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Clinical Trial Results:
A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

Summary
EudraCT number	2013-000935-29
Trial protocol	CZ DE GB IT DK NL NO
Global end of trial date	21 Nov 2017

Results information
Results version number	v1(current)
This version publication date	23 Nov 2018
First version publication date	23 Nov 2018
Other versions

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

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Sponsor protocol code

20120332

ISRCTN number

US NCT number

NCT01984424

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

21 Nov 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

The main objective of this 3-part study was to evaluate the effect of 24 weeks of evolocumab (AMG 145) administered subcutaneously (SC) every month (QM), compared with ezetimibe (part B), on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic participants who were unable to tolerate an effective dose of a statin due to muscle-related side effects (MRSE) (part B), as confirmed by a lead-in, double-blind, placebo-controlled, crossover statin rechallenge (part A).

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations and guidelines set forth in 21 Code of Federal Regulations parts 11, 50, 54, 56, and 312. All participants provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No participants were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Dec 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 17

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

South Africa: 2

Country: Number of subjects enrolled

Czech Republic: 26

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Netherlands: 32

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Canada: 13

Country: Number of subjects enrolled

United States: 62

Worldwide total number of subjects

218

EEA total number of subjects

121

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)

144

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 511 participants were enrolled in the 3-part study at 53 centers (parts A and B) and 48 centers (part C) in the United States of America, Europe, Australia, New Zealand, Canada, and South Africa from December 2013 to November 2017. Results are reported for participants enrolled in part B and part C.

Screening details

492 participants were randomized into part A. 199 of 202 participants that completed part A, along with additional 19 new participants, were randomized 2:1 (stratified by screening LDL-C level) to receive evolocumab or ezetimibe in 24-week, double-blind part B. A total of 209 participants from part B enrolled in 2-year, open-label extension part C.

Period 1 title

Study part B

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Blinding implementation details

Participants received either evolocumab SC or placebo SC and either ezetimibe orally (PO) or matching placebo PO. Participants disposition accounting for SC IP in part B are reported.

Are arms mutually exclusive

Yes

Ezetimibe in part B

Arm description

Participants received ezetimibe 10 milligram (mg) PO once a day (QD) and placebo matching to evolocumab SC injection QM for 24 weeks.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received placebo matching to evolocumab SC injection QM for 24 weeks.

Investigational medicinal product name

Ezetimibe

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received ezetimibe 10 mg tablet PO QD for 24 weeks.

Evolocumab in part B

Arm description

Participants received evolocumab 420 mg SC injection QM and placebo matching to ezetimibe PO QD for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received placebo matching to ezetimibe PO QD for 24 weeks.

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received evolocumab 420 mg SC injection QM for 24 weeks.

Number of subjects in period 1	Ezetimibe in part B	Evolocumab in part B
Started	73	145
Participants who received SC IP	73	145
Completed	69	138
Not completed	4	7
Consent withdrawn by subject	3	-
Physician decision	-	1
Adverse event, non-fatal	1	5
Lost to follow-up	-	1

Period 2 title

Study part C

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Ezetimibe in part B and Evolocumab in part C

Arm description

Participants who completed SC IP in part B were eligible and 2 participants who did not complete IP in part B were enrolled in part C and were allowed to choose quarterly during scheduled study center visits between evolocumab 420 mg SC QM or evolocumab 140 mg SC every 2 weeks (Q2W) for up to 104 weeks.

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants were allowed to choose quarterly during scheduled study center visits between evolocumab 420 mg SC QM or evolocumab 140 mg SC Q2W for up to 104 weeks.

Evolocumab in part B and part C

Arm description

Arm type

Experimental

Investigational medicinal product name

Evolocumab

Investigational medicinal product code

AMG 145

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen

Routes of administration

Subcutaneous use

Dosage and administration details

Participants were allowed to choose quarterly during scheduled study center visits between evolocumab 420 mg SC QM or evolocumab 140 mg SC Q2W for up to 104 weeks.

Number of subjects in period 2	Ezetimibe in part B and Evolocumab in part C	Evolocumab in part B and part C
Started	69	138
Participants who received Evolocumab	70	139
Completed	65	133
Not completed	5	6
Adverse event, serious fatal	-	1
Consent withdrawn by subject	4	3
Lost to follow-up	1	2
Joined	1	1
Enrolled without completing IP during part B	1	1

Baseline characteristics

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Reporting group title

Ezetimibe in part B

Reporting group description

Participants received ezetimibe 10 milligram (mg) PO once a day (QD) and placebo matching to evolocumab SC injection QM for 24 weeks.

