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Clinical Trial Results:
A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added on to Rosuvastatin versus Ezetimibe Added-on to Rosuvastatin versus Rosuvastatin Dose Increase in Patients Who are Not Controlled on Rosuvastatin

Summary
EudraCT number	2012-002333-11
Trial protocol	DE ES GB IT
Global end of trial date	08 May 2014

Results information
Results version number	v2(current)
This version publication date	08 Apr 2020
First version publication date	06 Aug 2015
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

R727-CL-1118

ISRCTN number

US NCT number

NCT01730053

WHO universal trial number (UTN)

Other trial identifiers

Study ID: ODYSSEY OPTIONS II

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Rd., Tarrytown, United States, 10591

Public contact

Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

Scientific contact

Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Jun 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 May 2014

Was the trial ended prematurely?

Main objective of the trial

To evaluate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to rosuvastatin in comparison with ezetimibe as add-on therapy to rosuvastatin, and in comparison with doubling the rosuvastatin dose, after 24 weeks of treatment in subjects with hypercholesterolemia at high cardiovascular (CV) risk.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Lipid-modifying therapies (LMT) that were allowed as background therapy included fish oils with ≥1000 mg of omega-3 fatty acids, fenofibrate, bile acid-binding sequestrates (eg, cholestyramine), and niacin. Doses of these medications were to remain stable for at least 4 weeks (at least 6 weeks for fenofibrate) before the screening visit, during the screening period, and during the double-blind treatment period.

Evidence for comparator

Actual start date of recruitment

23 Oct 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 29

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Mexico: 12

Country: Number of subjects enrolled

United States: 183

Country: Number of subjects enrolled

Australia: 21

Worldwide total number of subjects

305

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

188

From 65 to 84 years

115

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 79 sites in 8 countries. Overall, 672 subjects were screened between 29 October 2012 and 27 September 2013, 367 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

Screening details

Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment (rosuvastatin 10 or 20 mg). Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1:1:1:1 ratio after confirmation of selection criteria.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject, Carer, Assessor

Are arms mutually exclusive

Yes

Rosuvastatin 20 mg

Arm description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every two weeks (Q2W), and placebo for ezetimibe QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.

Arm type

Active comparator

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Crestor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin over-encapsulated tablets.

Investigational medicinal product name

Placebo (for Alirocumab and Ezetimibe)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Solution for injection

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm. Placebo matched to ezetimibe over-encapsulated tablet.

Ezetimibe 10 mg + Rosuvastatin 10 mg

Arm description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Arm type

Active comparator

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Crestor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin over-encapsulated tablets.

Investigational medicinal product name

Ezetimibe

Investigational medicinal product code

Other name

Ezetrol

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ezetimibe over-encapsulated tablet.

Investigational medicinal product name

Placebo (for Alirocumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Arm description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

Arm type

Experimental

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Crestor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin over-encapsulated tablets.

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

REGN727/SAR236553

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

Investigational medicinal product name

Placebo (for Ezetimibe)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo matched to ezetimibe over-encapsulated tablet.

Rosuvastatin 40 mg

Arm description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

Arm type

Active comparator

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Crestor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin over-encapsulated tablets.

Investigational medicinal product name

Placebo (for Alirocumab and Ezetimibe)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Solution for injection

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm. Placebo matched to ezetimibe over-encapsulated tablet.

Ezetimibe 10 mg + Rosuvastatin 20 mg

Arm description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Arm type

Active comparator

Investigational medicinal product name

Ezetimibe

Investigational medicinal product code

Other name

Ezetrol

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Ezetimibe over-encapsulated tablet.

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Crestor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin 20 mg over-encapsulated tablets.

Investigational medicinal product name

Placebo (for Alirocumab)

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo matched to alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg

Arm description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

REGN727/SAR236553

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

Investigational medicinal product name

Rosuvastatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Rosuvastatin over-encapsulated tablets.

Investigational medicinal product name

Placebo (for Ezetimibe)

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo matched to ezetimibe over-encapsulated tablet.

