Usability Study of the Commercial Auto-injector Device and the New Auto-injector Device (SYDNEY) in Patients With High or Very High CV Risk With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

SYDNEY-associated PTC was defined as any complaint reported on the participant complaint form that triggered an investigation by the device department and was categorized as either device-related, participant-related, or undetermined whether or not associated with an AE.

Time frame: From Week 4 up to Week 12

Population: Analysis was performed on safety population of the single-arm period.

SYDNEY-associated PTC was defined as any complaint reported on the participant complaint form that triggered an investigation by the device department and was categorized as either device-related, participant-related, or undetermined whether or not associated with an adverse event (AE). Overall category included total of all 3 types of PTCs. The percentage of SYDNEY-associated PTCs was calculated as: Number of PTCs / Number of unsupervised injections\*100. The confidence interval (CI) was calculated using the Wilson score method.

Time frame: From Week 4 up to Week 12

Population: Analysis was performed on safety population of the single-arm period which included all randomized participants who continued in the single-arm period and received at least 1 dose or part of a dose of investigational medicinal product (IMP) during this period.

AUC0-tau: area under the serum concentration versus time curve calculated using the trapezoidal method during a dosage interval tau, where dosing interval was 4 weeks.

Time frame: Pre-dose (Week 0) and on Day 7, 14 and 21

Population: Analysis was performed on PK population of the parallel-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

AUC0-tau: area under the serum concentration versus time curve calculated using the trapezoidal method during a dosage interval tau, where dosing interval was 4 weeks.

Time frame: Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection

Population: Analysis was performed on PK population of the single-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Free PCSK9 concentrations below the lower limit of quantification (LLOQ) were set to zero.

Time frame: Week 4

Population: Analysis was performed on PK population of the parallel-arm period. Here, Overall number of participants analyzed = participants evaluable for this outcome measure.

Free PCSK9 concentrations below the LLOQ were set to zero.

Time frame: Week 16

Population: Analysis was performed on PK population of the single-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Participants were given an injection experience questionnaire to complete after the self-injection they administered using SYDNEY device or current AI device on Day 1, for assessment of user experience and overall ease-of-use. The questionnaire included 9 questions about specific aspects of using the device. Overall ease of use was the 9th question, response of which ranged from 1 (very difficult) to 10 (very easy), with higher score indicated more ease of use.

Time frame: Week 0 (Day 1)

Population: Analysis was performed on safety population of the parallel-arm period.

The I-TAQ© was a well-established and validated questionnaire to measure participant satisfaction with SC auto-injector devices. The I-TAQ© (completed by the participant after the last injection) was self-administered questionnaire administered to participants in order to measure their acceptance of the injection. The overall acceptance is one of the five domain scores. The overall acceptance score ranged from 0 to 100, with 0 indicating low acceptance and 100 indicating high acceptance.

Time frame: At Week 12

Population: Analysis was performed on safety population of the single-arm period. Here, overall number of participants analyzed = participants who answered the I-TAQ.

Cmax: Maximum serum concentration observed.

Time frame: Pre-dose (Week 0) and on Day 7, 14 and 21

Population: Analysis was performed on pharmacokinetics (PK) population of the parallel-arm period which included all randomized participants 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. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Cmax: maximum serum concentration observed.

Time frame: Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection

Population: Analysis was performed on PK population of the single-arm period which included all randomized participants 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. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Number of participants with positive ADA during the TEAE period (time from the second IMP injection up to the day of last IMP injection + 70 days) were determined. Treatment-emergent positive ADA response in Single-arm period defined as 1) participants with no ADA positive response in the Parallel-arm period but with any positive response in the Single-arm period or 2) participants with a positive ADA response at baseline, with less than 4-fold increase in titer in the Parallel-arm period (Pre-existing ADA in Parallel-arm period) and at least a 4- fold increase in titer in the Single-arm period.

Time frame: Week 16

Population: Analysis was performed on ADA population of single-arm period which included all randomized participants who received at least 1 or partial dose of IMP during this period with available baseline and at least 1 post-baseline ADA sample available during this period. Here, Number analyzed = participants with ADA assessed at specified time point.

Anti-drug (alirocumab) antibodies samples were analyzed using a validated electrochemiluminescence assay. Number of participants with positive ADA during treatment emergent adverse event (TEAE) period (time from the first IMP injection to the day before the second IMP injection for participants entered into the single arm period or to 70 days after the first IMP injection, whichever comes first) was determined. Treatment-emergent positive ADA response defined as 1) participants with no ADA positive response at baseline but with any positive response in the post-baseline period or 2) participants with a positive ADA response at baseline and at least a 4- fold increase in titer in the post-baseline period.

Time frame: Up to Week 4

Population: Analysis was performed on ADA population of the parallel-arm period which included all randomized participants who received at least 1 or part of a dose of IMP during this period with baseline and at least one post-baseline available ADA sample during this period. All participants were analyzed according to the AI device they actually received.

The aim of the patient perspective questionnaire (completed by the participant after the last injection) was to generate data to support an understanding of the participant experience and satisfaction associated with use of the large volume SYDNEY to administer the 300 mg dose. The questionnaire consisted of 6 questions about level of satisfaction with various aspects of the SYDNEY; with response to each question ranging from 1 (very dissatisfied) to 10 (very satisfied), with higher scores indicated more satisfaction. An additional question (confidence that Sydney device was used correctly) regarding confidence of use of SYDNEY device in the study was evaluated on a scale of 10; where 1 being not at all confident, to 10 being very confident, higher scores indicated more confidence.

Time frame: At Week 12

Population: Analysis was performed on safety population of the single-arm period.

A PTC was defined as any complaint reported on the participant complaint form that triggered an investigation by the device department and was categorized as either device-related, participant-related, or undetermined, whether or not associated with an AE. Percentage of participants With a SYDNEY-associated PTC (for the reporting arm Alirocumab from new auto-injector device) or Current AI-Associated PTCs (for the reporting arm alirocumab from AI device) are reported.

Time frame: Week 0 (Day 1)

Population: Analysis was performed on safety population of the parallel-arm period which included all randomized participants who received at least 1 dose or part of a dose of IMP during this period.

A PTC was defined as any complaint reported on the participant complaint form that triggered an investigation by the device department and was categorized as either device-related, participant-related, or undetermined, whether or not associated with an AE. Percentage of Participants With a SYDNEY-associated PTC (for the reporting arm Alirocumab from new auto-injector device \[SYDNEY\]) are reported.

Time frame: From Week 4 up to Week 12

Population: Analysis was performed on safety population of the single-arm period.

Adjusted least square means and standard errors at Week 4 were calculated from analyses of covariance (ANCOVA) model with the fixed categorical effect of treatment group (SYDNEY, AI), as well as the continuous fixed covariate of baseline LDL-C value.

Time frame: From Baseline to Week 4

Population: Analysis was performed on modified intent-to-treat (mITT) population of the parallel-arm period which included all randomized participants who received at least 1 dose or part of a dose of IMP during this period and who had an evaluable baseline and an on-treatment LDL-C value within Week 4 analysis window and before second injection, if any.

Time frame: From Baseline to Weeks 8, 12, and 16

Population: mITT population of single-arm period included all randomized participants who continued in single-arm period \& received at least 1 dose/part of a dose of IMP \& who had an evaluable baseline \& at least 1 on-treatment LDL-C value within analysis windows (Week 8 to 16). Number analyzed=participants with available data at specified time-point.

Tmax: Time to reach Cmax.

Time frame: Pre-dose (Week 0) and on Day 7, 14 and 21

Population: Analysis was performed on PK population of the parallel-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Tmax: Time to reach Cmax.

Time frame: Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection

Population: Analysis was performed on PK population of the single-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.

Total PCSK9 concentrations below the LLOQ were set to zero.

Time frame: Week 4

Population: Analysis was performed on PK population of the parallel-arm period. Here, Overall number of participants analyzed = participants evaluable for this outcome measure.

Total PCSK9 concentrations below the LLOQ were set to zero.

Time frame: Week 16

Population: Analysis was performed on PK population of the single-arm period. Here, Overall number of participants analyzed = participants evaluable for this PK measure.