Reporting group title

Evolocumab in part B

Reporting group description

Participants received evolocumab 420 mg SC injection QM and placebo matching to ezetimibe PO QD for 24 weeks.

Reporting group values	Ezetimibe in part B	Evolocumab in part B	Total
Number of subjects	73	145	218
Age, Customized
Units: Subjects
< 65 years	52	92	144
≥ 65 years	21	53	74
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.5 ( 9.4 )	59.0 ( 11.1 )	-
Sex: Female, Male
Units: Subjects
Female	39	67	106
Male	34	78	112
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	1	2	3
Black or African American	3	3	6
Native Hawaiian or Other Pacific Islander	0	0	0
White	69	138	207
Other	0	2	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	2	2
Not Hispanic or Latino	73	143	216
Unknown or Not Reported	0	0	0
Stratification Factor: Screening LDL-C
Units: Subjects
< 180 mg/deciliter (dL)	21	40	61
≥ 180 mg/dL	52	105	157
LDL-C Concentation
Units: mg/dL
arithmetic mean (standard deviation)	221.9 ( 70.2 )	218.8 ( 73.1 )	-
Total Cholesterol Concentration
Units: mg/dL
arithmetic mean (standard deviation)	308.0 ( 73.8 )	306.5 ( 75.4 )	-
High-density Lipoprotein Cholesterol (HDL-C)
Units: mg/dL
arithmetic mean (standard deviation)	50.2 ( 15.5 )	49.7 ( 15.4 )	-
Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration
Units: mg/dL
arithmetic mean (standard deviation)	35.7 ( 14.3 )	37.1 ( 15.6 )	-
Non-high-density Lipoprotein Cholesterol (non-HDL-C) Concentration
Units: mg/dL
arithmetic mean (standard deviation)	257.8 ( 76.3 )	256.9 ( 73.8 )	-
Apolipoprotein B Concentration
N=71 and 144, respectively. Whereas, N is number of participants analysed.
Units: mg/dL
arithmetic mean (standard deviation)	155.0 ( 42.4 )	158.3 ( 41.5 )	-
Total Cholesterol/HDL-C Ratio
Units: ratio
arithmetic mean (standard deviation)	6.709 ( 2.746 )	6.668 ( 2.349 )	-
Apolipoprotein B/Apolipoprotein A1 Ratio
N=71 and 144, respectively.
Units: ratio
arithmetic mean (standard deviation)	1.063 ( 0.416 )	1.063 ( 0.340 )	-
Triglyceride Concentration
Units: mg/dL
median (inter-quartile range (Q1-Q3))	162.5 (127.0 to 231.0)	176.0 (128.0 to 233.5)	-
Lipoprotein(a) Concentration
N=71 and 144, respectively.
Units: nanomoles per liter (nmol/L)
median (inter-quartile range (Q1-Q3))	38.0 (18.0 to 164.0)	29.0 (12.5 to 152.5)	-

End points

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Reporting group title

Ezetimibe in part B

Reporting group description

Participants received ezetimibe 10 milligram (mg) PO once a day (QD) and placebo matching to evolocumab SC injection QM for 24 weeks.

Reporting group title

Evolocumab in part B

Reporting group description

Participants received evolocumab 420 mg SC injection QM and placebo matching to ezetimibe PO QD for 24 weeks.

Reporting group title

Ezetimibe in part B and Evolocumab in part C

Reporting group description

Reporting group title

Evolocumab in part B and part C

Reporting group description

Primary: Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

End point description

Co-primary endpoint. The full analysis set (FAS) population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Primary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	-16.70 ( 1.91 )	-54.50 ( 1.39 )

Treatment Difference at Mean of Weeks 22 and 24

Statistical analysis description

The null hypothesis was that there was no mean difference in the percent change from baseline at weeks 22 and 24 of part B in LDL-C between evolocumab 420 mg and ezetimibe, and the alternative hypothesis was that a mean difference did exist.

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-37.79

Confidence interval

level

95%

sides

2-sided

lower limit

-42.31

upper limit

-33.28

Variability estimate

Standard error of the mean

Dispersion value

2.29

Notes
[1] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[2] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Primary: Percent Change From Baseline in LDL-C at Week 24 in Part B

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End point title

Percent Change From Baseline in LDL-C at Week 24 in Part B

End point description

Co-primary endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Primary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	-16.69 ( 2.11 )	-52.76 ( 1.52 )

Treatment Difference at Week 24

Statistical analysis description

The null hypothesis was that there was no mean difference in the percent change from baseline at week 24 of part B in LDL-C between evolocumab 420 mg and ezetimibe, and the alternative hypothesis was that a mean difference did exist.

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001 ^[4]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-36.07

Confidence interval

level

95%

sides

2-sided

lower limit

-41.07

upper limit

-31.08

Variability estimate

Standard error of the mean

Dispersion value

2.53

Notes
[3] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[4] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

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End point title

Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: mg/dL
least squares mean (standard error)	-31.0 ( 3.8 )	-106.8 ( 2.7 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-75.8

Confidence interval

level

95%

sides

2-sided

lower limit

-84.7

upper limit

-67

Variability estimate

Standard error of the mean

Dispersion value

4.5

Notes
[5] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[6] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Change From Baseline in LDL-C at Week 24 in Part B

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End point title

Change From Baseline in LDL-C at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: mg/dL
least squares mean (standard error)	-31.2 ( 4.0 )	-102.9 ( 2.9 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.0001 ^[8]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-71.7

Confidence interval

level

95%

sides

2-sided

lower limit

-81.3

upper limit

-62.2

Variability estimate

Standard error of the mean

Dispersion value

4.8

Notes
[7] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[8] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at the Mean of Weeks 22 and 24 in Part B

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End point title

Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	73	145
Units: Percentage of participants
number (confidence interval 95%)	1.4 (0.3 to 7.7)	29.9 (22.9 to 38.1)

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Treatment Difference

Point estimate

28.5

Confidence interval

level

95%

sides

2-sided

lower limit

19.1

upper limit

36.7

Notes
[9] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[10] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Based on Cochran-Mantel Haenszel test stratified by the stratification factor (screening LDL-C).

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at Week 24 in Part B

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End point title

Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	73	145
Units: Percentage of participants
number (confidence interval 95%)	0.0 (0.0 to 6.3)	27.4 (20.1 to 36.1)

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Treatment Difference

Point estimate

27.4

Confidence interval

level

95%

sides

2-sided

lower limit

17.7

upper limit

36.1

Notes
[11] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[12] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Based on Cochran-Mantel Haenszel test stratified by the stratification factor (screening LDL-C).

Secondary: Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	-11.43 ( 1.41 )	-38.04 ( 1.03 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0001 ^[14]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-26.61

Confidence interval

level

95%

sides

2-sided

lower limit

-29.95

upper limit

-23.27

Variability estimate

Standard error of the mean

Dispersion value

1.69

Notes
[13] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[14] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Total Cholesterol at Week 24 in Part B

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End point title

Percent Change From Baseline in Total Cholesterol at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	-11.57 ( 1.52 )	-36.64 ( 1.10 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001 ^[16]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-25.08

Confidence interval

level

95%

sides

2-sided

lower limit

-28.67

upper limit

-21.48

Variability estimate

Standard error of the mean

Dispersion value

1.82

Notes
[15] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[16] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in non-HDL-C at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in non-HDL-C at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	-14.38 ( 1.72 )	-47.44 ( 1.25 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001 ^[18]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-33.06

Confidence interval

level

95%

sides

2-sided

lower limit

-37.12

upper limit

-28.99

Variability estimate

Standard error of the mean

Dispersion value

2.06

Notes
[17] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[18] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in non-HDL-C at Week 24 in Part B

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End point title

Percent Change From Baseline in non-HDL-C at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	-14.62 ( 1.83 )	-45.72 ( 1.32 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

< 0.0001 ^[20]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-31.1

Confidence interval

level

95%

sides

2-sided

lower limit

-35.44

upper limit

-26.76

Variability estimate

Standard error of the mean

Dispersion value

2.2

Notes
[19] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[20] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	68	136
Units: Percent change
least squares mean (standard error)	-11.42 ( 1.82 )	-45.28 ( 1.31 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001 ^[22]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-33.86

Confidence interval

level

95%

sides

2-sided

lower limit

-38.15

upper limit

-29.58

Variability estimate

Standard error of the mean

Dispersion value

2.17

Notes
[21] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[22] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change from Baseline in Apolipoprotein B at Week 24 in Part B

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End point title

Percent Change from Baseline in Apolipoprotein B at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	56	116
Units: Percent change
least squares mean (standard error)	-11.74 ( 1.94 )	-43.50 ( 1.40 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

< 0.0001 ^[24]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-31.75

Confidence interval

level

95%

sides

2-sided

lower limit

-36.35

upper limit

-27.16

Variability estimate

Standard error of the mean

Dispersion value

2.33

Notes
[23] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[24] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	-11.48 ( 1.75 )	-41.39 ( 1.27 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

< 0.0001 ^[26]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-29.91

Confidence interval

level

95%

sides

2-sided

lower limit

-34.06

upper limit

-25.77

Variability estimate

Standard error of the mean

Dispersion value

2.1

Notes
[25] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[26] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 in Part B

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End point title

Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	-12.84 ( 1.85 )	-40.04 ( 1.33 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

< 0.0001 ^[28]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-27.2

Confidence interval

level

95%

sides

2-sided

lower limit

-31.58

upper limit

-22.82

Variability estimate

Standard error of the mean

Dispersion value

2.22

Notes
[27] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[28] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	68	136
Units: Percent change
least squares mean (standard error)	-11.86 ( 1.89 )	-45.99 ( 1.36 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

< 0.0001 ^[30]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-34.13

Confidence interval

level

95%

sides

2-sided

lower limit

-38.59

upper limit

-29.67

Variability estimate

Standard error of the mean

Dispersion value

2.26

Notes
[29] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[30] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 in Part B

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End point title

Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 in Part B

End point description

Co-secondary tier 1 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	56	116
Units: Percent change
least squares mean (standard error)	-12.62 ( 1.97 )	-44.60 ( 1.41 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.0001 ^[32]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-31.98

Confidence interval

level

95%

sides

2-sided

lower limit

-36.64

upper limit

-27.32

Variability estimate

Standard error of the mean

Dispersion value

2.36

Notes
[31] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[32] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	68	136
Units: Percent change
least squares mean (standard error)	-1.63 ( 2.80 )	-22.71 ( 2.03 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

204

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

< 0.0001 ^[34]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-21.08

Confidence interval

level

95%

sides

2-sided

lower limit

-27.65

upper limit

-14.51

Variability estimate

Standard error of the mean

Dispersion value

3.33

Notes
[33] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[34] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 in Part B

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End point title

Percent Change From Baseline in Lipoprotein(a) at Week 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	56	116
Units: Percent change
least squares mean (standard error)	0.17 ( 3.05 )	-21.06 ( 2.19 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

< 0.0001 ^[36]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-21.24

Confidence interval

level

95%

sides

2-sided

lower limit

-28.42

upper limit

-14.05

Variability estimate

Standard error of the mean

Dispersion value

3.64

Notes
[35] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[36] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	-0.95 ( 3.94 )	-5.39 ( 2.84 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

= 0.37 ^[38]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-4.44

Confidence interval

level

95%

sides

2-sided

lower limit

-13.74

upper limit

4.87

Variability estimate

Standard error of the mean

Dispersion value

4.72

Notes
[37] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[38] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in Triglycerides at Week 24 in Part B

Top of page

End point title

Percent Change From Baseline in Triglycerides at Week 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	-1.07 ( 4.97 )	-2.88 ( 3.54 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.37 ^[40]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-1.82

Confidence interval

level

95%

sides

2-sided

lower limit

-13.64

upper limit

10.01

Variability estimate

Standard error of the mean

Dispersion value

Notes
[39] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[40] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in HDL-C at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in HDL-C at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	137
Units: Percent change
least squares mean (standard error)	1.66 ( 1.71 )	7.85 ( 1.24 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

207

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.0083 ^[42]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

6.18

Confidence interval

level

95%

sides

2-sided

lower limit

2.15

upper limit

10.22

Variability estimate

Standard error of the mean

Dispersion value

2.05

Notes
[41] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[42] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in HDL-C at Week 24 in Part B

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End point title

Percent Change From Baseline in HDL-C at Week 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	57	117
Units: Percent change
least squares mean (standard error)	2.90 ( 1.89 )	7.40 ( 1.36 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

