow, hoarseness, change in pitch of voice, incapacity to speak, wheezing, chest tightness, 
stridor, etc) should be considered to be reported on the General Allergic Event and/or Local 
Injection Site Reaction Complementary Form. 
Adverse events that are obviously not of allergic origin (eg, LISR related to mechanics of 
injection) should only be recorded on the Local Injection Site Reaction Complementary Form. 
However, injection site reactions that progress/expand/worsen/etc should be evaluated as 
recommended in Appendix G and General Allergic Reaction Complementary form should be 
completed. 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP. See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.3 for criteria for permanent treatment discontinuation. 
10.6.2.1 Allergic adverse event with cutaneous involvement 
Adverse events with cutaneous involvement which are obviously of allergic origin or injection 
site reactions which progress/expand/worsen/etc. should be evaluated by a dermatologist as soon 
as possible, and preferably within one week of the site first becoming aware of the event. 
The Investigator should evaluate the patient for possible etiologies (new medications, etc) and 
extracutaneous symptoms and signs. An unscheduled assessment for hematology, chemistry, liver 
panel, and PK should be obtained. An additional blood sample will have to be drawn for anti-
alirocumab antibody analyses (adequate instructions will be provided to the site by the Monitor). 
If it is possible, the site will take pictures of the skin lesions in order to provide the patient with 
them for the dermatologist’s visit. If the photos are obtained, then copies should be kept as source 
documents which may later be collected by the sponsor. The Investigator will provide a summary 
of the patient's case, reason for consultation, and information being requested to the consulting 
dermatologist.  
A full consultation report should be sent by the dermatologist to the Investigator. The full report 
should contain, at a minimum, the following information; a detailed description of the rash (such 
as the morphology [lesion type], shape of individual lesions, arrangement of multiple lesions [eg, 
scattered, grouped, linear], distribution, color, consistency, presence of pruritus or pain, and other 
clinical signs) and in case a skin biopsy (including histopathology and immunofluorescence) was 
done (if it was deemed necessary as per the dermatologist’s or Investigator’s medical judgment), 
the results of this investigation with, if applicable, a specific diagnosis of the AE. The Investigator 
will fax the full report and the corrected AE form if necessary, to the Monitoring Team 
Representative within 24 hours. 
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10.6.2.2 Acute allergic injection reactions 
Acute allergic injection reaction (which are considered under the category of general allergic 
events) is defined as any AE that occurs during or shortly after injection of the IMP (characterized 
by but not limited to hypotension, bronchoconstriction, urticaria, edema, angioedema, nausea, 
vomiting). Emergency equipment and medication for the treatment of these potential adverse 
effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, acetaminophen, and 
epinephrine) must be available for immediate use for the injections at the training, and inclusion 
visits. Patients will be observed at the investigational site for at least 30 minutes following the 
injection that takes place at the inclusion visit. Patients should be treated symptomatically if any 
AEs are observed. Patients are to remain at the site until any acute injection reaction is assessed as 
stable, per the Investigator’s discretion.  
A General Allergic Event and/or Local Injection Site Reaction Complementary Form will have to 
be completed. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size was calculated, the sample size is based on empirical considerations. 
Considering a drop-out rate of 10% it is planned to randomize 66 patients overall (33 in each 
group) in order to ensure 60 evaluable patients overall (30 in each group) resulting in 
180 unsupervised planned injections using SYDNEY, including the 2nd, 3rd and 4th unsupervised 
injections with SYDNEY for patients randomized in the AI group who will switch to SYDNEY 
group just before the second injection. 
 
With 60 evaluable patients using SYDNEY, a total of 180 unsupervised injections is expected to 
be achieved during the study. Expecting a maximum of 3 observed PTC over the 180 injections 
(observed PTC rate of 1.67%) with SYDNEY, the upper bound of the 2-sided 95% confidence 
interval calculated with the Wilson score method will be no higher than 5.2%.   
11.2 
 DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and none of the 
exclusion criteria, and signed the informed consent. 
Randomized patients are all screened patients with a treatment kit number allocated and recorded 
in the IRT database, regardless of whether or not the treatment kit was used. These patients form 
the randomized population. Patients treated without being randomized will not be considered as 
randomized. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be included in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Modified intent-to-treat populations 
The primary efficacy analysis population that will be used for the analyses of LDL-C will be the 
modified intent-to-treat (mITT ) population.  
The mITT population of the parallel arms period will consist of all randomized patients who 
receive at least 1 dose or part of a dose of IMP visit during this period and who had an evaluable 
value of LDL-C at baseline and an on-treatment LDL-C value within Week 4 analysis window. 
The treatment period for the parallel arms period is defined as the time period from the first IMP 
injection up to 35 days after this injection or up to the day before the second injection, whichever 
comes first. Patients in this mITT population will be analyzed according to the auto-injector 
device group allocated by randomization (ie, as-randomized treatment group). 
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The mITT population of the single-arm period will consist of all randomized patients who 
continue in single-arm period and receive at least 1 dose or part of a dose of IMP of this period 
and who had an evaluable value of LDL-C at baseline and at least one on-treatment LDL-C within 
one of the analysis windows from Week 8 to Week 16. The treatment period for the single-arm 
period is defined as the time period from the second IMP injection up to 35 days after the last IMP 
injection for patients entering into the single arm period. 
11.3.2 Safety populations 
The safety population of the parallel arms period will consist of all randomized patients who 
receive at least 1 dose or part of a dose of IMP during this period. Patient data will be analyzed 
according to the auto-injector device actually used. 
The safety population of the single-arm period will consist of all randomized patients who 
continue in the single-arm period and receive at least 1 dose or part of a dose of IMP during this 
period. 
All safety and PTC analyses will be performed on these populations.  
In addition: 
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
• For a patient receiving injections with an auto-injector device different than the 
randomized auto-injector device during the parallel-arms period, the auto-injector device 
group allocation for as-treated analysis will be the auto-injector device actually used. 
11.3.3 Pharmacokinetic populations 
The PK population of the parallel-arms period will consist of all randomized patients who receive 
at least at least 1 dose or part of a dose of IMP and had at least one evaluable blood sample for PK 
during this period. All patients will be analyzed according to the auto-injector device that they 
actually used.  
The PK population of the single-arm period will consist of all randomized patients who receive at 
least 1 dose or part of a dose of IMP and had at least one evaluable blood sample for PK during 
this period. 
These PK populations will be used for the analyses of alirocumab concentrations and PCSK9 
concentrations. 
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11.3.4 Anti-alirocumab antibody population 
The anti-alirocumab antibody population of the parallel-arm period will consist of all randomized 
patients who receive at least 1 dose or part of a dose of IMP during this period (safety population) 
with an available ADA sample at baseline and at least one post-baseline available ADA sample 
during this period. 
The anti-alirocumab antibody population of the single-arm period will consist of all randomized 
patients who receive at least 1 dose or part of a dose of IMP during this period (safety population) 
with an available ADA sample at baseline and at least one post-baseline available ADA sample 
during this period. 
11.4 
STATISTICAL METHODS 
Unless otherwise specified, analyses will be performed by auto-injector device group in the 
parallel-arms period and overall in the single-arm period.  
The baseline value is defined as the last available value obtained up to the date and time of the 
first IMP administration. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual auto-injector device used within the safety population for each study period. 
11.4.1.1 Extent of investigational medicinal product exposure 
No duration of IMP exposure will be calculated for the parallel-arms period since patients will 
receive only one injection during this period. The proportion of patients having received the first 
injection will be summarized. 
The duration of IMP exposure for the single-arm period is defined as: last IMP injection 
date - first IMP injection date during this period + 28 days (regardless of unplanned intermittent 
discontinuations). The number of injections received during the single-arm period will also be 
summarized.   
11.4.1.2 Compliance  
No treatment compliance to the IMP will be calculated for the parallel-arms period since patients 
will receive only one injection during this period. 
Treatment compliance to the IMP for the single-arm period will be assessed using the mean 
injection frequency, defined for each patient, as the average number of days between 2 
consecutive injections, that is: (last injection date – first injection date during this period)/(number 
of injections -1) for patients receiving at least 2 injections during this period. 
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11.4.2 Analyses of primary endpoint 
The primary endpoint (ie, number (%) and types of SYDNEY-associated PTCs related to the 
unsupervised injections [Section 9.1]) will be described on the safety population for the single 
arm period. The number and % of PTCs will be provided with the 95% CI using Wilson score 
method. If applicable, the number of PTCs per patient will be described. In addition the type of 
PTCs will be described. 
11.4.3 Analyses of secondary efficacy endpoints 
All secondary device-related endpoints (Section 9.2.1) will be analyzed on the safety population 
using descriptive statistics. In addition, 95% CI for the number of PTCs, number and % of 
patients with any PTCs will be provided using Wilson score method.   
11.4.4 Analyses of safety data 
Safety data will be presented on the safety population of the parallel-arm period and of the 
single-arm period. Treatment-emergent adverse events (TEAEs), treatment-emergent SAEs, 
treatment-emergent AESIs,  and TEAEs leading to treatment discontinuation, will be summarized 
based on the Medical Dictionary for Regulatory Activities (MedDRA) coding of verbatim terms 
reported by investigators (Section 9.2.5). 
All safety analyses will be performed using the following common rules: 
• The observation period to be used for the safety population is the TEAE period. The 
TEAE period is defined  
- 
For the parallel-arms period as the time from the first IMP injection to the day before 
the second IMP injection (for patients entering into the single arm period period) or to 
70 days after the first IMP injection, whichever comes first 
- 
For the single-arm period as the time from the first IMP injection received in the single 
arm period to 70 days after the last IMP injection. 
The following definitions will be applied to laboratory parameters, and vital signs: 
• The potentially clinically significant abnormality (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. 
• Potentially clinically significant abnormality criteria will determine which patients had at 
least 1 PCSA during the TEAE period, taking into account all evaluations performed, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
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• Treatment period: the treatment period used for quantitative analysis is defined: 
- 
For the parallel-arms period as the time from the first IMP injection to 35 days after 
this injection or to the day before the second IMP injection (for patients entering into 
the single arm period period) whichever comes first. 
- 
For the single-arm period as the time from the first IMP injection received in the single 
arm period to 35 days after the last IMP injection. 
11.4.4.1 Analysis of the adverse event data 
The analyses of AEs will focus on TEAEs. Treatment-emergent AEs are defined as any AEs that 
are newly developed or worsened or that become serious during the TEAE period.  
Treatment-emergent AE incidence tables will present the number (%) of patients experiencing at 
least 1 TEAE by system organ class (SOC) (sorted by internationally agreed order), high-level 
group term (HLGT), high-level term (HLT) and preferred term (PT) sorted in alphabetical order. 
Multiple occurrences of the same event in the same patient will be counted only once in the tables 
within a treatment phase. The denominator for computation of percentages is the safety population 
within each auto-injector device group. 
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all 
treatment-emergent AESI (defined with a PT or a prespecified grouping), all treatment-emergent 
SAEs and all TEAEs leading to permanent treatment discontinuation. 
Death: The following summaries will be provided: 
• Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population  
• Death in nonrandomized patients or randomized and not treated patients 
• TEAE leading to death (death as an outcome on the Adverse Event CRF page as reported 
by the Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of 
patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, 
HLT, and PT. 
11.4.4.2 Analysis of the laboratory data 
For laboratory data, including the incidence of PCSAs, actual values and change from baseline 
will be summarized by treatment group.  
The number and percentage of patients with at least 1 PCSA at any time during the TEAE period 
will be summarized for each laboratory parameter.  Shift tables showing changes with respect to 
the baseline status will be provided. 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory variables will be calculated for each visit (baseline, each post-baseline 
time point, endpoint) by auto-injector device group.  
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11.4.4.3 Summary of the vital sign data 
The number and percentage of patients with at least 1 PCSA at any time during the TEAE period 
will be summarized for each vital signs variable. Shift tables showing changes with respect to the 
baseline status will be provided.  
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables will be calculated over time. 
11.4.5 Analyses of pharmacokinetic, pharmacodynamics and anti-alirocumab antibodies 
variables 
Pharmacokinetic parameters (Cmax, tmax, AUC0-tau and Ctrough) will be summarized (mean, 
geometric mean, median, standard deviation, standard error of mean, coefficient of variation, 
minimum, and maximum) for each  auto-injector device in the parallel-arms period and overall in 
the single-arm period (See Section 9.2.2). 
For PK parameters log-transformed Cmax, AUC0-tau and Ctrough, estimates and 90% CI for the ratio 
of geometric means (SYDNEY/current AI) will be provided using a linear fixed effects model 
with baseline body weight as covariate. 
Total and free PCSK9 concentrations will be summarized by visit using descriptive statistics.   
Percent and absolute change from baseline in LDL-C will be summarized descriptively for each 
auto-injector device. 
The anti-drug antibodies (ADA) status (positive/negative) and antibody titers will be summarized 
using descriptive statistics. Further details will be provided in SAP. 
11.4.6 Analyses of efficacy variables 
Lipid variables will be summarized (mean, median, standard deviation, minimum, and maximum) 
in percent and absolute change from baseline (See efficacy assessments - Section 9.2.4). 
In addition, at Week 4 only, percent change from baseline in LDL-C will be analyzed using an 
ANCOVA model to determine the estimates and 95% confidence intervals for both SYDNEY and 
AI. 
11.5 
INTERIM ANALYSIS 
Not applicable. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Sub investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda or labeling documents (summary of product characteristics, package insert), 
Investigator’s curriculum vitae, etc) and the date of the review should be clearly stated on the 
written (IRB/IEC) approval/favorable opinion. 
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The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file.  
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database, shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio 
• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European 
Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The 
Fifth Joint Task Force of the European Society of Cardiology and Other Societies on 
Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 
nine societies and by invited experts). Eur Heart J. 2012 Jul;33(13):1635-701. 
2. 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. M3(R2): Guidance on nonclinical safety studies for the 
conduct of human clinical trials and marketing authorization for pharmaceuticals. ICH. 
June 2009. 30 p. 
3. 
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density 
lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin 
Chem.1972; 18(6): 499-502. 
 
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17 
APPENDICES 
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Appendix A 
Guidance on contraceptive methods  
 
Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulationb 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method(s) of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
• Sexual abstinence 
(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 drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects 
participating in clinical studies. It is also recommended to continue using an effective contraceptive 
method for at least 4 weeks after the last injection of IMP. 
 
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Appendix B 
Procedures for handling patient complaints with identification of potential product technical complaints  
 
PROCEDURE FOR IDENTIFICATION OF POTENTIAL PRODUCT TECHNICAL COMPLAINTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient’s responsibility  
For self-injection at home: to complete the diary and 
identify potential PTC associated with the device  
To bring to the next site visit the device together with 
the diary, or provide it to the nurse for a home visit 
Investigator’s responsibility  
Prepare the "Complaint Sample": Patient Complaints 
Form + the concerned device (To be shipped together) 
Sponsor’s responsibility  
R&D complaint office : first assessment to decide whether the 
complaint is: packaging related or device or patient related / 
potential PTC
Packaging related: 
Other sites (e.g. clinical packaging 
Device related or patient 
related/potential PTC: 
Technical evaluation 
Patient-related 
Device-related  
undetermined 
  
PTC = product technical complaint 
 Not related to 
device nor patient 
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Appendix C 
Patient Related Questionnaires 
 
1. Injection experience questionnaire 
Patient Questions for Praluent/Sydney Take-Home Bridging Study 
STUDY NUMBER: MSC14864 
 