Number of subjects in period 1	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Started	48	48	49	53	53	54
Treated	48	48	49	53	53	54
Completed	43	34	38	45	44	41
Not completed	5	14	11	8	9	13
Physician decision	-	-	-	1	-	-
Adverse event	2	6	3	3	2	2
Other than specified	2	6	5	4	7	9
Subject moved	-	-	1	-	-	-
Poor compliance to protocol	1	2	2	-	-	2

Baseline characteristics

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Reporting group title

Rosuvastatin 20 mg

Reporting group description

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 10 mg

Reporting group description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Reporting group description

Reporting group title

Rosuvastatin 40 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 20 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg

Reporting group description

Reporting group values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg	Total
Number of subjects	48	48	49	53	53	54	305
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.5 ( 11.15 )	60.4 ( 10.38 )	62.2 ( 11.11 )	60.6 ( 10.11 )	63.1 ( 10.2 )	57.9 ( 8.86 )	-
Gender categorical
Units: Subjects
Female	15	22	18	15	22	26	118
Male	33	26	31	38	31	28	187
Low density lipoprotein cholesterol (LDL-C) in mg/dL
Calculated LDL-C from Friedewald formula.
Units: mg/dL
arithmetic mean (standard deviation)	105.9 ( 36 )	102.4 ( 41.9 )	107.3 ( 26.4 )	112.9 ( 43.3 )	119 ( 48 )	118.3 ( 32.2 )	-
LDL-C in mmol/L
Units: mmol/L
arithmetic mean (standard deviation)	2.743 ( 0.933 )	2.653 ( 1.085 )	2.78 ( 0.684 )	2.924 ( 1.122 )	3.082 ( 1.243 )	3.065 ( 0.834 )	-

End points

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Reporting group title

Rosuvastatin 20 mg

Reporting group description

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 10 mg

Reporting group description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Reporting group description

Reporting group title

Rosuvastatin 40 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 20 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg

Reporting group description

Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis

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End point title

Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis

End point description

Calculated LDL-C values were obtained using the Friedewald formula. Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.

End point type

Primary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-16.3 ( 4.1 )	-14.4 ( 4.4 )	-50.6 ( 4.2 )	-15.9 ( 7.1 )	-11 ( 7.2 )	-36.3 ( 7.1 )

Alirocumab v Rosuvastatin 20 mg

Statistical analysis description

Alirocumab group was compared to the corresponding active control group using an appropriate contrast statement.

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-34.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-49.2

upper limit

-19.3

Notes
[1] - Threshold for significance ≤ 0.0125.

Alirocumab v Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

As described in statistical analysis 1 of the endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-36.1

Confidence interval

level

98.75%

sides

2-sided

lower limit

-51.5

upper limit

-20.7

Notes
[2] - Threshold for significance ≤ 0.0125.

Alirocumab v Rosuvastatin 40 mg

Statistical analysis description

As described in statistical analysis 1 of the endpoint.

Comparison groups

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg v Rosuvastatin 40 mg

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0453 ^[3]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-20.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-45.8

upper limit

5.1

Notes
[3] - Threshold for significance ≤ 0.0125.

Alirocumab v Ezetimibe 10 mg + Rosuvastatin 20 mg

Statistical analysis description

As described in statistical analysis 1 of the endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg

Number of subjects included in analysis

103

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0136 ^[4]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-25.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-50.9

upper limit

0.3

Notes
[4] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis

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End point title

Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis

End point description

Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis). Modified ITT (mITT) population: all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	46	48	50	50	51
Units: percent change
least squares mean (standard error)	-18.3 ( 3.3 )	-20.3 ( 3.6 )	-53.5 ( 3.5 )	-17 ( 6.9 )	-16.5 ( 6.9 )	-41.5 ( 6.9 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 1.25 % level.

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-35.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-47.4

upper limit

-23

Notes
[5] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-33.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-45.9

upper limit

-20.5

Notes
[6] - Threshold for significance ≤ 0.0125.

Alirocumab vs Rosuvastatin 40 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Rosuvastatin 40 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0131 ^[7]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-24.5

Confidence interval

level

98.75%

sides

2-sided

lower limit

-49.2

upper limit

0.2

Notes
[7] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis

End point description

Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis). ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-17.1 ( 4.1 )	-17.4 ( 4.2 )	-49.6 ( 4.1 )	-22.1 ( 5.3 )	-19.3 ( 5.4 )	-32.3 ( 5.2 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-35.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-47.4

upper limit

-17.9

Notes
[8] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-32.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-47

upper limit

-17.5

Notes
[9] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis

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End point title

Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis

End point description

Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis). mITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	46	48	50	50	51
Units: percent change
least squares mean (standard error)	-17.2 ( 3.6 )	-20.3 ( 3.8 )	-52.6 ( 3.6 )	-22.9 ( 5.2 )	-21.8 ( 5.2 )	-35.1 ( 5.2 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-35.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-48.2

upper limit

-22.5

Notes
[10] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-32.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-45.6

upper limit

-19

Notes
[11] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	44	44	44	51	48	49
Units: percent change
least squares mean (standard error)	-7.3 ( 3 )	-9.7 ( 3.1 )	-36.5 ( 3.1 )	-9.8 ( 4.1 )	-11.2 ( 4.3 )	-28.3 ( 4.3 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[12]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-29.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-40.1

upper limit

-18.3

Notes
[12] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Ezetimibe 10 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[13]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-26.8

Confidence interval

level

98.75%

sides

2-sided

lower limit

-37.9

upper limit

-15.7

Notes
[13] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis

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End point title

Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis

End point description

Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first). Subjects analyzed: subjects of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	44	42	43	50	47	48
Units: percent change
least squares mean (standard error)	-8.8 ( 2.6 )	-11.2 ( 2.7 )	-39.5 ( 2.6 )	-12.7 ( 4 )	-12.6 ( 4.1 )	-30.4 ( 4.2 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[14]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-30.7

Confidence interval

level

98.75%

sides

2-sided

lower limit

-40.1

upper limit

-21.3

Notes
[14] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[15]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-28.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-38

upper limit

-18.7

Notes
[15] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Non-High-density lipoprotein cholesterol (non-HDL-C) at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Non-High-density lipoprotein cholesterol (non-HDL-C) at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-11.3 ( 3.4 )	-13.4 ( 3.7 )	-42.7 ( 3.5 )	-11.2 ( 5.1 )	-12.9 ( 5.2 )	-31.4 ( 5.2 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[16]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-31.4

Confidence interval

level

98.75%

sides

2-sided

lower limit

-43.9

upper limit

-18.9

Notes
[16] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[17]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-29.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-42.1

upper limit

-16.4

Notes
[17] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis

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End point title

Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	46	48	50	50	51
Units: percent change
least squares mean (standard error)	-12.9 ( 2.8 )	-17.5 ( 3.1 )	-45.7 ( 2.9 )	-14.9 ( 4.2 )	-18.2 ( 4.2 )	-35.6 ( 4.3 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[18]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-32.8

Confidence interval

level

98.75%

sides

2-sided

lower limit

-43.2

upper limit

-22.4

Notes
[18] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[19]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-28.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-39.1

upper limit

-17.3

Notes
[19] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-8.3 ( 2.4 )	-8.7 ( 2.6 )	-28.9 ( 2.5 )	-8.5 ( 3.6 )	-12.4 ( 3.6 )	-20.6 ( 3.6 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-20.6

Confidence interval

level

98.75%

sides

2-sided

lower limit

-29.4

upper limit

-11.8

Notes
[20] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[21]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-20.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

-29.3

upper limit

-11.2

Notes
[21] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Apo B at Week 12 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Apo B ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	44	44	44	51	48	49
Units: percent change
least squares mean (standard error)	-8.1 ( 3.2 )	-12.1 ( 3.3 )	-36.1 ( 3.2 )	-13.7 ( 3.3 )	-14.3 ( 3.3 )	-29 ( 3.3 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[22]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-28.1

Confidence interval

level

98.75%

sides

2-sided

lower limit

-39.7

upper limit

-16.5

Notes
[22] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[23]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-24

Confidence interval

level

98.75%

sides

2-sided

lower limit

-35.7

upper limit

-12.3

Notes
[23] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Non-HDL-C ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-11.7 ( 3.5 )	-16.3 ( 3.6 )	-41.2 ( 3.5 )	-18 ( 3.6 )	-18.7 ( 3.7 )	-29.8 ( 3.6 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[24]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-29.5

Confidence interval

level

98.75%

sides

2-sided

lower limit

-42.1

upper limit

-16.9

Notes
[24] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[25]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-24.9

Confidence interval

level

98.75%

sides

2-sided

lower limit

-37.7

upper limit

-12.2

Notes
[25] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Total-C at Week 12 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Total-C ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-8.9 ( 2.6 )	-11.8 ( 2.7 )	-29 ( 2.6 )	-13.8 ( 2.8 )	-13.9 ( 2.8 )	-19.4 ( 2.7 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[26]

Method

Mixed models analysis

Parameter type

LS Mean difference

Point estimate

-20.1

Confidence interval

level

98.75%

sides

2-sided

lower limit

-29.4

upper limit

-10.7

Notes
[26] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[27]

Method

Mixed models analysis

Parameter type

LS Mean Difference

Point estimate

-17.2

Confidence interval

level

98.75%

sides

2-sided

lower limit

-26.7

upper limit

-7.7

Notes
[27] - Threshold for significance ≤ 0.0125.

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis

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End point title

Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis

End point description

Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to week 24 regardless of status on- or off-treatment were included in the imputation model. (ITT analysis). ITT population.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percentage of subjects
number (not applicable)	45	57.2	84.9	40.1	52.2	66.7

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.

Comparison groups

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[28]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

12.4

Confidence interval

level

98.75%

sides

2-sided

lower limit

2.6

upper limit

59.5

Notes
[28] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007 ^[29]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

8.4

Confidence interval

level

98.75%

sides

2-sided

lower limit

1.8

upper limit

40.5

Notes
[29] - Threshold for significance ≤ 0.0125.

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis

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End point title

Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis

End point description

Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule [rosuvastatin or ezetimibe], whichever came first (on-treatment analysis). mITT population.

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	46	48	50	50	51
Units: percentage of subjects
number (not applicable)	47	60.5	86.4	41.3	54.8	70.4

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[30]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

15.6

Confidence interval

level

98.75%

sides

2-sided

lower limit

2.58

upper limit

88.2

Notes
[30] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[31]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.9

Confidence interval

level

98.75%

sides

2-sided

lower limit

1.7

upper limit

56.7

Notes
[31] - Threshold for significance ≤ 0.0125.

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis

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End point title

Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percentage of subjects
number (not applicable)	31.3	43.1	77.8	29.9	43.6	60.1

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[32]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

18.6

Confidence interval

level

98.75%

sides

2-sided

lower limit

3.6

upper limit

96.2

Notes
[32] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[33]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

11.6

Confidence interval

level

98.75%

sides

2-sided

lower limit

2.5

upper limit

53.1

Notes
[33] - Threshold for significance ≤ 0.0125.

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis

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End point title

Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis

End point description

End point type

Secondary

End point timeframe

Up to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	46	48	50	50	51
Units: percentage of subjects
number (not applicable)	34.8	46.7	76.5	30.6	45.1	66.1

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[34]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

20.3

Confidence interval

level

98.75%

sides

2-sided

lower limit

2.4

upper limit

67.7

Notes
[34] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[35]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

12.7

Confidence interval

level

98.75%

sides

2-sided

lower limit

2.4

upper limit

67.7

Notes
[35] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis

End point description

Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects analyzed: subjects of the ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
arithmetic mean (standard error)	-4 ( 4.3 )	-4.3 ( 4.5 )	-27.9 ( 4.1 )	-5.2 ( 4.8 )	-5.8 ( 4.6 )	-22.7 ( 5.1 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Comparison groups

Rosuvastatin 20 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[36]

Method

Regression, Robust

Parameter type

Adjusted Mean Difference

Point estimate

-23.9

Confidence interval

level

98.75%

sides

2-sided

lower limit

-38.6

upper limit

-9.1

Notes
[36] - Threshold for significance ≤ 0.0125.

Alirocumab vs Ezetimibe 10 mg + Rosuvastatin 10 mg

Statistical analysis description

Analysis description as per the statistical analysis 1 of this endpoint.

Comparison groups

Ezetimibe 10 mg + Rosuvastatin 10 mg v Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[37]

Method

Regression, Robust

Parameter type

Adjusted Mean Difference

Point estimate

-23.6

Confidence interval

level

98.75%

sides

2-sided

lower limit

-39

upper limit

-8.2

Notes
[37] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	1.7 ( 2.4 )	4 ( 2.5 )	9.1 ( 2.4 )	1.5 ( 2.3 )	-1.8 ( 2.3 )	7.2 ( 2.3 )

Alirocumab vs Rosuvastatin 20 mg

Statistical analysis description

Comparison groups

Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg v Rosuvastatin 20 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0311 ^[38]

Method

Regression, Robust

Parameter type

Adjusted Mean Difference

Point estimate

7.4

Confidence interval

level

98.75%

sides

2-sided

lower limit

-1.2

upper limit

16.1

Notes
[38] - Threshold for significance ≤ 0.0125.

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	-1.8 ( 4.5 )	-8.3 ( 4.8 )	-11.2 ( 4.6 )	-9.9 ( 4.1 )	-11.1 ( 4.3 )	-8.7 ( 4.5 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis

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End point title

Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	44	44	44	51	48	49
Units: percent change
least squares mean (standard error)	5.4 ( 1.9 )	5 ( 1.9 )	6.7 ( 1.9 )	2.9 ( 1.9 )	-0.9 ( 1.9 )	6.7 ( 2 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis

End point description

Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Lipoprotein (a) ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
arithmetic mean (standard error)	-0.7 ( 3.5 )	-3.9 ( 3.6 )	-20.7 ( 3.5 )	3.5 ( 4.2 )	7.9 ( 4.1 )	-16 ( 4.2 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. HDL-C ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	0.7 ( 2.1 )	0.2 ( 2.2 )	5.9 ( 2.1 )	0.6 ( 2.5 )	3.1 ( 2.5 )	8 ( 2.5 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis

End point description

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	48	47	48	52	50	53
Units: percent change
least squares mean (standard error)	8.1 ( 4.1 )	-8.2 ( 4.2 )	-14 ( 4.1 )	-2.7 ( 4 )	-12.4 ( 4 )	-10.1 ( 4 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis

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End point title

Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis

End point description

Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Apo A-1 ITT population.

End point type

Secondary

End point timeframe

From Baseline to Week 12

End point values	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
Number of subjects analysed	44	44	44	51	48	49
Units: percent change
least squares mean (standard error)	4 ( 1.6 )	2.6 ( 1.6 )	4.3 ( 1.6 )	0.9 ( 1.8 )	1.8 ( 1.8 )	9.1 ( 1.8 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Baseline to Week 24

Adverse event reporting additional description

Treatment emergent adverse events that developed during treatment emergent adverse events period (the time period from the first double-blind injection of study drug up to the day of last injection + 70 days) are reported.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Rosuvastatin 20 mg

Reporting group description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 10 mg

Reporting group description

Subjects, who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75/up to 150 + Rosuvastatin 20 mg

Reporting group description

Reporting group title

Rosuvastatin 40 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks.

Reporting group title

Ezetimibe 10 mg + Rosuvastatin 20 mg

Reporting group description

Subjects, who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks.

Reporting group title

Alirocumab 75/up to 150 + Rosuvastatin 10 mg

Reporting group description

Serious adverse events	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75/up to 150 + Rosuvastatin 20 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75/up to 150 + Rosuvastatin 10 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 48 (8.33%)	5 / 48 (10.42%)	4 / 54 (7.41%)	4 / 53 (7.55%)	3 / 53 (5.66%)	2 / 49 (4.08%)
number of deaths (all causes)	0	0	0	0	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Small cell lung cancer metastatic
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina unstable
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Subarachnoid haemorrhage
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombotic thrombocytopenic purpura
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-Cardiac chest pain
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	1 / 53 (1.89%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychotic disorder
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	1 / 54 (1.85%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Spinal cord infection
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 48 (0.00%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Obesity
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Rosuvastatin 20 mg	Ezetimibe 10 mg + Rosuvastatin 10 mg	Alirocumab 75/up to 150 + Rosuvastatin 20 mg	Rosuvastatin 40 mg	Ezetimibe 10 mg + Rosuvastatin 20 mg	Alirocumab 75/up to 150 + Rosuvastatin 10 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 48 (22.92%)	11 / 48 (22.92%)	15 / 54 (27.78%)	20 / 53 (37.74%)	12 / 53 (22.64%)	11 / 49 (22.45%)
Nervous system disorders
Headache
subjects affected / exposed	0 / 48 (0.00%)	1 / 48 (2.08%)	0 / 54 (0.00%)	3 / 53 (5.66%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences all number	0	1	0	4	0	0
Dizziness
subjects affected / exposed	3 / 48 (6.25%)	1 / 48 (2.08%)	2 / 54 (3.70%)	2 / 53 (3.77%)	1 / 53 (1.89%)	1 / 49 (2.04%)
occurrences all number	4	1	2	2	1	1
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	2 / 48 (4.17%)	0 / 48 (0.00%)	3 / 54 (5.56%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences all number	3	0	5	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 48 (0.00%)	2 / 48 (4.17%)	2 / 54 (3.70%)	3 / 53 (5.66%)	0 / 53 (0.00%)	0 / 49 (0.00%)
occurrences all number	0	2	2	3	0	0
Nausea
subjects affected / exposed	1 / 48 (2.08%)	1 / 48 (2.08%)	0 / 54 (0.00%)	1 / 53 (1.89%)	1 / 53 (1.89%)	3 / 49 (6.12%)
occurrences all number	1	3	0	1	1	3
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 48 (2.08%)	3 / 48 (6.25%)	0 / 54 (0.00%)	0 / 53 (0.00%)	0 / 53 (0.00%)	1 / 49 (2.04%)
occurrences all number	1	3	0	0	0	1
Arthralgia
subjects affected / exposed	1 / 48 (2.08%)	0 / 48 (0.00%)	0 / 54 (0.00%)	2 / 53 (3.77%)	1 / 53 (1.89%)	4 / 49 (8.16%)
occurrences all number	1	0	0	2	1	4
Myalgia
subjects affected / exposed	1 / 48 (2.08%)	3 / 48 (6.25%)	4 / 54 (7.41%)	1 / 53 (1.89%)	1 / 53 (1.89%)	0 / 49 (0.00%)
occurrences all number	2	3	5	1	1	0
Pain in extremity
subjects affected / exposed	3 / 48 (6.25%)	1 / 48 (2.08%)	0 / 54 (0.00%)	5 / 53 (9.43%)	2 / 53 (3.77%)	2 / 49 (4.08%)
occurrences all number	3	1	0	5	2	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 48 (2.08%)	2 / 48 (4.17%)	2 / 54 (3.70%)	6 / 53 (11.32%)	3 / 53 (5.66%)	2 / 49 (4.08%)
occurrences all number	1	2	2	6	3	2
Upper respiratory tract infection
subjects affected / exposed	3 / 48 (6.25%)	0 / 48 (0.00%)	4 / 54 (7.41%)	6 / 53 (11.32%)	4 / 53 (7.55%)	2 / 49 (4.08%)
occurrences all number	3	0	4	7	4	2

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Were there any global substantial amendments to the protocol? Yes

13 Feb 2013

The purpose of this amendment was to: - Redefine the exclusion of subjects with HbA 1c >8.5% to HbA 1c >9%. - Clarify that a repeat lab was allowed for Thyroid-stimulating hormone (TSH) eligibility laboratory results. - Clarify fulfillment of applicable local regulatory requirements through the informed consent form or a local protocol addendum in women of childbearing potential and add a definition for the duration of required contraception use after discontinuation of the study drug. - Clarify LMTs that were allowed as background therapy. - Add contingency language to ensure the continuity of study drug treatment without interruption (in the event the manufacturer faced any performance or supply issues of the auto-injector). - Remove hospitalization for unanticipated coronary revascularization from the list of Clinical Events Committee (CEC) adjudication categories, and add that all coronary revascularizations would be submitted to the CEC. - Clarify that reporting of Adverse event of special interest (AESI) that required accelerated reporting would be done within 24 hours of learning of the event. - Make miscellaneous administrative clarifications.

08 Apr 2014

The purpose of this amendment was to: - Modify the primary efficacy analysis population to the ITT population for the primary and secondary efficacy endpoints, which would include assessments both on study treatment and off study treatment through the analysis period. - An MMRM would be used for the primary endpoint and for other continuous secondary endpoints anticipated to have normally distributed data. - For continuous endpoints expected to have non-normally distributed data, the robust regression method would be used to test the treatment group differences and missing data would be handled using multiple imputation approach. - For binary endpoints, logistic regression method would be used to test the treatment group differences and missing data would be handled using multiple imputation approach. - Supportive analyses had been added for the primary and secondary efficacy endpoints, pooling treatment arms across the dose regimens. - Primary and key secondary endpoints would also be analyzed in the mITT population to assess the drug effect during the study treatment period (on-treatment approach). - The list of key and other secondary efficacy endpoints and estimands (ITT estimand or on-treatment estimand) were adjusted. - For safety, the initial review of data would be based on the pooled dose regimens, with the individual treatment groups within the rosuvastatin dose regimens as supportive. - Update language on cardiovascular events to be reported to the CEC for adjudication, and to clarify cerebrovascular events. - Clarify that LDL-C measured and calculated would be performed at weeks 0 and 24. - Update language on collection of partner pregnancy data, per the ODYSSEY program. - Update categorization of AEs (update language on how to record injection site reactions that were not related to study drug). - Make minor corrections/clarifications.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added on to Rosuvastatin versus Ezetimibe Added-on to Rosuvastatin versus Rosuvastatin Dose Increase in Patients Who are Not Controlled on Rosuvastatin

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis

Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Non-High-density lipoprotein cholesterol (non-HDL-C) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Non-High-density lipoprotein cholesterol (non-HDL-C) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis

Secondary: Percentage of Very High CV Risk Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Subjects Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis

Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis

Secondary: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added on to Rosuvastatin versus Ezetimibe Added-on to Rosuvastatin versus Rosuvastatin Dose Increase in Patients Who are Not Controlled on Rosuvastatin