= 0.0083 ^[44]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

8.98

Variability estimate

Standard error of the mean

Dispersion value

2.27

Notes
[43] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[44] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in VLDL-C at the Mean of Weeks 22 and 24 in Part B

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End point title

Percent Change From Baseline in VLDL-C at the Mean of Weeks 22 and 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Weeks 22 and 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	70	136
Units: Percent change
least squares mean (standard error)	-2.15 ( 3.22 )	-6.81 ( 2.33 )

Treatment Difference at Mean of Weeks 22 and 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

= 0.37 ^[46]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-4.65

Confidence interval

level

95%

sides

2-sided

lower limit

-12.25

upper limit

2.94

Variability estimate

Standard error of the mean

Dispersion value

3.85

Notes
[45] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[46] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Secondary: Percent Change From Baseline in VLDL-C at Week 24 in Part B

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End point title

Percent Change From Baseline in VLDL-C at Week 24 in Part B

End point description

Co-secondary tier 2 endpoint. The FAS population include all randomized participants in part B who received at least 1 dose of part B IP (SC or PO).

End point type

Secondary

End point timeframe

Baseline (part A Day 1 for those who entered part A, and part B Day 1 for those who bypassed part A) and Week 24 of part B

End point values	Ezetimibe in part B	Evolocumab in part B
Number of subjects analysed	56	115
Units: Percent change
least squares mean (standard error)	-2.66 ( 3.88 )	-3.90 ( 2.78 )

Treatment Difference at Week 24

Comparison groups

Ezetimibe in part B v Evolocumab in part B

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.37 ^[48]

Method

Repeated Measures Model

Parameter type

Least Square Mean Treatment Difference

Point estimate

-1.23

Confidence interval

level

95%

sides

2-sided

lower limit

-10.45

upper limit

7.98

Variability estimate

Standard error of the mean

Dispersion value

4.67

Notes
[47] - Treatment difference calculated with ezetimibe in part B reporting group as the reference.
[48] - Multiplicity adjusted p-value is significant if less than the familywise error rate of 0.05. Model includes treatment group, stratification factor (screening LDL-C), scheduled visit and interaction of treatment with scheduled visit.

Other pre-specified: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part C

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End point title

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part C

End point description

An adverse event (AE) is defined as any untoward medical occurrence or worsening of a pre-existing medical condition in a participant. A serious AE is defined as an AE that meets at least 1 of following serious criteria: fatal, life threatening (immediate risk of death), requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect and other medically important serious event. AEs that occurred after IP administration in part C until 30 days after end of IP or EOS were considered treatment emergent in part C. Adverse device effect included AEs resulting from insufficient or inadequate instructions for use, or any malfunction of device, or use error or from intentional misuse of device. The long-term analysis set (LAS) population included all participants enrolled in part C of study who received at least 1 dose of open-label IP and was used in all analyses for part C of study.

End point type

Other pre-specified

End point timeframe

From the first dose of IP in part C until 30 days after the end of IP or end of study (EOS), whichever was earlier (up to 104 weeks)

End point values	Ezetimibe in part B and Evolocumab in part C	Evolocumab in part B and part C
Number of subjects analysed	70 ^[49]	139 ^[50]
Units: Participants
TEAEs	55	111
TESAEs	14	36
Device related TEAEs	1	1
TEAEs leading to discontinuation of IP	3	4
Fatal AE	0	1

Notes
[49] - One participant enrolled in to this group of part C without completing IP during part B.
[50] - One participant enrolled in to this group of part C without completing IP during part B.

No statistical analyses for this end point

Other pre-specified: Number of Participants who Experienced the Maximum Toxicity Grade [Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3] Shift From Baseline in the Clinical Laboratory Parameters During Part C

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End point title

Number of Participants who Experienced the Maximum Toxicity Grade [Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3] Shift From Baseline in the Clinical Laboratory Parameters During Part C

End point description

Blood and urine samples for determination of clinical chemistry, haematology and urinalysis parameters were taken every 3 months and at the EOS or safety follow-up visit during part C of the study. The results were based on the shift of laboratory parameters from study baseline grade 0 to 2 to postbaseline grade 3 to 4 during part C. All baseline values were collected at the start of the study, ie, baseline values from the start of part A for participants who entered part A, and from the start of part B for participants who bypassed part A. Laboratory shift values for specific analytes were provided using the CTCAE version 4.03 toxicity criteria. The LAS population included all participants enrolled in part C of the study who received at least 1 dose of open-label IP and was used in all analyses for part C of the study. AST = aspartate aminotransferase and INR = international normalized ratio.

End point type

Other pre-specified

End point timeframe

From the first dose of IP in part C until 30 days after the end of IP or EOS, whichever was earlier (up to 104 weeks)

End point values	Ezetimibe in part B and Evolocumab in part C	Evolocumab in part B and part C
Number of subjects analysed	70 ^[51]	139 ^[52]
Units: Participants
AST (shift from grade 0 to 3)	0	1
Creatine kinase (shift from grade 0 to 4)	0	1
Creatine kinase (shift from grade 1 to 3)	0	1
Creatine kinase (shift from grade 1 to 4)	0	1
Creatine kinase (shift from grade 2 to 3)	0	1
Creatinine (shift from grade 2 to 3)	1	0
Sodium (shift from grade 1 to 3)	0	1
Total bilirubin (shift from grade 0 to 3)	1	0
INR (shift from grade 2 to 3)	0	1

Notes
[51] - One participant enrolled in to this group of part C without completing IP during part B.
[52] - One participant enrolled in to this group of part C without completing IP during part B.

No statistical analyses for this end point

Other pre-specified: Number of Participants With Positive Anti-Evolocumab Antibody Formation in Part C

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End point title

Number of Participants With Positive Anti-Evolocumab Antibody Formation in Part C

End point description

Blood samples were collected annually and at the end of study or safety follow-up visit during part C of the study for the measurement of anti-evolocumab binding antibodies. The LAS population included all participants enrolled in part C of the study who received at least 1 dose of open-label IP and was used in all analyses for part C of the study.

End point type

Other pre-specified

End point timeframe

From the first dose of IP in part C until 30 days after the end of IP or EOS, whichever was earlier (up to 104 weeks)

End point values	Ezetimibe in part B and Evolocumab in part C	Evolocumab in part B and part C
Number of subjects analysed	70 ^[53]	139 ^[54]
Units: Participants
Binding antibody positive	0	0
Neutralizing antibody positive	0	0

Notes
[53] - One participant enrolled in to this group of part C without completing IP during part B.
[54] - One participant enrolled in to this group of part C without completing IP during part B.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of IP in part B until the EOS visit in part C or early termination from the study, up to 128 weeks

Adverse event reporting additional description

The FAS population and LAS population were analyzed for AEs in part B and part C of study, respectively. MedDRA dictionary version 18.1 was used for part B and 20.1 for part C.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1 20.1

Reporting group title

Evolocumab in Part B

Reporting group description

Participants received evolocumab 420 mg SC injection QM and placebo matching to ezetimibe orally QD for 24 weeks.

Reporting group title

Ezetimibe in Part B and Evolocumab in Part C

Reporting group description

Reporting group title

Ezetimibe in Part B

Reporting group description

Participants received ezetimibe 10 mg orally QD and placebo matching to evolocumab SC injection QM for 24 weeks.

