Conditions: Hypercholesterolaemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
Primary Objective:

To collect 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.

Secondary Objective:

Device-related:

* To collect real-use (usability) data assessing the robustness and user interaction of SYDNEY and the current alirocumab auto-injector device (which is referred to as AI) in supervised settings.

Pharmacokinetics:

* To compare alirocumab pharmacokinetics (PK) administered using SYDNEY and AI.
* To evaluate alirocumab PK administered using SYDNEY.

Anti-drug antibodies:

* To evaluate the development of anti-drug (alirocumab) antibodies (ADA).

Efficacy/pharmacodynamics:

* To compare the percent and absolute change in low-density lipoprotein cholesterol (LDL-C) using SYDNEY and AI.
* To evaluate the percent and absolute change in LDL-C using SYDNEY.

Safety:

* To evaluate the safety and tolerability of alirocumab using both SYDNEY and AI.

Detailed description:
Total study duration per participant was expected to be up to 18 weeks, with up to 2 weeks of screening period and 16 weeks of study treatment period.

Arms:
arm 1: Alirocumab 300 milligram (mg) subcutaneous (SC) injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm treatment period of 4 weeks. From Week 4, participants switched to other arm of SYDNEY device to receive Alirocumab 300 mg, self- administered (unsupervised) using new auto-injector device (SYDNEY) every 4 weeks (Q4W) from Week 4 until Week 16 in the single arm treatment period added to lipid modifying therapy (LMT). arm 2: Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using new auto-injector device (SYDNEY), on-site under supervision in the parallel arm treatment period of 4 weeks. From Week 4, same treatment (Alirocumab 300 mg) with the same device (SYDNEY) was self-administered, (unsupervised) Q4W until Week 16 in the single arm treatment period added to LMT. Duration of single arm treatment period was 12 weeks, i.e. from Week 4 to 16.

Interventions: intervention 1: Alirocumab SAR236553 intervention 2: Current auto-injector device (AI) intervention 3: New auto-injector device (SYDNEY) intervention 4: Atorvastatin intervention 5: Rosuvastatin
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection Route of administration: Subcutaneous intervention 2: Pharmaceutical form:

Route of administration: Subcutaneous self-administration of alirocumab intervention 3: Pharmaceutical form:

Route of administration: Subcutaneous self-administration of alirocumab intervention 4: Pharmaceutical form:tablet Route of administration: oral intervention 5: Pharmaceutical form:tablet Route of administration: oral

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
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 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
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 
 
4.0)
Page 2


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  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 4 
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)
Page 4


Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 5 
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)
Page 5


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 
(electronic 
 
 
 
4.0)
Page 6


Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
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. 
(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 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). 
(electronic 
 
 
 
4.0)
Page 8


Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
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
(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 10 
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 
 
 
 
 
(electronic 
 
 
4.0)
Page 10


Clinical Trial Protocol  
20-Nov-2017 
SAR236553-MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 11 
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. 
(electronic 
 
 
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Clinical Trial Protocol  
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Page 12 
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). 
 
 
 
(electronic 
 
 
 
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Page 94 
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 
 
 
 
4.0)
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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 
 
 
 
4.0)
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Clinical Trial Protocol  
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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 
 
 
 
4.0)
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Clinical Trial Protocol  
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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 
 
 
 
4.0)
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Clinical Trial Protocol  
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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 
(electronic 
 
 
 
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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 
 
 
 
4.0)
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

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
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 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity. 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
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 
SAR236553/REGN727 - MSC14864
STATISTICIAN: 
 (
)/ 
Statistical Project Leader: 
DATE OF ISSUE: 27-Mar-2018 
Total number of pages: 
44 
(electronic 1.0)
1
NCT Number:  NCT03415178


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................5 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................5 
1.2 
OBJECTIVES...................................................................................................................................5 
1.2.1 
Primary objective..............................................................................................................................5 
1.2.2 
Secondary objectives .......................................................................................................................5 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................6 
1.4 
STUDY PLAN...................................................................................................................................7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................7 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .......................................................................8 
2.1 
ANALYSIS ENDPOINTS..................................................................................................................8 
2.1.1 
Demographic and baseline characteristics ......................................................................................8 
2.1.2 
Prior or concomitant medications...................................................................................................10 
2.1.3 
Primary endpoint ............................................................................................................................10 
2.1.4 
Secondary endpoints......................................................................................................................11 
2.1.4.1 
Device-related endpoints................................................................................................................11 
2.1.4.2 
Pharmacokinetic variables .............................................................................................................11 
2.1.4.3 
Anti-drug antibodies variables........................................................................................................11 
2.1.4.4 
Pharmacodynamic variables (lipid variables).................................................................................12 
2.1.4.5 
Safety endpoints.............................................................................................................................12 
2.1.5 
Other endpoints..............................................................................................................................16 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................16 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................17 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................17 
2.3.1 
Modified intent-to-treat population..................................................................................................18 
2.3.2 
Safety population............................................................................................................................18 
(electronic 1.0)
2


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
2.3.3 
Pharmacokinetic populations .........................................................................................................18 
2.3.4 
Anti-alirocumab antibody population ..............................................................................................19 
2.4 
STATISTICAL METHODS .............................................................................................................19 
2.4.1 
Demographics and baseline characteristics ..................................................................................19 
2.4.2 
Prior or concomitant medications...................................................................................................19 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................20 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................20 
2.4.3.2 
Compliance ....................................................................................................................................20 
2.4.4 
Analyses of endpoints ....................................................................................................................21 
2.4.4.1 
Analysis of primary endpoint ..........................................................................................................21 
2.4.4.2 
Analysis of secondary endpoints....................................................................................................21 
2.4.4.3 
Analysis of other endpoints ............................................................................................................27 
2.4.5 
Multiplicity issues............................................................................................................................27 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................27 
2.5.1 
General conventions ......................................................................................................................27 
2.5.2 
Data handling conventions for secondary variables.......................................................................28 
2.5.3 
Missing data ...................................................................................................................................28 
2.5.4 
Windows for time points.................................................................................................................30 
2.5.5 
Unscheduled visits .........................................................................................................................30 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................30 
2.5.7 
Statistical technical issues .............................................................................................................30 
3 
INTERIM ANALYSIS .....................................................................................................................31 
4 
DATABASE LOCK ........................................................................................................................32 
5 
SOFTWARE DOCUMENTATION..................................................................................................33 
6 
REFERENCES...............................................................................................................................34 
7 
LIST OF APPENDICES .................................................................................................................35 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......................36 
APPENDIX B 
LIST OF MEDDRA TERMS FOR CMQ ...............................................................................42 
(electronic 
 
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Page 3


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug (alirocumab) antibodies 
AE: 
adverse event 
AESI: 
adverse events of special interest 
AI: 
auto injector 
ALP: 
alkaline phosphatase 
ALT: 
alanine amino transferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
AUC0-tau: 
area under the curve concentation versus time curve extrapolated to infinity 
CHD: 
coronary heart disease 
CI: 
confidence interval 
Cmax: 
maximum plasma concentration 
CMQ: 
company MedDRA query 
Ctrough: 
trough concentration 
e-CRF: 
electronic case report form 
HDL-C: 
high-density lipoprotein cholesterol 
heFH: 
heterozygous famililal hypercholesterolemia 
HLGT: 
high level group term 
HLT: 
high level term 
IMP: 
investigational medicinal product 
LDL-C: 
low density lipoprotein cholesterol 
LLOQ: 
lower limit of quantification 
LMT: 
lipid modifying therapy 
mITT: 
modified intent-to-treat 
PCSA: 
potentially clinically significant abnormality 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PK: 
pharmacokinetic 
PT: 
preferred term 
PTC: 
product technical complaint 
Q4W: 
every four weeks 
SAE: 
serious adverse event 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
TG: 
triglyceride 
tmax: 
maximum time 
Total-C: 
total-cholesterol 
ULN: 
upper limit of normal 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Page 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical technique to be used for the clinical study reports of MSC14864 study.  
The overall goal of this study, MSC14864, is to assess the usability of SYDNEY (New device). 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a multicenter, randomized, open-label, 16-week study conducted in the USA, 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. 
Eligible patients will be randomly allocated to receive alirocumab 300 mg Q4W, self-administered 
using either the approved AI or the new investigational AI (SYDNEY) device for the first 
injection on Day 1. This injection will be performed at the clinical site under supervision and 
guidance by staff from the site. 
Subsequently, all patients will receive alirocumab 300 mg Q4W self-administered using only 
SYDNEY device for the injections on Week 4 (Day 29), Week 8 (Day 57) and Week 12 (Day 85) 
respectively.  
1.2 
OBJECTIVES 
1.2.1 Primary objective 
To collect 12 weeks of real-use (usability) data assessing the robustness and user interaction of 
SYDNEY, in unsupervised settings on Weeks 4, 8, and 12. 
1.2.2 Secondary objectives 
Device related: 
•
To collect real-use (usability) data assessing the robustness and user interaction of
SYDNEY and the current AI 1 mL alirocumab auto-injector device in supervised settings
on Week 0 (Day 1).
Pharmacokinetics: 
•
To compare alirocumab pharmacokinetics 300 mg Q4W administered using SYDNEY and
the current AI, from baseline until Week 4.
•
To evaluate alirocumab PK 300 mg Q4W administered using SYDNEY, until Week 16.
(electronic 1.0)
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Statistical Analysis Plan  
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Anti-drug antibodies: 
•
To evaluate the development of ADA.
Pharmacodynamics: 
•
To compare the percent and absolute change in LDL-C from baseline to Week 4 using
SYDNEY and the current 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 Auto
Injector Devices.
1.3 
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 approved AI group who will switch to 
SYDNEY group just before the second injection. 
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% CI calculated with the Wilson score method 
will be no higher than 5.2%. 
(electronic 
 
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Statistical Analysis Plan  
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Page 7 
1.4 
STUDY PLAN 
The following figure presents the graphical study design: 
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Page 8 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Analyses will be performed in each study phase (parallel arms phase and the single arm phase) 
separately unless otherwise specified. The results will be presented by treatment arm (SYDNEY, 
and approved AI) for the parallel arm phase and overall for the single arm phase. 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
For both study phases, the baseline value is defined as the last available value prior to the first 
dose of study medication planned at Day 1. 
All baseline safety and pharmacodynamics parameters (apart from those listed below) will be 
presented along with the on-treatment summary statistics in the safety and pharmacodynamics 
sections (Section 2.4.4.2.5 and Section 2.4.4.2.4). 
Demographic characteristics 
Demographic variables are: 
•
Gender (Male, Female)
•
Race (White, Black or African American, Asian, American Indian or Alaska Native,
Native Hawaiian or other Pacific Island)
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
•
Age in years (quantitative and qualitative variable: <65, ≥65 to <75, and ≥75 years)
Medical or surgical history 
Medical or surgical history includes: 
•
CHD
- 
Acute myocardial infarction
- 
Silent myocardial infarction
- 
Unstable angina
- 
Coronary revascularization procedure
- 
Other clinically significant CHD diagnosed by invasive or non-invasive testing
•
Non-CHD Cardiovascular disease
- 
Ischemic stroke
- 
Peripheral arterial disease
(electronic 1.0)
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- 
Abdominal aortic aneurysm 
- 
Atherosclerotic renal artery stenosis 
- 
Carotid artery disease 
• 
Other risk factors 
- 
Moderate chronic kidney disease (as defined in protocol) 
- 
Type 1 or type 2 diabetes mellitus. 
- 
Calculated 10-year fatal Cardiovascular disease risk SCORE ≥5%  
• 
Patient’s history of allergies (described using all pre-printed terms collected in the medical 
allergic history e-CRF page) 
Medical or surgical history will be based on items or combination of items pre-listed in the 
dedicated medical history e-CRF page (unless otherwise specified). 
All medical history information pre-listed or not in the e-CRF, will be coded using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time 
of database lock. 
Disease characteristics at baseline 
Specific disease characteristics include: 
• Type of hypercholesterolemia 
- 
heFH 
- 
Non-familial hypercholesterolemia 
• For heFH patients 
- 
Time from diagnosis of heFH (years) 
Confirmation of diagnosis (genotyping (Yes, No), clinical criteria (Yes, No)) 
 
• For Non-familial hypercholesterolemia patients: 
- 
Time from diagnosis of hypercholesterolemia (years) 
• Background LMT at randomization as reported in dedicated prior and concomitant 
medications e-CRF pages 
- 
Atorvastatin daily dose in mg (10, 20, 40,80, Other) 
- 
Rosuvastatin daily dose in mg (5, 10, 20, 40 Other) 
- 
Other statins (if any) 
- 
Any LMT other than statins 
- 
Any LMT other than nutraceuticals (by therapeutic class and drug name) 
(electronic 
 
 
 
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Statistical Analysis Plan  
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- 
Nutraceuticals (Omega 3 Fatty Acids, Plantago Seed, Phytosterol, Other 
Nutraceutical) 
Other baseline characteristics 
Other baseline characteristics include body mass index in kg/m² (quantitative and qualitative 
variable: <30, ≥30), alcohol habits. 
Lipid parameters (quantitative variables for all parameters and the following qualitative variable) 
will be also summarized at baseline (definitions in Section 2.1.3): 
•
Calculated LDL-C: <70, ≥70 to <100, ≥100 to <130, ≥130 to <160, ≥160 to <190,
≥190 mg/dL, ie, <1.81, ≥1.81 to <2.59, ≥2.59 to <3.37, ≥3.37 to <4.14, ≥4.14 to <4.91,
≥4.91 mmol/L
Any technical details related to computation, dates and imputation for missing data are described 
in Section 2.5.3.  
2.1.2 Prior or concomitant medications  
All medications will be coded using the World Health Organization-Drug Dictionary using the 
versions currently in effect at Sanofi at the time of database lock. 
•
Prior medications are those the patient used prior to first IMP intake. Prior medications can
be discontinued before first dosing or can be ongoing during treatment phase.
•
Concomitant medications during the parallel-arm period are any treatments received by the
patient from first IMP injection to first IMP injection +70 days for patients choosing not to
continue into the single-arm period. For patients entering in the single-arm period,
concomitant medications will be truncated at the day before second IMP injection.
•
Concomitant medications during the single-arm period are defined as any treatments
received by the patient from the second IMP injection to the last open-label IMP injection
+70 days.
•
Post-treatment medications are those the patient took in the period starting from 71 days
after the last IMP injection.
2.1.3 Primary endpoint 
The primary endpoint is the number (%) and types of SYDNEY-associated PTCs at the 
unsupervised injections on Weeks 4, 8, and 12. 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 classified by this department as device-related, patient-related, or undetermined, whether 
or not associated with an AE. The complaints categorized as not related to device or patient will 
not be considered as a PTC. This definition will be used for both primary and secondary 
endpoints. 
(electronic 1.0)
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Statistical Analysis Plan  
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2.1.4 Secondary endpoints 
2.1.4.1 Device-related endpoints 
During the parallel-arm period, patients are to receive injection(s) with either SYDNEY device or 
current AI. During the single arm period, all patients are to receive 3 separate injections with the 
SYDNEY device only. 
The following endpoints will be analyzed: 
• For both devices: 
- 
Number and percentage of patients with SYDNEY or current AI- associated PTCs 
(overall and by type) at the supervised injections on Day 1 
- 
Injection experience questionnaire on Day 1 
• For SYDNEY only: 
- 
Number and percentage 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 
2.1.4.2 Pharmacokinetic variables  
Concentrations of total alirocumab, total and free PCSK9 in serum are assessed at Day 1, Week 1, 
Week 2, Week 3,Week 4, Week 8 ,Week 12, Week 13, Week 14, Week 15 and Week 16. 
The PK parameters will include, but may not be limited to Cmax, tmax and AUC0-tau. 
2.1.4.3 Anti-drug antibodies variables 
ADA will be assessed at baseline (Day 1), Week 4 and Week 16. The following variables will be 
described: 
• 
ADA response (Positive or Negative). For ADA positive: 
- 
Titer levels 
• 
Pre-existing positive ADA defined as patients with positive ADA response at baseline 
with less than 4-fold increase in titer in the post-baseline period 
(electronic 
 
 
 
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Statistical Analysis Plan  
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•
Treatment-emergent positive ADA response defined as 1) Patients with no ADA positive
response at baseline but with any positive response in the post-baseline period or 2)
Patients with a positive ADA response at baseline and at least a 4- fold increase in titer in
the post-baseline period. For treatment-emergent positive ADA, the following categories
for ADA duration will be applied:
- 
A persistent positive response is a treatment-emergent ADA positive response detected
in at least 2 consecutive post-baseline samples separated by at least a 12-week period 
- 
An indeterminate duration positive response is defined as ADA present only at the last 
sampling time point 
- 
A transient positive response is defined as any treatment-emergent positive ADA 
response that is neither considered persistent nor indeterminate 
2.1.4.4 Pharmacodynamic variables (lipid variables) 
Lipid parameters include LDL-C, Total-C, HDL-C and TG. Each parameter will be assessed at 
baseline (Day 1), Week 4, Week 8, Week 12 and Week 16 during the treatment period 
(on-treatment estimand) as defined in Section 2.1.4.5. Post-treatment data will not be considered. 
The pharmacodynamic endpoints will be the percent change in LDL-C, Total-C, HDL-C, and TG 
values from baseline to Week 4, Week 8, Week 12 and Week 16.  
All calculated and measured LDL-C, Total-C, HDL-C, and TG values (scheduled or unscheduled, 
fasting or not fasting) may be used in the analyses if appropriate according to above definition and 
analysis windows (as defined in Table 1) used to allocate a time point to a measurement. In case 
both calculated and measured LDL-C are provided for the same sampling, the measured LDL-C 
will be considered. For TG, only fasting measurements will be used, measurements with missing 
fasting status will be excluded from the analyses. 
2.1.4.5 Safety endpoints 
The safety analysis will be based on the reported adverse events including SAE AESIs and other 
safety information, such as clinical laboratory data and vital signs. 
Observation period 
The period of safety observation starts from the time when the patient gives informed consent and 
is divided into the following periods: 
•
The pre-treatment period: defined as the time from the signed informed consent up to the
first IMP injection;
(electronic 1.0)
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Statistical Analysis Plan  
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• 
The TEAE period of the parallel-arm period defined as the time from the first IMP 
injection to the day before the second IMP injection for patients entering into the single 
arm period or to 70 days after the first IMP injection, whichever comes first; 
- 
The TEAE period of the parallel-arm period will include the TREATMENT period 
defined as the time from the first IMP injection to the day before the second IMP 
injection for patients entering into the single arm period, or to 35 days after the first 
IMP injection, whichever comes first. 
• The TEAE period of the single-arm period is defined as the time from the second IMP 
injection up to the day of last IMP injection + 70 days. 
- 
The TEAE period of the single-arm period will include the TREATMENT period 
defined as the time from the second IMP injection up to the day of last IMP injection 
+ 35 days. 
• The post-treatment period: defined as the time starting 71 days after the day of last IMP 
injection. 
The on-study observation period of the parallel-arm period is defined as the time from the day of 
first IMP injection until the Week 4 visit of the patient, if done, or 4 weeks after the randomization 
of the patient. 
The on-study observation period of the single-arm period is defined as the time from the second 
IMP injection until the Week 16 visit of the patient, if done, or 16 weeks after the randomization 
of the patient. 
2.1.4.5.1 Adverse events variables 
Adverse events (including SAEs and AESIs) are recorded from the time of signed informed 
consent until the end of study. 
All AEs will be coded to a “lowest level term”, “PT”, “HLT”, “HLGT”, and associated primary 
“SOC”using the version of MedDRA currently in effect at Sanofi at the time of database lock. 
Adverse event observation period 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pretreatment period. 
• 
Treatment-emergent adverse events are AEs that developed or worsened or became serious 
during the TEAE period. 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
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Statistical Analysis Plan  
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Adverse events of special interest 
AESIs are AEs (serious or non-serious) that need to be monitored, documented, and managed in a 
pre-specified manner described in the protocol. In this study, AESI are the following (their 
complete descriptions are provided in the protocol): 
•
Local injection site reactions, selected using e-CRF specific tick box on the AE page;
•
Allergic events:
- 
General allergic events will be tabulated. Events will be selected using standardized
MedDRA query (SMQ) “hypersensitivity” (broad and narrow) excluding the following 
PTs linked to local injection site reactions (“infusion site dermatitis”, “infusion site 
hypersensitivity”, “infusion site rash”, “infusion site urticaria”, “injection site 
dermatitis”, “injection site hypersensitivity”, “injection site rash”, “injection site 
urticaria” and “injection site vasculitis”); 
- 
General allergic events and local allergic reactions at IMP injection site will be 
described. This selection will be based on the above selection for general allergic event 
and on the following selection of PT from the symptoms complementary form for local 
injection site reaction ("Injection site dermatitis", "Injection site hypersensitivity", 
"Injection site oedema", "Injection site rash", "Injection site urticaria", "Injection site 
eczema", "Injection site vasculitis", "Injection site swelling", "Infusion site dermatitis", 
"Infusion site hypersensitivity", "Infusion site oedema", "Infusion site rash", "Infusion 
site urticaria", "Infusion site swelling") 
•
ALT ≥3 ULN (if baseline ALT < ULN) or ALT ≥2 times the baseline value (if baseline
ALT ≥ ULN), selected using laboratory data
•
Neurologic events selected using a CMQ, based on SMQs “demyelination” (broad and
narrow), “peripheral neuropathy” (broad and narrow), and “Guillain-Barre syndrome”
(broad and narrow) excluding the following PTs “acute respiratory distress syndrome”,
“asthenia”, “respiratory arrest” and “respiratory failure” and including selected PTs from
SMQ "optic nerve disorders" (see Table 2 for the list of terms)
•
Neurocognitive events:
- 
Selected using a CMQ, based on the following 5 HLGTs: “deliria (including
confusion)”, “cognitive and attention disorders and disturbances”, “dementia and 
amnestic conditions”, “disturbances in thinking and perception”, and “mental 
impairment disorders” 
- 
A second grouping of terms for neurocognitive events was defined based on 
Regulatory Agency request (see Table 3 for the list of terms) 
•
Pregnancy occurring in a female patient (including male subject’s partner) selected using
appropriate MedDRA codes.
•
Symptomatic overdose with IMP, selected using events reported as “Overdose of
Alirocumab” and with “symptomatic overdose ticked “Yes” in the “Overdose” e-CRF
page;
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Statistical Analysis Plan  
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2.1.4.5.2 Deaths 
The deaths observation period are per the observation periods defined above.  
•
Death on-study during the parallel-arm period: deaths occurring during the on-study
observation period of the parallel-arm period,
•
Death on-treatment during the parallel-arm period: deaths occurring during the TEAE
period of the parallel-arm period,
•
Death on-study during the single-arm period: deaths occurring during the on-study
observation period of the single-arm period,
•
Death on-treatment during single-arm period: deaths occurring during the TEAE period of
the single-arm period,
•
Death post-study: deaths occurring after the on-study period.
2.1.4.5.3 Laboratory safety variables 
Clinical laboratory data consist of blood analysis, including hematology and clinical chemistry, 
and urinalysis. Clinical laboratory values will be analyzed into international units. International 
units will be used in all listings and tables. Clinical laboratory values converted into conventional 
(US) units will be also available in the database. Analyses can be provided upon request. 
The laboratory parameters (excluding those considered as pharmacodynamic parameters) will be 
classified as follows: 
•
Hematology
- 
Red blood cells count and platelets: hemoglobin, hematocrit, platelet count, Red blood
cells count 
- 
White blood cells: White blood cells count, White blood cells differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils) 
•
Clinical chemistry
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase
- 
Electrolytes: sodium, potassium, chloride, calcium.
- 
Renal function: estimated glomerular filtration rate, creatinine, urea nitrogen
- 
Liver function: ALT/ Serum Glutamic-Pyruvic Transaminase, AST/ Serum
Glutamooxaloacetate Transferase, ALP, albumin, total bilirubin, Gamma-Glutamyl 
Transferase. 
2.1.4.5.4 Vital signs 
Vital signs parameters include heart rate, systolic and diastolic blood pressure measured after 5 
minutes in seating resting position. 
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2.1.5 Other endpoints 
The proportion of patients with LDL-C <25 mg/dL (<0.65 mmol/L) within the treatment period of 
the parallel and single-arm periods (and with two consecutives results below this limit if 
applicable, spaced out by at least 21 days) and the time to the first LDL-C <25 mg/dL for these 
patients will be provided. The same analysis will be provided with 15 mg/dL (0.39 mmol/L). 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent. 
Randomized patients consist of all screened patients with a treatment kit number allocated and 
recorded in the Interactive Response Technology database, regardless of whether the treatment kit 
was used. Patients treated without being randomized or treated with a double-blind treatment kit 
before the randomization will not be considered as randomized and will not be included in any 
analysis population. For patient study status, the following analyses will be performed in each 
period separately (by treatment group for parallel-arm period and overall for the single-arm 
period), if applicable: 
• Screened patients 
• Screen failure patients and reasons for screen failure 
• Nonrandomized but treated patients (if any) 
• Randomized patients 
• Patients who completed the study treatment period as per protocol 
• Patients who prematurely discontinued study treatment by main reason for permanent 
treatment discontinuation 
• Status at last study contact (Alive/ Dead) 
All critical or major deviations potentially impacting analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group (when applicable). 
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Additionally, the following populations (for each study periods) will be summarized by treatment 
group for the populations of the parallel-arm period and overall for the populations of the single-
arm period. 
•
Randomized population
•
mITT population
•
Safety population
•
PKs population
•
ADA population
Definitions of the study populations are provided in Section 2.3. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method,
such as a patient is randomized twice.
OR
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization
(which may or may not contain the correct-as-randomized IMP), or b) a nonrandomized
patient is treated with IMP reserved for randomized patients.
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are not 
limited to: 
Randomization and drug allocation irregularities 
Kit dispensation without Interactive Response Technology 
transaction 
Erroneous kit dispensation 
Patient randomized twice 
2.3 
ANALYSIS POPULATIONS 
Patients treated without or before being randomized will not be considered randomized and will 
not be included in any analysis populations. The safety experience of patients treated and not 
randomized will be reported separately. 
Randomized population: includes all randomized patients as defined in Section 2.2. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Modified intent-to-treat population  
The mITT population of the parallel arms period will consist of all randomized patients who 
received at least 1 dose or part of a dose of IMP 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. Patients 
in this mITT population will be analyzed according to the auto-injector device group allocated by 
randomization (ie, as-randomized treatment group). 
The mITT population of the single arm period will consist of all randomized patients who 
continued in single arm period and received at least 1 dose or part of a dose of IMP during 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 periods are defined in Section 2.1.4.5. 
2.3.2 Safety population 
The safety population of the parallel arms period will consist of all randomized patients who 
received 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 
continued 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 (if any) 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. 
2.3.3 Pharmacokinetic populations 
The PK population of the parallel arms period will consist of all randomized patients who 
received at least 1 dose or part of a dose of IMP (safety population) 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 received. 
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The PK population of the single arm period will consist of all randomized patients who received at 
least 1 dose or part of a dose of IMP and had at least one evaluable blood sample for PK during 
this period. 
The PK population will be used for the analyses of alirocumab concentrations and PCSK9 
concentrations. 
2.3.4 Anti-alirocumab antibody population 
The ADA population of the parallel arms period will consist of all randomized patients who 
received 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. All patients will be analyzed according to the auto-injector device that they actually 
received. 
The ADA 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. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized on the randomized population by 
treatment group using descriptive statistics.  
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum, and maximum for each treatment group. Categorical and ordinal data 
will be summarized using the number and percentage of patients in each treatment group.  
Medical and surgical history will be summarized by primary SOC and HLT. The tables will be 
sorted by internationally agreed order of SOC and by the decreasing frequency of HLT based on 
the overall incidence across treatment groups. In addition all medical history of specific interest 
will be presented by treatment group. 
2.4.2 Prior or concomitant medications 
The prior and concomitant medications will be presented for the safety population. 
Medications received during the parallel-arm period will be summarized by treatment group and 
medications received during the single -arm period will be summarized overall. Medications will 
be summarized according to the World Health Organization-Drug Dictionary, considering the first 
digit of the ATC class and the first 3 digits of the ATC class (therapeutic category). All ATC 
codes corresponding to a medication will be summarized, and patients will be counted once in 
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each ATC category (anatomic or therapeutic) linked to the medication. Therefore patients may be 
counted several times for the same medication. 
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency across anatomic or therapeutic categories, alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by therapeutic class based on the incidence in the SYDNEY group. In case of equal frequency 
across anatomic or therapeutic categories, alphabetical order will be used. 
In addition, concomitant LMTs will be summarized by pre-specified categories, chemical class or 
therapeutic class and standardized medication name. 
2.4.3 Extent of investigational medicinal product exposure and compliance 
The extent of IMP exposure and compliance will be assessed and summarized by actual device 
within the safety population for the parallel-arms period and overall for the single-arm period. 
2.4.3.1 Extent of investigational medicinal product exposure 
No duration of IMP exposure will be calculated for the parallel-arms period since patients will 
receive injection(s) at Day 1 only during this period. The proportion of patients having received 
the first injection(s) 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) and will be described quantitatively. The number of injections received during 
the single-arm period will also be summarized. The number of patients receiving 1, 2 and 3 
injections during the single-arm period will be provided. 
2.4.3.2 Compliance  
No treatment compliance to the IMP will be calculated for the parallel-arms period since patients 
will receive injection(s) at Day 1 only during this period. For patients randomized to receive the 
current AI, it will be described whether all patients received the 2 injections as planned. 
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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2.4.4 Analyses of endpoints 
2.4.4.1 Analysis of primary endpoint 
The primary endpoint (ie, number [%]) and types of SYDNEY-associated PTCs related to 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. In addition the type of PTCs will be 
described. 
In addition, all the reported complaints (including complaints not confirmed as fulfilling PTC 
definition) will be described. 
2.4.4.2 Analysis of secondary endpoints  
2.4.4.2.1 Device-related 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. 
Questionnaires will be analyzed with descriptive statistics. 
2.4.4.2.2 Pharmacokinetic variables 
All analyses for PK variables will be presented by treatment group for the parallel-arms period and 
overall for the single-arm period. 
All the PK analyses will be performed using the PK population in each period.  
PK 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 the parallel-arms period, log-transformed Cmax, AUC0-tau and Ctrough, estimates and 90% CI 
for the ratio of geometric means (SYDNEY/ AI) will be provided using an ANCOVA model with 
treatment group (SYDNEY, AI) as fixed effect and baseline body weight as covariate. 
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2.4.4.2.3 Anti-drug antibodies variables 
The following summaries will be performed on the ADA population by treatment group for the 
parallel-arm period and overall for the single-arm period, taking into account all samples 
regardless of timing in relation to injections:  
• 
ADA results (negative or positive) by time point  
• 
ADA titers using descriptive statistics (median, minimum, and maximum) for positive 
ADA by time point  
• 
Number (%) of patients with pre-existing ADA and number (%) of patients with treatment 
emergent ADA positive response  
• 
Number (%) of patients with persistent/indeterminate /transient treatment-emergent ADA 
positive response  
• 
Time to onset of treatment-emergent ADA positive response using descriptive statistics. 
2.4.4.2.4 Pharmacodynamic variables (lipid variables) 
Continuous endpoints anticipated to have a normal distribution 
Continuous variables anticipated to have a normal distribution (ie, percent change in LDL-C, 
Total-C, HDL-C at Week 4) will be analyzed in the mITT population of the parallel-arm period 
using an ANCOVA model with fixed categorical effect of treatment group (SYDNEY, AI), as 
well as the continuous fixed covariate of corresponding baseline value. LS means and 95% CI will 
be provided for both SYDNEY and AI. 
Depending on the number of missing LDL-C values at Week 4, a sensitivity analysis may be 
performed using multiple imputations (with baseline LDL-C and device group factors included in 
the imputation model) using the MI SAS® procedure to impute missing data followed by 
ANCOVA model. Results will be combined using Rubin’s formulae with the SAS MIANALYZE 
procedure. 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous variables anticipated to have a non-normal distribution (ie, percent change in TG at 
Week 4) will be analyzed in the mITT population of the parallel-arm period using the robust 
regression model with endpoint of interest as response variable using M-estimation (using SAS 
ROBUSTREG procedure) with treatment group (SYDNEY, AI) and corresponding baseline value 
as effects to compare treatment effects. Combined means estimates for both treatment groups with 
their corresponding 95% CIs will be provided. 
Descriptive statistics will be provided for the 4 lipid parameters at Week 8, Week 12 and Week 16 
on the mITT population of the single-arm period. 
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2.4.4.2.5 Safety variables 
The summary of safety results will be presented separately for the parallel-arm and single-arm 
periods. The parallel-arm period will be presented by treatment group and the single-arm period 
will be presented by overall patients. No formal inferential testing will be performed for either 
study period. Summaries will be descriptive in nature. All summaries of safety results described in 
this section will be presented for each study period respectively, unless otherwise noted. 
General common rules 
All safety analyses will be performed on the safety populations as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
•
Safety data in patients who do not belong to the safety population (eg, exposed but not
randomized) will be listed separately.
•
The baseline value, for both parallel arms and single arm periods, is defined as the last
available value obtained up to the date and time of the first IMP administration.
•
The 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, vital signs, and electrocardiogram (PCSA
version dated May 2014 [Appendix A]). In case the PCSA threshold is within the normal
laboratory ranges, the analysis will be done using “<Low Limit Normal” or “>ULN”
threshold instead of “<PCSA threshold” or “>PCSA threshold” respectively.
•
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period,
taking into account all evaluations performed during the TEAE period, including
nonscheduled or repeated evaluations. The treatment-emergent PCSA denominator for a
given parameter will be based on the number of patients assessed for that given parameter
at least once during the TEAE period.
•
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to
analysis windows defined in Section 2.5.4 in order to provide an assessment for Week 4 to
Week 16 time points.
•
For quantitative safety parameters based on central laboratory/reading measurements,
descriptive statistics will be used to summarize results and change from baseline values by
visit and treatment group using analysis windows.  Summaries will also include the last
on-treatment value and the worst on-treatment value. The last on-treatment value is
defined as the last value collected during the treatment period of each study period. The
worst on-treatment value is defined as the nadir and /or the peak value during the treatment
period of each study period according to the direction (minimum or maximum) of the
abnormality as defined in the PCSA list.
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2.4.4.2.5.1 Adverse events 
Generalities 
The primary focus of adverse event reporting will be on TEAEs. Pre-treatment and post-treatment 
AEs will be described separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as treatment-emergent, or post-treatment. The 
algorithm for imputing date/time of onset will be conservative and will classify an AE as 
treatment emergent unless there is definitive information to determine it is pre- or post-treatment. 
Details on classification of AEs with missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC, HLGT (when applicable), HLT (when applicable), and PT. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase. 
Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pre-treatment, TEAE, and post-treatment). For that purpose, the table of all TEAEs 
presented by SOC and PT sorted by the internationally agreed SOC order and decreasing 
frequency of PTs within SOCs (in the SYDNEY group for the tables of the parallel-arm period) 
will define the presentation order for all other tables by SOC and PT, unless otherwise specified. 
The tables of AEs by SOC, HLGT, HLT and PT will be sorted by the SOC internationally agreed 
order and the other levels (HLGT, HLT, PT) will be presented in alphabetical order, unless 
otherwise specified. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated. 
•
Overview of TEAEs, summarizing number (%) of patients with any
- 
TEAE
- 
Serious TEAE
- 
TEAE leading to death
- 
TEAE leading to permanent treatment discontinuation
•
All TEAEs by primary SOC, HLGT, HLT, and PT
•
All TEAEs by primary SOC and PT
•
All TEAEs by treatment group regardless of relationship in one column and, in the same
table a second column with TEAEs related to alirocumab according to investigator’s
opinion by primary SOC, HLGT, HLT and PT
•
All TEAEs by maximal intensity (ie, mild, moderate or severe), presented by primary SOC
and PT
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Analysis of all treatment emergent serious adverse event(s) 
•
All serious TEAEs by primary SOC, HLGT, HLT, and PT and by SOC/PT
•
All serious TEAEs by treatment group regardless of relationship in one column and, in the
same table a second column with TEAEs related to alirocumab according to investigator’s
opinion, by primary SOC, HLGT, HLT, and PT
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
•
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT
and by SOC/PT
Analysis of groupings of adverse events including selected adverse events of special interest: 
•
All grouping of TEAEs including AESI as listed in Section 2.1.4.5.1 will be analyzed
using selections defined in Section 2.1.4.5.1 and will be presented by SMQ/CMQ and PT
(when selection is based on SMQs/CMQs) and by SOC and PT (when selection is based
on the e-CRF tick box or HLGT/HLT). The summaries will be sorted by decreasing
incidence of PT within each SOC/SMQ (in the SYDNEY group for tables performed on
the parallel-arm period)
In addition, the following variables will be tabulated for the local injection site reactions TEAEs: 
•
Intensity of the event (mild, moderate, severe)
•
Number of events divided by the number of IMP injections received
•
Time from first IMP injection to first injection site reaction
•
Description of the highest intensity of each symptom recorded in the specific e-CRF page
Analysis of TEAE(s) linked to PTC: 
•
All TEAEs related to PTC by primary SOC, HLGT, HLT, and PT
Analysis of pre-treatment and post-treatment adverse events 
•
All pre-treatment AEs by primary SOC and PT
•
All pre-treatment AEs leading to treatment discontinuation by primary SOC and PT
•
All post-treatment AEs by primary SOC and PT
•
All post-treatment SAE by primary SOC and PT
2.4.4.2.5.2 Deaths 
The following summaries of deaths will be generated. 
•
Number (%) of patients who died by study period (on-study, on-treatment, post-study)
Deaths in nonrandomized patients or randomized but not treated patients.
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• TEAEs leading to death (death as an outcome on the AE reported by the Investigator) by 
primary SOC , HLGT, HLT, and PT showing number (%) of patients sorted by 
internationally agreed SOC order, with HLGT, HLT, and PT presented in alphabetical 
order within each SOC .  
• TEAEs leading to death (death as an outcome on the AE as reported by the Investigator) by 
primary SOC, HLGT, HLT, and PT. TEAEs leading to death are TEAEs that led to death 
regardless of timing of death in relation to IMP injection (i.e. death occurring in the TEAE 
period or during the post-treatment period). 
2.4.4.2.5.3 Laboratory variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post-baseline time point, last on-
treatment and worst on-treatment value). 
The incidence of PCSAs (list provided in Appendix A) at any time during the TEAE period will 
be summarized by biological function irrespective of the baseline level and/or according to the 
following baseline status categories: 
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity. The proportion of patients with PCSA values or ALT increase as 
defined in Adverse Events of Special Interests section (see Section 2.1.4.5.1) during TEAE period 
by baseline status will be displayed for each parameter. 
An evaluation of drug-induced serious hepatotoxicity with the graph of distribution of peak values 
of ALT versus peak values of total bilirubin will also be presented using post-baseline values 
during TEAE period. Note that the ALT and total bilirubin values will be presented on a 
logarithmic scale. The graph will be divided into 4 quadrants with a vertical line corresponding to 
3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified (ie, patients with any elevated ALT>3 x ULN, and 
associated with an increase in bilirubin >2 x ULN, concomitantly or not) with ALT, AST, ALP, 
total bilirubin, and if available direct and indirect bilirubin will be provided. 
The incidence of liver-related TEAEs will be summarized by treatment group. The selection of 
PTs will be based on SMQ Hepatic disorder (see Section 2.1.4.5.1). 
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2.4.4.2.5.4 Vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post-baseline time point, last on-
treatment, worst on-treatment value).  
Vital signs without position filled in will only be used for the PCSA analysis described below. 
The incidence of PCSAs at any time during the TEAE period will be summarized. 
2.4.4.3 Analysis of other endpoints 
Other endpoints defined in Section 2.1.5 will be described using count and percentage.  
2.4.5 Multiplicity issues 
Not applicable. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Time from diagnosis 
Time from diagnosis (years) = (Date of informed consent - Date of diagnosis*) / 365.25. 
(*):In case the month of diagnosis would be missing, it will be put equal to JANUARY if the year 
of diagnosis equals the year of informed consent; it will be put equal to JUNE otherwise. 
Date of last dose of IMP (for single-arm period) 
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page, or missing if the last administration date is unknown. 
Renal function formulas 
eGFR value will be derived using the Modification of the Diet in Renal Disease equation:175 × 
(creatinine in µmol/L / 88.4)-1.154 × (age in years)-0.203 (x 0.742 if female, x 1.212 if race is 
"black or African American"). 
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Lipids variables, laboratory safety variables, hs-CRP 
For data below the lower limit of quantification (LLOQ) / limit of linearity, half of the lower limit 
value (ie, LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification / limit of linearity, the upper limit value (ie, upper limit of quantification will be 
used for quantitative analyses. 
Pharmacokinetic variables 
Data below the LLOQ are set to zero. 
2.5.2 Data handling conventions for secondary variables 
See Section 2.1.4. 
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data is 
presented. 
Handling of baseline definition if time of first IMP injection or time of assessment at Week 0 
visit is missing 
If the time of the first IMP injection or the time of assessment at Week 0 visit is missing then the 
baseline value is defined as the last available value obtained before or on the day of the first blind 
IMP injection. 
Handling of computation of treatment duration if last IMP injection date is missing  
If the last IMP injection date is missing, the exposure duration will be left as missing.  
Handling of analysis periods if last IMP injection date is missing 
If the last IMP injection date is missing, then this date will be imputed to the earliest between 
•
the last day of the month and year, when applicable or else the 31st of December of the
year,
•
the date of the end of treatment visit (Week 12 visit for completers, early end of treatment
visit for patients who prematurely discontinued the IMP),
•
and the date of the last contact,
to determine the analysis periods end. 
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Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial AE onset dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, the 
AE will be classified as treatment-emergent. These data imputations are for categorization purpose 
only and will not be used in listings. No imputation is planned for date/time of adverse event 
resolution. 
Handling of adverse events when date and time of first IMP injection is missing 
When the date of the first IMP injection is missing, all adverse events that occurred on or after the 
day of randomization will be considered as TEAEs. 
Handling of missing assessment of relationship of AEs to IMP 
If the assessment of the relationship to IMP is missing, then the relationship to IMP will be 
assumed as possibly related in the frequency tables, but no imputation will be done at the data 
level. 
Handling of missing severity of AEs 
If the severity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered.  If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities 
Patients with missing baseline value will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, with the first condition being missing, the PCSA will be based 
only on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN if 
ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
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2.5.4 Windows for time points 
Data analyzed by time point (except PK and PCSK9 variables) will be summarized using the 
analysis windows given in Table 1. These analysis windows will be applicable for all analyses, 
and they are defined to provide more homogeneous data for time point-specific analyses. For PK, 
since measurements are planned every week, e-CRF visits will be used instead of analysis 
windows. 
Table 1 - Analysis windows definition 
Time 
point 
Targeted study 
day 
Analysis window in study days 
Week 4 
29 
15 to 42 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to 98 
Week 16 
113 
99 to 126 
Study days are calculated from the day of first IMP injection, the day of first open-label IMP injection being Day 1. For randomized but not treated 
patients, Day 1 is the day of randomization. 
If multiple valid values of a variable exist within an analysis window, the nearest from the 
targeted study day will be selected. If the difference is a tie, the value after the targeted study day 
will be used. If multiple valid values of a variable exist within a same day, then the first value of 
the day will be selected when time is available, else the scheduled visit will be selected. 
2.5.5 Unscheduled visits 
For pharmacodynamics, safety laboratory data, or vital signs, unscheduled visit measurements 
may be used to provide a measurement for a time point, a baseline, a last or a worst value, if 
appropriate according to their definitions. The measurements may also be used to determine 
abnormal/PCSA. 
2.5.6 Pooling of centers for statistical analyses 
Not applicable. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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4 
DATABASE LOCK 
The database is planned to be locked approximately 28 days after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.2 or higher. 
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6 
REFERENCES 
Not applicable. 
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7 
LIST OF APPENDICES 
Appendix A 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B  
List of MedDRA terms for CMQ 
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Appendix A 
Potentially clinically significant abnormalities criteria 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT >3 ULN and TBILI >2 ULN 
Concept paper on DILI - FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 µmol/L 
<120 µmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
(electronic 
 
 
 
1.0)
Page 37


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 38 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
ADA May 2005. 
ADA Jan 2008. 
HbA1c
>8%
Albumin 
≤25 g/L 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
Basophils 
>0.1 Giga/L 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets
<100 Giga/L
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
(electronic 1.0)
Page 38


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 39 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
Urinalysis 
pH 
≤4.6 
≥8 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
≤-20 mmHg 
≤-10 mmHg 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
(electronic 1.0)
Page 39


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 40 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
(electronic 
 
 
 
1.0)
Page 40


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 41 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
QTc 
Absolute values (ms) 
>450 ms 
>480 ms 
>500 ms 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
QTc >480 ms and ∆QTc>60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings. 
(electronic 1.0)
Page 41


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 42 
Appendix B 
List of MedDRA terms for CMQ 
Table 2 - Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for neurologic 
MedDRA Term Label 
Preferred Term Code 
Benign neoplasm of optic nerve 
10057424 
Optic atrophy 
10030910 
Optic discs blurred 
10030923 
Optic nerve disorder 
10061322 
Optic nerve injury 
10030938 
Optic nerve neoplasm 
10053645 
Optic nerve operation 
10053272 
Optic neuropathy 
10061323 
Papillitis
10033708
Pseudopapilloedema
10037141
Subacute myelo-opticoneuropathy 
10058009 
Toxic optic neuropathy 
10044245 
Visual evoked potentials abnormal 
10047549 
Amaurosis fugax 
10001903 
Blindness
10005169
Blindness unilateral 
10005186 
Colour blindness acquired 
10010051 
Colour vision tests abnormal 
10010056 
Cranial nerve injury 
10061094 
Delayed myelination 
10076456 
Fundoscopy abnormal 
10017520 
Hemianopia
10019452
Hemianopia heteronymous 
10019455 
Hemianopia homonymous 
10019456 
Loss of visual contrast sensitivity 
10064133 
Neuro-ophthalmological test abnormal 
10029256 
Night blindness 
10029404 
Ophthalmological examination abnormal 
10056836 
Optic pathway injury 
10030949 
Optical coherence tomography abnormal 
10073561 
(electronic 1.0)
Page 42


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 43 
MedDRA Term Label 
Preferred Term Code 
Quadranopia
10075427
Visual acuity reduced 
10047531 
Visual acuity reduced transiently 
10047532 
Visual acuity tests abnormal 
10047534 
Visual field defect 
10047555 
Visual field tests abnormal 
10047567 
Visual impairment 
10047571 
Visual pathway disorder 
10061411 
Table 3 - CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD
10001949
Amnesia
PTCD
10061423
Amnestic disorder
PTCD
10002711
Anterograde Amnesia
PTCD 
10066842 
Behavioural and Psychiatric Symptoms of Dementia 
PTCD 
10008398 
Change in sustained attention 
LLTCD
10009843
Cognitive Deterioration
PTCD
10057668
Cognitive Disorder
LLTCD
10010300
Confusion
LLTCD
10048321
Confusion Aggravated
PTCD
10010305
Confusional State
PTCD
10012218
Delirium
PTCD
10012267
Dementia
PTCD 
10012271 
Dementia Alzheimer's type 
LLTCD
10012290
Dementia Nos
LLTCD 
10012291 
Dementia Nos Aggravated 
LLTCD 
10012292 
Dementia of the Alzheimer's type NOS 
PTCD 
10067889 
Dementia with Lewy Bodies 
PTCD
10013395
Disorientation
PTCD 
10013496 
Disturbance in attention 
PTCD
10070246
Executive dysfunction
PTCD
10068968
Frontotemporal Dementia
LLTCD
10058669
Global Amnesia
(electronic 1.0)
Page 43


Statistical Analysis Plan  
27-Mar-2018 
SAR236553/REGN727 - MSC14864 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 44 
MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD
10021402
Illogical Thinking
PTCD
10071176
Impaired reasoning
PTCD
10021630
Incoherent
PTCD
10023236
Judgement impaired
PTCD
10027175
Memory Impairment
PTCD
10027374
Mental Impairment
LLTCD 
10027376 
Mental Impairment Nos 
LLTCD 
10048345 
Mental State Abnormal Aggravated 
PTCD 
10048294 
Mental Status Changes 
PTCD 
10065424 
Mini Mental Status Examination Abnormal 
PTCD
10036631
Presenile Dementia
PTCD
10038965
Retrograde Amnesia
PTCD
10039966
Senile Dementia
LLTCD 
10039967 
Senile Dementia Nos 
LLTCD 
10040602 
Short-term Memory Loss 
PTCD
10043431
Thinking Abnormal
LLTCD
10043438
Thinking Slowed
PTCD 
10044380 
Transient Global Amnesia 
PTCD
10057678
Vascular Dementia
(electronic 1.0)
Page 44


 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
MSC14864 16.1.9 Statistical Analysis Plan
Clinical Approval
27-Mar-2018 16:09 GMT+0200
Clinical Approval
27-Mar-2018 16:49 GMT+0200
Page 45