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

• ClinicalTrials.gov Identifier: NCT03415178
• Recruitment Status: Completed
• First Posted: January 30, 2018
• Results First Posted: September 9, 2019
• Last Update Posted: September 9, 2019
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolaemia	Drug: Alirocumab SAR236553; Device: Current auto-injector device (AI); Device: New auto-injector device (SYDNEY); Drug: Atorvastatin; Drug: Rosuvastatin	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: March 29, 2018
• Actual Primary Completion Date: August 9, 2018
• Actual Study Completion Date: August 9, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Auto-Injector Device (AI); 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; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Device: Current auto-injector device (AI); Pharmaceutical form: Route of administration: Subcutaneous self-administration of alirocumab; Drug: Atorvastatin; Pharmaceutical form:tablet Route of administration: oral; Drug: Rosuvastatin; Pharmaceutical form:tablet Route of administration: oral
Experimental: New Auto-injector Device (SYDNEY); 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; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Device: New auto-injector device (SYDNEY); Pharmaceutical form: Route of administration: Subcutaneous self-administration of alirocumab; Drug: Atorvastatin; Pharmaceutical form:tablet Route of administration: oral; Drug: Rosuvastatin; Pharmaceutical form:tablet Route of administration: oral

Outcome Measures

Primary Outcome Measures :

1. Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (Overall) at the Unsupervised Injections: Single-Arm Period [ Time Frame: From Week 4 up to Week 12 ]
   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.
2. Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (by Type) at the Unsupervised Injections: Single-Arm Period [ Time Frame: From Week 4 up to Week 12 ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Investigational Site Number 8400024

Los Angeles, California, United States, 90057

United States, Florida

Investigational Site Number 8400007

Jacksonville, Florida, United States, 32216

Investigational Site Number 8400017

Jacksonville, Florida, United States, 32223

Investigational Site Number 8400013

Ponte Vedra, Florida, United States, 32081

Investigational Site Number 8400014

Wellington, Florida, United States, 33449

United States, Iowa

Investigational Site Number 8400001

West Des Moines, Iowa, United States, 50266

United States, Kansas

Investigational Site Number 8400019

Topeka, Kansas, United States, 66606

United States, Ohio

Investigational Site Number 8400006

Cincinnati, Ohio, United States, 45201

Investigational Site Number 8400010

Cincinnati, Ohio, United States, 45219

United States, South Carolina

Investigational Site Number 8400022

Summerville, South Carolina, United States, 29485

United States, Texas

Investigational Site Number 8400026

Amarillo, Texas, United States, 79106

United States, Virginia

Investigational Site Number 8400005

Richmond, Virginia, United States, 23227

United States, Wisconsin

Investigational Site Number 8400027

Manitowoc, Wisconsin, United States, 54220

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] November 20, 2017

Statistical Analysis Plan  [PDF] March 27, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Frias JP, Koren MJ, Loizeau V, Merino-Trigo A, Louie MJ, Raudenbush MA, Batsu I. The SYDNEY Device Study: A Multicenter, Randomized, Open-label Usability Study of a 2-mL Alirocumab Autoinjector Device. Clin Ther. 2020 Jan;42(1):94-107.e5. doi: 10.1016/j.clinthera.2019.11.008. Epub 2019 Dec 24.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03415178
• Other Study ID Numbers: MSC14864; U1111-1186-3466 ( Other Identifier: UTN )
• First Posted: January 30, 2018
• Results First Posted: September 9, 2019
• Last Update Posted: September 9, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Rosuvastatin Calcium; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors