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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hypercholesterolaemia

Intervention / Treatment
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* Drug: Alirocumab SAR236553
* Device: Current auto-injector device (AI)
* Device: New auto-injector device (SYDNEY)
* Drug: Atorvastatin
* Drug: Rosuvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Participants were in either category A or B (below), and were 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 LMT: A. Participants with heterozygous familial hypercholesterolemia (heFH) (diagnosis based on either genotyping or clinical criteria) OR B. Non-FH Participants at high or very high cardiovascular (CV) risk. High and very high cardiovascular risk participants included participants with coronary heart disease (CHD), non-CHD cardiovascular disease (CVD), and other risk factors. Participant willing and able to self-inject for the duration of the study. Exclusion criteria: LDL-C <70 milligrams per deciliter (mg/dL) (<1.81 millimoles per litre [mmol/L]) at the screening visit. Currently taking a daily dose of statin that was 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 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. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Auto-Injector Device (AI)<br>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). | Drug: Alirocumab SAR236553<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Device: Current auto-injector device (AI)<br>* Pharmaceutical form: Route of administration: Subcutaneous self-administration of alirocumab<br>Drug: Atorvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: Rosuvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>|
| Experimental: New Auto-injector Device (SYDNEY)<br>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. | Drug: Alirocumab SAR236553<br>* Pharmaceutical form: Solution for injection Route of administration: Subcutaneous<br>Device: New auto-injector device (SYDNEY)<br>* Pharmaceutical form: Route of administration: Subcutaneous self-administration of alirocumab<br>Drug: Atorvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: Rosuvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (Overall) at the Unsupervised Injections: 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. | From Week 4 up to Week 12 | 
| Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (by Type) at the Unsupervised Injections: 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 AE. | From Week 4 up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a SYDNEY or Current Auto-Injector (AI)-Associated Product Technical Complaint (PTCs) (Overall and by Type) at the Supervised Injections on Week 0 (Day 1): Parallel-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. | Week 0 (Day 1) | 
| Percentage of Participants With SYDNEY-Associated Product Technical Complaint (PTCs) (Overall and by Type) at the Unsupervised Injections : 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 [SYDNEY]) are reported. | From Week 4 up to Week 12 | 
| Injection Experience Questionnaire at Initial Supervised Injection: Overall Ease of Use Scores: Parallel-Arm Period | 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. | Week 0 (Day 1) | 
| Patient Perspective Questionnaire After the Last Injection (at Week 12): Single-Arm Period | 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. | At Week 12 | 
| Injection-Treatment Acceptance Questionnaire (I-TAQ©) After Last Injection (at Week 12) - Overall Acceptance Scores: Single-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. | At Week 12 | 
| Maximum Serum Alirocumab Concentration Observed - Cmax : Parallel-Arm Period | Cmax: Maximum serum concentration observed. | Pre-dose (Week 0) and on Day 7, 14 and 21 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alirocumab : Parallel-Arm Period | Tmax: Time to reach Cmax. | Pre-dose (Week 0) and on Day 7, 14 and 21 | 
| Area Under the Curve-During the Dosing Interval Tau (AUC [0-tau]) : Parallel-Arm 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. | Pre-dose (Week 0) and on Day 7, 14 and 21 | 
| Maximum Serum Alirocumab Concentration Observed - Cmax : Single-Arm Period | Cmax: maximum serum concentration observed. | Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alirocumab: Single-Arm Period | Tmax: Time to reach Cmax. | Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection | 
| Area Under the Curve-During the Dosing Interval Tau (AUC [0-tau]) : Single-Arm 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. | Pre-dose (Week 4, Week 8 and Week 12) and on Day 7, 14, 21 and 28 days following the last injection | 
| Free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Parallel-Arm Period | Free PCSK9 concentrations below the lower limit of quantification (LLOQ) were set to zero. | Week 4 | 
| Free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Single-Arm Period | Free PCSK9 concentrations below the LLOQ were set to zero. | Week 16 | 
| Total Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Parallel-Arm Period | Total PCSK9 concentrations below the LLOQ were set to zero. | Week 4 | 
| Total Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Single-Arm Period | Total PCSK9 concentrations below the LLOQ were set to zero. | Week 16 | 
| Number of Participants With Treatment-Emergent Anti-Alirocumab Antibodies (ADA) Positive Response: Parallel-Arm Period | 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. | Up to Week 4 | 
| Number of Participants With Treatment-Emergent Anti-Alirocumab Antibodies (ADA) Positive Response According to ADA Status During Parallel-Arm Period: Single Arm Period | 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. | Week 16 | 
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 4: Parallel-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. | From Baseline to Week 4 | 
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 8, 12, 16: Single-Arm Period |  | From Baseline to Weeks 8, 12, and 16 |