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

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03415178
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 69
• Locations: 13
• Arms: 2
• Actual Duration (Months): 4.4
• Patients Per Site: 5.3
• Patients Per Site Per Month: 1.2

Study Details

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
• 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: Mar 29, 2018
• Actual Primary Completion Date: Aug 9, 2018
• Actual Study Completion Date: Aug 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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [From Baseline to Weeks 8, 12, and 16]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

• 1. Participants with heterozygous familial hypercholesterolemia (heFH) (diagnosis based on either genotyping or clinical criteria) OR
• 1. 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

	Site	City	State	Country	Postal Code
1	Investigational Site Number 8400024	Los Angeles	California	United States	90057
2	Investigational Site Number 8400007	Jacksonville	Florida	United States	32216
3	Investigational Site Number 8400017	Jacksonville	Florida	United States	32223
4	Investigational Site Number 8400013	Ponte Vedra	Florida	United States	32081
5	Investigational Site Number 8400014	Wellington	Florida	United States	33449
6	Investigational Site Number 8400001	West Des Moines	Iowa	United States	50266
7	Investigational Site Number 8400019	Topeka	Kansas	United States	66606
8	Investigational Site Number 8400006	Cincinnati	Ohio	United States	45201
9	Investigational Site Number 8400010	Cincinnati	Ohio	United States	45219
10	Investigational Site Number 8400022	Summerville	South Carolina	United States	29485
11	Investigational Site Number 8400026	Amarillo	Texas	United States	79106
12	Investigational Site Number 8400005	Richmond	Virginia	United States	23227
13	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)

• Study Protocol - Nov 20, 2017
• Statistical Analysis Plan - Mar 27, 2018

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03415178
• Other Study ID Numbers: MSC14864; U1111-1186-3466
• First Posted: Jan 30, 2018
• Last Update Posted: Sep 9, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Hypercholesterolemia; Atorvastatin; Rosuvastatin Calcium

Study Results

Participant Flow

Recruitment Details	The study was conducted at 13 centers in the United States. A total of 92 participants were screened on 29-March-2018 with randomization between 05 April 2018 and 12 April 18 of whom 23 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Detail	Randomization to treatment arms was done centrally using treatment allocation system (Interactive Response Technology) in a 1:1 ratio (alirocumab from auto-injector device [AI] : alirocumab from new auto-injector device [SYDNEY]). A total of 69 participants were randomized.

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	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).	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.
Period Title: Parallel-Arm Period (up to Week 4)
STARTED	34	35
Treated	34	33
COMPLETED	34	33
NOT COMPLETED	0	2
Period Title: Parallel-Arm Period (up to Week 4)
STARTED	0	66
COMPLETED	0	65
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Auto-Injector Device (AI)	New Auto-injector Device (SYDNEY)	Total
Arm/Group Description	Alirocumab 300 mg 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) Q4W from Week 4 until Week 16 in the single arm treatment period added to LMT.	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.	Total of all reporting groups
Overall Participants	34	35	69
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.1 (8.6)	65.4 (8.1)	65.3 (8.3)
Sex: Female, Male (Count of Participants)
Female	19 55.9%	9 25.7%	28 40.6%
Male	15 44.1%	26 74.3%	41 59.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 5.9%	1 2.9%	3 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 23.5%	3 8.6%	11 15.9%
White	24 70.6%	31 88.6%	55 79.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Low-Density Lipoprotein Cholesterol (LDL-C) (milligram per deciliter (mg/dL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligram per deciliter (mg/dL)]	98.6 (24.3)	91.0 (15.0)	94.8 (20.4)

Outcome Measures

1. Primary Outcome

Title	Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (Overall) at the Unsupervised Injections: Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	66
Measure Number of unsupervised injections	196
Number (95% Confidence Interval) [percentage of PTCs]	0.5

2. Primary Outcome

Title	Percentage of SYDNEY-Associated Product Technical Complaints (PTCs) (by Type) at the Unsupervised Injections: Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	66
Measure Number of unsupervised injections	196
Device-related	0
Participant-related	0.5
Undetermined	0

3. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	34	33
Overall	0 0%	0 0%
Type: Device-related	0 0%	0 0%
Type: Participant-related	0 0%	0 0%
Type: Undetermined	0 0%	0 0%

4. Secondary Outcome

Title	Percentage of Participants With SYDNEY-Associated Product Technical Complaint (PTCs) (Overall and by Type) at the Unsupervised Injections : Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	66
Overall	1.5 4.4%
Type: Device-related	0 0%
Type: Participant-related	1.5 4.4%
Type: Undetermined	0 0%

5. Secondary Outcome

Title	Injection Experience Questionnaire at Initial Supervised Injection: Overall Ease of Use Scores: Parallel-Arm Period
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Auto-Injector Device (AI)	New Auto-injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	34	33
Mean (Standard Deviation) [score on a scale]	9.9 (0.2)	9.8 (0.5)

6. Secondary Outcome

Title	Patient Perspective Questionnaire After the Last Injection (at Week 12): Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	66
Size of the auto-injector	9.7 (0.8)
Ease of holding the auto-injector in hand	9.8 (0.6)
2-step operation:remove cap, press AI against skin	9.9 (0.4)
Length of time it took to complete the injection	9.9 (0.3)
Fact that needle is hidden prior & after injection	10.0 (0.3)
Once monthly injection	10.0 (0.1)
Confidence that Sydney device was used correctly	9.9 (0.4)

7. Secondary Outcome

Title	Injection-Treatment Acceptance Questionnaire (I-TAQ©) After Last Injection (at Week 12) - Overall Acceptance Scores: Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	65
Mean (Standard Deviation) [score on a scale]	93.08 (9.94)

8. Secondary Outcome

Title	Maximum Serum Alirocumab Concentration Observed - Cmax : Parallel-Arm Period
Description	Cmax: Maximum serum concentration observed.
Time Frame	Pre-dose (Week 0) and on Day 7, 14 and 21

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	33	31
Mean (Standard Deviation) [nanogram per milliliter (ng/mL)]	25800 (8430)	26800 (8420)

9. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alirocumab : Parallel-Arm Period
Description	Tmax: Time to reach Cmax.
Time Frame	Pre-dose (Week 0) and on Day 7, 14 and 21

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	33	31
Median (Full Range) [days]	7.00	7.00

10. Secondary Outcome

Title	Area Under the Curve-During the Dosing Interval Tau (AUC [0-tau]) : Parallel-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	32	31
Mean (Standard Deviation) [ng*day/mL]	381000 (147000)	414000 (152000)

11. Secondary Outcome

Title	Maximum Serum Alirocumab Concentration Observed - Cmax : Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	New Auto-injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	64
Mean (Standard Deviation) [ng/mL]	31900 (13100)

12. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alirocumab: Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	64
Median (Full Range) [days]	7.00

13. Secondary Outcome

Title	Area Under the Curve-During the Dosing Interval Tau (AUC [0-tau]) : Single-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	63
Mean (Standard Deviation) [ng*day/mL]	509000 (264000)

14. Secondary Outcome

Title	Free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Parallel-Arm Period
Description	Free PCSK9 concentrations below the lower limit of quantification (LLOQ) were set to zero.
Time Frame	Week 4

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	33	32
Mean (Standard Deviation) [ng/mL]	90.1 (110.5)	78.3 (103.1)

15. Secondary Outcome

Title	Free Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Single-Arm Period
Description	Free PCSK9 concentrations below the LLOQ were set to zero.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	65
Mean (Standard Deviation) [ng/mL]	88.9 (116.4)

16. Secondary Outcome

Title	Total Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Parallel-Arm Period
Description	Total PCSK9 concentrations below the LLOQ were set to zero.
Time Frame	Week 4

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	33	32
Mean (Standard Deviation) [ng/mL]	3329.7 (1147.7)	3370.0 (916.6)

17. Secondary Outcome

Title	Total Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Concentrations : Single-Arm Period
Description	Total PCSK9 concentrations below the LLOQ were set to zero.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	65
Mean (Standard Deviation) [ng/mL]	3481.4 (1290.1)

18. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Anti-Alirocumab Antibodies (ADA) Positive Response: Parallel-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	32	32
Count of Participants [Participants]	2 5.9%	1 2.9%

19. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Anti-Alirocumab Antibodies (ADA) Positive Response According to ADA Status During Parallel-Arm Period: Single Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	64
Pre-existing ADA	0 0%
Negative ADA status	2 5.9%
Treatment-emergent ADA positive	0 0%

20. Secondary Outcome

Title	Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 4: Parallel-Arm Period
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Auto-Injector Device (AI)	New Auto-Injector Device (SYDNEY)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.	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 period of 4 weeks added to LMT.
Measure Participants	32	31
Least Squares Mean (Standard Error) [percent change]	-51.2 (4.4)	-66.2 (4.4)

21. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	New Auto-Injector Device (SYDNEY)
Arm/Group Description	All participants who were randomized to Alirocumab 300 mg SC injection using either AI device or SYDNEY in the parallel arm treatment period of 4 weeks and continued in single arm period, Alirocumab 300 mg self-administered (unsupervised) SC injection using SYDNEY device Q4W at Week 4, 8 and 12 in single arm period added to LMT. Duration of single arm treatment period was 12 weeks (i.e. from Week 4 to 16).
Measure Participants	66
Week 8	-53.737 (32.641)
Week 12	-58.610 (25.068)
Week 16	-56.991 (25.930)

Adverse Events

Time Frame	All AEs were collected from signature of the informed consent form up to final visit (Week 16) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (the time from first IMP injection to the second IMP injection for participants entering into the single-arm period, or to 70 days after first IMP injection, whichever comes first [Parallel arm period] or the time from the second IMP injection up to the day of last IMP injection + 70 days [Single arm period]). Analysis was performed on safety population.
Arm/Group Title	Auto-Injector Device (AI) (Parallel Arm Period)		New Auto-Injector Device (Parallel-arm Period)		New Auto-Injector Device (Single-arm Period)
Arm/Group Description	Alirocumab 300 mg SC injection on Week 0 (Day 1), self-administered using AI device, on-site under supervision in the parallel arm period of 4 weeks added to LMT.		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 period of 4 weeks added to LMT.		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 at Week 4, 8 and 12 in the single arm treatment period. Duration of single arm treatment period was 12 weeks, i.e. from Week 4 to 16 added to LMT.
All Cause Mortality
	Auto-Injector Device (AI) (Parallel Arm Period)		New Auto-Injector Device (Parallel-arm Period)		New Auto-Injector Device (Single-arm Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/33 (0%)		0/66 (0%)
Serious Adverse Events
	Auto-Injector Device (AI) (Parallel Arm Period)		New Auto-Injector Device (Parallel-arm Period)		New Auto-Injector Device (Single-arm Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)		1/33 (3%)		2/66 (3%)
Cardiac disorders
Acute Myocardial Infarction	1/34 (2.9%)	1	0/33 (0%)	0	0/66 (0%)	0
Coronary Artery Disease	0/34 (0%)	0	0/33 (0%)	0	1/66 (1.5%)	1
Investigations
Alanine Aminotransferase Increased	0/34 (0%)	0	1/33 (3%)	1	0/66 (0%)	0
Musculoskeletal and connective tissue disorders
Chondritis	0/34 (0%)	0	0/33 (0%)	0	1/66 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Auto-Injector Device (AI) (Parallel Arm Period)		New Auto-Injector Device (Parallel-arm Period)		New Auto-Injector Device (Single-arm Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/34 (5.9%)		5/33 (15.2%)		8/66 (12.1%)
Infections and infestations
Upper Respiratory Tract Infection	0/34 (0%)	0	3/33 (9.1%)	3	0/66 (0%)	0
Urinary Tract Infection	0/34 (0%)	0	0/33 (0%)	0	4/66 (6.1%)	4
Injury, poisoning and procedural complications
Contusion	2/34 (5.9%)	2	1/33 (3%)	1	1/66 (1.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/34 (0%)	0	2/33 (6.1%)	2	3/66 (4.5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.