Injection Experience Questionnaire – Arm 1/Current AI device 
 (For Day 1 injection only) 
To be completed after each injection 
 
Please answer these questions immediately after you finish each injection. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Injection Experience Questionnaire – Arm 2 + Arm 1 after switch to 
modified device (SYDNEY) 
To be completed after each injection 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. Patient Perspective Questionnaire 
Patient Perspective Questionnaire 
To be completed after your final injection 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
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3. Injection – Treatment Acceptance Questionnaire (I-TAQ) 
 
 
 
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Appendix D 
Definition of Cardiovascular Disease Risk Categories  
 
• Very high CV risk is defined as a history of documented CHD, ischemic stroke, transient 
ischemic attack, carotid artery occlusion >50% without symptoms, carotid endarterectomy 
or carotid artery stent procedure, peripheral arterial disease, abdominal aortic aneurysm, 
renal artery stenosis, renal artery stent procedure, type 1 or type 2 diabetes mellitus with 
target organ damage. 
A history of documented CHD includes 1 or more of the following: 
- 
Acute myocardial infarction. 
- 
Silent myocardial infarction. 
- 
Unstable angina. 
- 
Coronary revascularization procedure (eg, percutaneous coronary intervention or 
coronary artery bypass graft surgery). 
- 
Clinically significant CHD diagnosed by invasive or non-invasive testing (such as 
coronary angiography, stress test using treadmill, stress echocardiography or nuclear 
imaging). 
• High CV risk is defined as a calculated 10-year fatal CVD risk SCORE ≥5% (1), 
moderate chronic kidney disease, type 1 or type 2 diabetes mellitus without target organ 
damage, or heFH. 
• Moderate CV risk is defined as a calculated 10-year fatal CVD risk SCORE ≥1 and 
<5% (1). 
 
 
 
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Appendix E 
General guidance for the follow-up of ALT increase by Sanofi 
INCREASE IN ALT
ALT ≥3 ULN (if baseline ALT <ULN) 
Or, ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)
ALT ≤5 ULN
(if baseline ALT < ULN)
Or, ALT ≤3 times the baseline 
value
ALT > 5 ULN
(if baselineALT < ULN)
Or, ALT > 3 times the 
baseline value
Total bilirubin ≤2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOWthe instructions #1 to 6 listed in the box below. 
1. INVESTIGATEspecifically for malaise with or without loss of consciousness,dizziness, and/or hypotension 
and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
2. PERFORMthe following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubinand ProthrombinTime / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, 
- Auto-antibodies : anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
- Depending on the clinical context, check for recent infection with ?EBV, Herpes viruses and toxoplasma
- Hepatobiliaryultrasonography(can be completed by other imaging investigations if needed)
3. CONSIDERconsultation with hepatologist
4. CONSIDERpatient hospitalisationif INR>2 (or PT<50%) and/or central nervous system disturbancesuggesting 
hepatic encephalopathy.
5. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hoursuntil return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal productis discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
6. FREEZEserum (5 ml X 2) 
Monitor LFTs
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
ALT ≥3 ULN (if baseline ALT <ULN) 
Or, ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)
ALT ≤5 ULN
(if baseline ALT < ULN)
Or, ALT ≤3 times the baseline 
value
ALT > 5 ULN
(if baselineALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ≥ULN 
Total bilirubin ≤2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOWthe instructions #1 to 6 listed in the box below. 
1. INVESTIGATE specifically for malaise with or without loss of consciousness,dizziness, and/or hypotension 
and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
2. PERFORMthe following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubin and ProthrombinTime / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti- CMV IgM and anti- HEV IgM antibodies, 
- Auto-antibodies : anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
- Depending on the clinical context, check for recent infection with EBV, Herpes viruses and toxoplasma
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDERconsultation with hepatologist
4. CONSIDERpatient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disturbancessuggesting 
hepatic encephalopathy.
5. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal productis discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
6. FREEZEserum (5 ml X 2) 
Monitor LFTs
every 48 hours
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
COMPLETE the 
specific CRF form 
for “Liver Injury”
and INFORM the 
Monitoring Team 
within 24 hours
(if baseline ALT ≥ULN 
INCREASE IN ALT
ALT ≥3 ULN (if baseline ALT <ULN) 
Or, ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)
ALT ≤5 ULN
(if baseline ALT < ULN)
Or, ALT ≤3 times the baseline 
value
ALT > 5 ULN
(if baselineALT < ULN)
Or, ALT > 3 times the 
baseline value
Total bilirubin ≤2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOWthe instructions #1 to 6 listed in the box below. 
1. INVESTIGATEspecifically for malaise with or without loss of consciousness,dizziness, and/or hypotension 
and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
2. PERFORMthe following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubinand ProthrombinTime / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, 
- Auto-antibodies : anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
- Depending on the clinical context, check for recent infection with ?EBV, Herpes viruses and toxoplasma
- Hepatobiliaryultrasonography(can be completed by other imaging investigations if needed)
3. CONSIDERconsultation with hepatologist
4. CONSIDERpatient hospitalisationif INR>2 (or PT<50%) and/or central nervous system disturbancesuggesting 
hepatic encephalopathy.
5. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hoursuntil return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal productis discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
6. FREEZEserum (5 ml X 2) 
Monitor LFTs
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
ALT ≥3 ULN (if baseline ALT <ULN) 
Or, ALT ≥2 times the baseline value 
(if baseline ALT ≥ULN)
ALT ≤5 ULN
(if baseline ALT < ULN)
Or, ALT ≤3 times the baseline 
value
ALT > 5 ULN
(if baselineALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ≥ULN 
Total bilirubin ≤2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOWthe instructions #1 to 6 listed in the box below. 
1. INVESTIGATE specifically for malaise with or without loss of consciousness,dizziness, and/or hypotension 
and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
2. PERFORMthe following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubin and ProthrombinTime / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti- CMV IgM and anti- HEV IgM antibodies, 
- Auto-antibodies : anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
- Depending on the clinical context, check for recent infection with EBV, Herpes viruses and toxoplasma
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDERconsultation with hepatologist
4. CONSIDERpatient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disturbancessuggesting 
hepatic encephalopathy.
5. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal productis discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
6. FREEZEserum (5 ml X 2) 
Monitor LFTs
every 48 hours
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
COMPLETE the 
specific CRF form 
for “Liver Injury”
and INFORM the 
Monitoring Team 
within 24 hours
(if baseline ALT ≥ULN 
 
(electronic 
 
 
 
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Clinical Trial Protocol  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 95 
Appendix F 
Procedure for collection, handling, storage and shipment of 
SAR236533, pharmacokinetic, and anti-SAR236553 antibody 
samples 
1. SAMPLING SUPPLIES DESCRIPTION   
Collection material: 5mL red-top vacutainer tubes (containing no additives or 
anti-coagulant, B-D Cat #367814; Vacutainer 5mL tubes) for serum 
Serum SAR236553 samples 
Storage tube:  
 
Aliquot approximately equal volumes of serum into TWO separate 1.8 mL plastic 
2D barcoded cryovials, one for the primary aliquot and one for the duplicate 
aliquot. Do not exceed 1.0 mL of serum into each cryovial. Use one of the 
approved cryovials listed below. 
• Nunc Item # 374502 
• VWR: Catalog # 89233-708 
• ThermoFisher/USA Scientific: Catalog # 12590007 
 
Collection material: 5mL red-top vacutainer tubes (containing no additives or 
anti-coagulant, B-D Cat #367814; Vacutainer 5mL tubes) for serum 
Serum Anti-SAR236553 
antibody (ADA) samples 
Storage tube:  
Aliquot approximately equal volumes of serum into TWO separate 1.8 mL plastic 
2D barcoded cryovials, one for the primary aliquot and one for the duplicate 
aliquot. Do not exceed 1.0 mL of serum into each cryovial. Use one of the 
approved cryovials listed below. 
• Nunc Item# 374502 
• VWR: Catalog # 89233-708 
• ThermoFisher/USA Scientific: Catalog # 12590007 
 
Refrigerated centrifuge 
Collection material provided by Contract Research Organization (CRO) 
Specimen storage labels for SAR236553 provided by: CRO 
Specimen storage labels for anti- SAR236553 provided by: CRO 
Specimen storage tube labels for pharmacogenetic specimens provided by 
Covance, Indianapolis, IN 
Miscellaneous 
Styrofoam shippers with boxes, shipping labels, Ziplock storage bag, and any 
other necessary packaging supplies in order to comply with IATA Dangerous 
Goods 
Regulations, Packing Instructions 650 for shipment below 0°C. 
 
(electronic 
 
 
 
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Clinical Trial Protocol  
20-Nov-2017 
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 96 
 
2. SERUM SAR236553 AND ANTI-SAR236553 ANTIBODY (ADA) SAMPLES 
2. 1 Collection/Handling/Processing of Samples 
Collection schedule 
Per protocol 
PK Serum Sample Collection and Preparation 
• At intervals stated in the clinical study protocol, whole blood from subjects will be 
collected in 5-mL red-top vacutainer tubes (US B-D Cat #367814, European B-D Cat 
#369032) containing clot activator and no additional additives or anti-coagulant for PK 
SERUM sample preparation.  
• Collect 5 mL blood directly into 5-mL red-top vacutainer tube and invert 5 times. 
• Allow blood to clot for 30 minutes.   
• Centrifuge at approximately 1200 x g for 15 minutes to separate clot from serum. 
• Within 30 minutes after centrifugation, draw off serum very slowly with transfer pipette, 
approaching no closer than 0.5 cm of the buffy coat and taking great care not to disturb the 
buffy coat (any contamination may invalidate the assay).   
• All cryovials must be properly labeled with labels provided by CRO as per the laboratory 
manual.  
• Aliquot approximately equal volumes of serum into TWO separate 1.8-mL plastic 2D 
barcoded cryovials, one for the primary aliquot and one for the duplicate aliquot.  Do not 
exceed 1 mL of serum into each cryovial. Use one of the approved cryovials listed below. 
- 
Nunc Item # 374502 
- 
VWR: Catalog # 89233-708  
- 
ThermoFisher/USA Scientific: Catalog # 12590007 
• Freeze all cryovials immediately.  All serum samples must be stored in a -20° C or colder 
freezer that does NOT auto-defrost until the next earliest shipment. For long-term storage, 
all serum samples should be stored in a -80° C freezer. 
- 
Note:  If the site does not have a -20°C or colder freezer that does NOT 
auto-defrost, ship the serum samples on dry ice on the day of collection to CRO. 
• Sites must ship the primary aliquot in a separate shipment from the duplicate aliquot. 
(electronic 
 
 
 
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 97 
ADA Serum Sample Collection and Preparation 
• At intervals stated in the clinical study protocol, whole blood from subjects will be 
collected in 5-mL red-top vacutainer tubes (US BD Cat #367814, European B-D Cat 
#369032) containing clot activator and no additional additives or anti-coagulant for ADA 
SERUM sample preparation.  
• Collect 5 mL blood directly into 5-mL red-top vacutainer tube and invert 5 times. 
• Allow blood to clot for 30 minutes.   
• Centrifuge at approximately 1200 x g for 15 minutes to separate clot from serum. 
• Within 30 minutes after centrifugation, draw off serum very slowly with transfer pipette, 
approaching no closer than 0.5 cm of the buffy coat and taking great care not to disturb the 
buffy coat (any contamination may invalidate the assay). 
• All cryovials must be properly labeled, with labels provided by CRO as per the laboratory 
manual. 
• Aliquot approximately equal volumes of serum into TWO separate 1.8-mL plastic 2D 
barcoded cryovials, one for the primary aliquot and one for the duplicate aliquot.  Do not 
exceed 1 mL of serum into each cryovial. Use one of the approved cryovials listed below. 
- 
Nunc Item# 374502 
- 
VWR: Catalog # 89233-708  
- 
ThermoFisher/USA Scientific: Catalog # 12590007 
• Freeze all cryovials immediately.  All serum samples must be stored in a -20° C or colder 
freezer that does NOT auto-defrost until the next earliest shipment. For long-term storage, 
all serum samples should be stored in a -80° C freezer. 
- 
Note:  If the site does not have a -20°C or colder freezer that does NOT 
auto-defrost, ship the serum samples on dry ice on the day of collection to PPD 
Central Labs.  
• Sites must ship the primary aliquots in a separate shipment from the duplicate aliquots. 
2.2 
Labeling of specimens 
Additional instructions will be provided by the central lab vendor and/or the Sponsor. 
(electronic 
 
 
 
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Clinical Trial Protocol  
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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 98 
Appendix G 
Local injection site reactions assessment 
 
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 
 
 
(electronic 
 
 
 
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Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 99 
Appendix H 
Clinical diagnosis of heterozygous familial hypercholesterolemia 
(heFH) 
WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosis of Heterozygous 
Familial Hypercholesterolemia (heFH) 
 
Diagnostic Scoring for Heterozygous Familial Hypercholesterolemia 
Family history 
a 
First degree relative with known premature (men <55 yrs, women <60 yrs) coronary and vascular disease. 
1 
b 
First degree relative with known LDL-cholesterol >95th percentile for age and sex. 
 
and/or 
a 
First degree relative with tendon xanthomata and/or arcus cornealis. 
2 
b 
Children below 18 yrs. with LDL-cholesterol >95th percentile for age and sex. 
 
 
 
 
Clinical history 
a 
Patient has premature (men <55 yrs, women <60 yrs) coronary artery disease 
2 
b 
Patient has premature (men <55 yrs, women <60 yrs) cerebral or peripheral vascular disease. 
1 
 
 
 
Physical examination 
a 
Tendon xanthomata 
6 
b 
Arcus cornealis below the age of 45 yrs. 
4 
 
 
 
Laboratory analysis 
 
 
mmol/L 
mg/dL 
 
a 
LDL-cholesterol 
>8.5 
>330 
8 
b 
LDL-cholesterol 
6.5-8.4 
250-329 
5 
c 
LDL-cholesterol 
5.0-6.4 
190-249 
3 
d 
LDL-cholesterol 
4.0-4.9 
155-189 
1 
 
(HDL-cholesterol and triglycerides are normal) 
 
 
 
 
DNA-analysis 
a 
Functional mutation low-density lipoprotein receptor gene present 
8 
 
 
 
Diagnosis of heFH is: 
Certain When 
>8 points 
Probable When 
6-8 points 
Possible When 
3-5 points 
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20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 100 
Simon Broome Register Diagnostic Criteria for Heterozygous Familial 
ypercholesterolemia 
 
Definite familial hypercholesterolemia is defined as: 
• 
Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment). 
PLUS 
• 
Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd 
degree relative (grandparent, uncle, aunt). 
OR 
• 
DNA-based evidence of an LDL receptor mutation or familial defective apo B-100. 
 
Possible familial hypercholesterolemia is defined as: 
• 
Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment). 
And at least one of the following: 
• 
Family history of MI below 50 years of age in 2nd degree relative or below 60 years of 
age in 1st degree relative. 
• 
Family history of raised cholesterols >7.5 mmol/L (290 mg/dL) in adult 1st or 2nd degree 
relative or >6.7 mmol/L (260 mg/dL) in child or sibling under 16 years of age. 
 
 
(electronic 
 
 
 
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Page 10

 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MSC14864 16.1.1 Protocol
Clinical Approval
21-Nov-2017 16:09 GMT+0100
Clinical Approval
21-Nov-2017 19:44 GMT+0100
1