Reporting group title

Evolocumab in Part B and Part C

Reporting group description

Serious adverse events	Evolocumab in Part B	Ezetimibe in Part B and Evolocumab in Part C	Ezetimibe in Part B	Evolocumab in Part B and Part C
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 145 (6.21%)	14 / 70 (20.00%)	10 / 73 (13.70%)	36 / 139 (25.90%)
number of deaths (all causes)	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Invasive lobular breast carcinoma
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipoma
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer stage I
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Spinal fusion surgery
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	3 / 139 (2.16%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Vocal cord cyst
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar I disorder
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in respiratory tract
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ligament sprain
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural urine leak
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cystic kidney disease
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	1 / 73 (1.37%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 145 (0.69%)	4 / 70 (5.71%)	2 / 73 (2.74%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 145 (1.38%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery perforation
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Heart valve incompetence
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Myocardial ischaemia
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine with aura
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myasthenia gravis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal angiodysplasia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 145 (0.00%)	2 / 70 (2.86%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 145 (0.69%)	1 / 70 (1.43%)	0 / 73 (0.00%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Arthritis infective
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	1 / 145 (0.69%)	0 / 70 (0.00%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	3 / 139 (2.16%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	1 / 73 (1.37%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 145 (0.00%)	0 / 70 (0.00%)	0 / 73 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Obesity
subjects affected / exposed	0 / 145 (0.00%)	1 / 70 (1.43%)	0 / 73 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Evolocumab in Part B	Ezetimibe in Part B and Evolocumab in Part C	Ezetimibe in Part B	Evolocumab in Part B and Part C
Total subjects affected by non serious adverse events
subjects affected / exposed	86 / 145 (59.31%)	34 / 70 (48.57%)	44 / 73 (60.27%)	76 / 139 (54.68%)
Nervous system disorders
Headache
subjects affected / exposed	10 / 145 (6.90%)	3 / 70 (4.29%)	7 / 73 (9.59%)	8 / 139 (5.76%)
occurrences all number	12	3	8	10
General disorders and administration site conditions
Fatigue
subjects affected / exposed	12 / 145 (8.28%)	0 / 70 (0.00%)	5 / 73 (6.85%)	6 / 139 (4.32%)
occurrences all number	12	0	5	6
Influenza like illness
subjects affected / exposed	1 / 145 (0.69%)	2 / 70 (2.86%)	4 / 73 (5.48%)	5 / 139 (3.60%)
occurrences all number	1	3	5	7
Gastrointestinal disorders
Constipation
subjects affected / exposed	3 / 145 (2.07%)	2 / 70 (2.86%)	4 / 73 (5.48%)	4 / 139 (2.88%)
occurrences all number	3	2	4	4
Diarrhoea
subjects affected / exposed	6 / 145 (4.14%)	2 / 70 (2.86%)	4 / 73 (5.48%)	3 / 139 (2.16%)
occurrences all number	6	3	5	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	13 / 145 (8.97%)	7 / 70 (10.00%)	1 / 73 (1.37%)	10 / 139 (7.19%)
occurrences all number	13	10	1	12
Back pain
subjects affected / exposed	10 / 145 (6.90%)	6 / 70 (8.57%)	5 / 73 (6.85%)	9 / 139 (6.47%)
occurrences all number	10	7	6	9
Muscle spasms
subjects affected / exposed	13 / 145 (8.97%)	4 / 70 (5.71%)	5 / 73 (6.85%)	10 / 139 (7.19%)
occurrences all number	15	6	6	10
Musculoskeletal pain
subjects affected / exposed	5 / 145 (3.45%)	2 / 70 (2.86%)	1 / 73 (1.37%)	8 / 139 (5.76%)
occurrences all number	5	2	1	8
Myalgia
subjects affected / exposed	20 / 145 (13.79%)	8 / 70 (11.43%)	16 / 73 (21.92%)	16 / 139 (11.51%)
occurrences all number	22	10	21	26
Pain in extremity
subjects affected / exposed	13 / 145 (8.97%)	3 / 70 (4.29%)	1 / 73 (1.37%)	6 / 139 (4.32%)
occurrences all number	15	3	1	7
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 145 (0.69%)	1 / 70 (1.43%)	4 / 73 (5.48%)	10 / 139 (7.19%)
occurrences all number	1	1	4	13
Influenza
subjects affected / exposed	7 / 145 (4.83%)	3 / 70 (4.29%)	1 / 73 (1.37%)	9 / 139 (6.47%)
occurrences all number	7	3	2	12
Nasopharyngitis
subjects affected / exposed	14 / 145 (9.66%)	3 / 70 (4.29%)	2 / 73 (2.74%)	15 / 139 (10.79%)
occurrences all number	14	4	2	18
Sinusitis
subjects affected / exposed	4 / 145 (2.76%)	3 / 70 (4.29%)	2 / 73 (2.74%)	7 / 139 (5.04%)
occurrences all number	5	3	2	9
Upper respiratory tract infection
subjects affected / exposed	4 / 145 (2.76%)	1 / 70 (1.43%)	1 / 73 (1.37%)	7 / 139 (5.04%)
occurrences all number	4	1	1	11
Urinary tract infection
subjects affected / exposed	5 / 145 (3.45%)	4 / 70 (5.71%)	3 / 73 (4.11%)	7 / 139 (5.04%)
occurrences all number	6	4	4	11
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 145 (0.00%)	2 / 70 (2.86%)	1 / 73 (1.37%)	7 / 139 (5.04%)
occurrences all number	0	2	3	7

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Were there any global substantial amendments to the protocol? Yes

27 Sep 2013

The main purpose of this amendment was to add Vitamin E reflex testing to part C of the protocol in cases where LDL-C is < 25 mg/dL. To clarify language for laboratory testing on Day 1 of part B in participants who complete part A. As prior version was incorrect with respect to participants who go directly to part B due to 10x upper limit of normal (ULN) creatine kinase (CK). Add the potential to use the automated mini-doser in part C of the study. Remove duplicate exclusion criteria regarding malignancy. Remove Statin Intolerance Questionnaire as it is redundant with the Short Form (36) Health Survey (SF-36). Make the Brief Pain Inventory (BPI) mandatory in part A. Add the BPI and the SF-36 to part B and add corresponding exploratory analysis and statistical language. Clarify language on MRSE that in the opinion of the investigator lead to discontinuation of IP. Update statin inclusion criteria per FDA comment.

15 Jan 2014

The main purpose of this amendment was to clarify that participants must bypass part A and be randomized directly into part B if they have a documented history of CK elevation > 10 x ULN accompanied by muscle symptoms while on statin therapy and documented resolution of both CK elevation and muscle symptoms upon discontinuation of statin therapy. Update duration of part A to approximately 24 weeks. Modify inclusion criterion to specify that participants with fasting LDL-C ≥ 160 mg/dL (4.14 millimoles per liter) without diagnosed coronary heart disease or risk equivalent should have 1 or more risk factors. To clarify text to reflect that participants must discontinue statins and ezetimibe for ≥ 4 weeks before LDL-C screening. To Modify timing of non-protocol testing of specific analytes to at least 12 weeks after participant’s last blinded IP administration. Add Hepatitis C virus viral load testing for participants positive for Hepatitis C virus on Day 1 (part B). Remove Hemoglobin A1c from exploratory endpoints.

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.

The efficacy and safety evaluations were presented only for part B and C of 3-part study. The AE data was not included for part A as this was designed to confirm presence of statin-related MRSE and ensure that only these participants entered part B.

http://www.ncbi.nlm.nih.gov/pubmed/27039291

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Clinical trials

Clinical Trial Results: A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

Primary: Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

Primary: Percent Change From Baseline in LDL-C at Week 24 in Part B

Primary: Percent Change From Baseline in LDL-C at Week 24 in Part B

Secondary: Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Change From Baseline in LDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Change From Baseline in LDL-C at Week 24 in Part B

Secondary: Change From Baseline in LDL-C at Week 24 in Part B

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at the Mean of Weeks 22 and 24 in Part B

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at the Mean of Weeks 22 and 24 in Part B

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at Week 24 in Part B

Secondary: Percentage of Participants Who Achieved LDL-C of Less Than 70 mg/dL at Week 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol at Week 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol at Week 24 in Part B

Secondary: Percent Change From Baseline in non-HDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in non-HDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in non-HDL-C at Week 24 in Part B

Secondary: Percent Change From Baseline in non-HDL-C at Week 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change from Baseline in Apolipoprotein B at Week 24 in Part B

Secondary: Percent Change from Baseline in Apolipoprotein B at Week 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 in Part B

Secondary: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 in Part B

Secondary: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24 in Part B

Secondary: Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 in Part B

Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 in Part B

Secondary: Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in Triglycerides at Week 24 in Part B

Secondary: Percent Change From Baseline in Triglycerides at Week 24 in Part B

Secondary: Percent Change From Baseline in HDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in HDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in HDL-C at Week 24 in Part B

Secondary: Percent Change From Baseline in HDL-C at Week 24 in Part B

Secondary: Percent Change From Baseline in VLDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in VLDL-C at the Mean of Weeks 22 and 24 in Part B

Secondary: Percent Change From Baseline in VLDL-C at Week 24 in Part B

Secondary: Percent Change From Baseline in VLDL-C at Week 24 in Part B

Other pre-specified: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part C

Other pre-specified: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Part C

Other pre-specified: Number of Participants who Experienced the Maximum Toxicity Grade [Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3] Shift From Baseline in the Clinical Laboratory Parameters During Part C

Other pre-specified: Number of Participants who Experienced the Maximum Toxicity Grade [Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3] Shift From Baseline in the Clinical Laboratory Parameters During Part C

Other pre-specified: Number of Participants With Positive Anti-Evolocumab Antibody Formation in Part C

Other pre-specified: Number of Participants With Positive Anti-Evolocumab Antibody Formation in Part C

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of AMG 145, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects