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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Varying Doses and Dose Regimens of Evinacumab in Patients with Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy

Summary
EudraCT number	2017-001508-31
Trial protocol	CZ NL NO SE DK PL AT ES GB
Global end of trial date	14 Dec 2020

Results information
Results version number	v1(current)
This version publication date	29 Dec 2021
First version publication date	29 Dec 2021
Other versions

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

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Trial information

Top of page

Sponsor protocol code

R1500-CL-1643

ISRCTN number

US NCT number

NCT03175367

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

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

Public contact

Clinical Trial Adminstrator, Regeneron Pharmaceuticals, Inc., 001 8447346643, clinicaltrials@regeneron.com

Scientific contact

Clinical Trial Adminstrator, Regeneron Pharmaceuticals, Inc., 001 8447346643, 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

14 Dec 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Dec 2020

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate the reduction of LDL-C by evinacumab in comparison to placebo after 16 weeks in subjects with primary hypercholesterolemia (HeFH, or non-HeFH with a history of clinical ASCVD) with persistent hypercholesterolemia despite receiving maximally-tolerated LMT. Persistent hypercholesterolemia is defined as LDL-C ≥70 mg/dL (1.81 mmol/L) for those subjects with clinical ASCVD and LDL-C ≥100 mg/dL (2.59 mmol/L) for those subjects without clinical ASCVD.

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 Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

10 Nov 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 3

Country: Number of subjects enrolled

Austria: 8

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Czechia: 5

Country: Number of subjects enrolled

Denmark: 6

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Japan: 3

Country: Number of subjects enrolled

Jordan: 19

Country: Number of subjects enrolled

Netherlands: 21

Country: Number of subjects enrolled

New Zealand: 2

Country: Number of subjects enrolled

Norway: 7

Country: Number of subjects enrolled

Poland: 8

Country: Number of subjects enrolled

Russian Federation: 31

Country: Number of subjects enrolled

South Africa: 23

Country: Number of subjects enrolled

Spain: 17

Country: Number of subjects enrolled

Sweden: 5

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

United States: 75

Worldwide total number of subjects

266

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)

214

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Study participants were recruited from 20 countries in Europe, Africa, Asia, North America, and Australasia

Screening details

A total of 327 participants were screened and 272 participants randomized. 6 participants were randomized but never treated.

Period 1 title

Double-blind treatment period (DBTP)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Group A: Placebo SC QW (DBTP)

Arm description

Placebo Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo of Evinacumab subcutaneous treatment

Group A: Evinacumab 300mg SC Q2W (DBTP)

Arm description

Evinacumab 300 mg Subcutaneous (SC) treatment every other week (alternating with placebo on opposite weeks) for 16 weeks followed by a 23-week follow-up period

Arm type

Experimental

Investigational medicinal product name

Evinacumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Evinacumab subcutaneous treatment

Group A: Evinacumab 300mg SC QW (DBTP)

Arm description

Evinacumab 300 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Arm type

Experimental

Investigational medicinal product name

Evinacumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Evinacumab subcutaneous treatment

Group A: Evinacumab 450mg SC QW (DBTP)

Arm description

Evinacumab 450 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period.

Arm type

Experimental

Investigational medicinal product name

Evinacumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Evinacumab subcutaneous treatment

Group B: Placebo IV Q4W (DBTP)

Arm description

Placebo Intravenous (IV) treatment every 4 weeks for 24 weeks. Group B (IV treatment groups) entered a 48-week OLTP after completing the 24-week double-blind treatment period (DBTP) and received evinacumab 15 mg/kg IV Q4W regardless of their treatment assignment in the DBTP.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Placebo of Evinacumab intravenous treatment

Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Arm description

Evinacumab 5mg/kg IV treatment every 4 weeks. Group B (IV treatment groups) entered a 48-week OLTP after completing the 24-week double-blind treatment period (DBTP) and received evinacumab 15 mg/kg IV Q4W regardless of their treatment assignment in the DBTP.

Arm type

Experimental

Investigational medicinal product name

Evinacumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Evinacumab intravenous treatment

Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Arm description

Arm type

Experimental

Investigational medicinal product name

Evinacumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Evinacumab intravenous treatment

Number of subjects in period 1	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Started	39	39	42	40	33	35	38
Completed	30	31	30	30	31	32	34
Not completed	9	8	12	10	2	3	4
Consent withdrawn by subject	1	1	2	2	-	1	-
Physician decision	6	5	8	6	-	-	-
Adverse event, non-fatal	2	2	-	-	1	2	2
Lost to follow-up	-	-	1	-	1	-	-
Protocol deviation	-	-	1	2	-	-	2

Period 2 title

Open-Label treatment period (OLTP)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Group B: DB Placebo IV Q4W (OLTP)

Arm description

Group B (IV treatment groups) entered a 48-week OLTP after completing the 24-week double-blind treatment period (DBTP) and received evinacumab 15 mg/kg IV Q4W regardless of their treatment assignment in the DBTP.

Arm type

Experimental

Investigational medicinal product name

Evinacumab intravenous treatment

Investigational medicinal product code

Evinacumab

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Evinacumab intravenous treatment

Group B: DB Evinacumab 5mg/kg IV Q4W (OLTP)

Arm description

Arm type

Experimental

Investigational medicinal product name

Evinacumab intravenous treatment

Investigational medicinal product code

Evinacumab

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Evinacumab intravenous treatment

Group B: DB Evinacumab 15mg/kg IV Q4W (OLTP)

Arm description

Arm type

Experimental

Investigational medicinal product name

Evinacumab intravenous treatment

Investigational medicinal product code

Evinacumab

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Evinacumab intravenous treatment

Number of subjects in period 2 ^[1]	Group B: DB Placebo IV Q4W (OLTP)	Group B: DB Evinacumab 5mg/kg IV Q4W (OLTP)	Group B: DB Evinacumab 15mg/kg IV Q4W (OLTP)
Started	31	32	34
Treated in OLTP	31	32	33
Completed	31	30	32
Not completed	0	2	2
Consent withdrawn by subject	-	2	1
Completed DBTP but did not continue to OLTP	-	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: All patients who successfully complete this study (or successfully complete the double-blind treatment period and open-label treatment period for patients in the IV treatment groups) may have the opportunity to enroll in an open-label extension or safety study. All patients who enroll in the open-label extension or safety study will continue to receive evinacumab.

Baseline characteristics

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Reporting group title

Group A: Placebo SC QW (DBTP)

Reporting group description

Placebo Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 300mg SC Q2W (DBTP)

Reporting group description

Evinacumab 300 mg Subcutaneous (SC) treatment every other week (alternating with placebo on opposite weeks) for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 300mg SC QW (DBTP)

Reporting group description

Evinacumab 300 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 450mg SC QW (DBTP)

Reporting group description

Evinacumab 450 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period.

Reporting group title

Group B: Placebo IV Q4W (DBTP)

Reporting group description

Reporting group title

Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Reporting group description

Reporting group title

Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Reporting group description

Reporting group values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)	Total
Number of subjects	39	39	42	40	33	35	38	266
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	34	29	34	30	26	28	33	214
From 65-84 years	5	10	8	10	7	7	5	52
85 years and over	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	52.4 ( 12.69 )	55.0 ( 13.01 )	54.0 ( 12.22 )	54.5 ( 15.14 )	56.2 ( 10.91 )	55.7 ( 9.58 )	52.1 ( 12.12 )	-
Sex: Female, Male
Units:
Female	27	21	23	29	18	22	19	159
Male	12	18	19	11	15	13	19	107
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0
Asian	1	2	0	0	1	1	0	5
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	3	0	0	1	2	0	0	6
White	34	34	39	38	27	32	35	239
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	1	3	3	1	3	2	3	16
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	5	2	2	3	7	2	23
Not Hispanic or Latino	36	31	38	38	30	28	36	237
Unknown or Not Reported	1	3	2	0	0	0	0	6

End points

Top of page

Reporting group title

Group A: Placebo SC QW (DBTP)

Reporting group description

Placebo Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 300mg SC Q2W (DBTP)

Reporting group description

Evinacumab 300 mg Subcutaneous (SC) treatment every other week (alternating with placebo on opposite weeks) for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 300mg SC QW (DBTP)

Reporting group description

Evinacumab 300 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period

Reporting group title

Group A: Evinacumab 450mg SC QW (DBTP)

Reporting group description

Evinacumab 450 mg Subcutaneous (SC) treatment every week for 16 weeks followed by a 23-week follow-up period.

Reporting group title

Group B: Placebo IV Q4W (DBTP)

Reporting group description

Reporting group title

Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Reporting group description

Reporting group title

Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Reporting group description

Reporting group title

Group B: DB Placebo IV Q4W (OLTP)

Reporting group description

Reporting group title

Group B: DB Evinacumab 5mg/kg IV Q4W (OLTP)

Reporting group description

Reporting group title

Group B: DB Evinacumab 15mg/kg IV Q4W (OLTP)

Reporting group description

Primary: Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 (ITT Estimand)

End point description

End point type

Primary

End point timeframe

Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	8.8 ( 6.4 )	-29.7 ( 6.4 )	-44.0 ( 6.3 )	-47.2 ( 6.2 )	0.6 ( 6.6 )	-23.5 ( 6.6 )	-49.9 ( 6.1 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-38.5

Confidence interval

level

95%

sides

2-sided

lower limit

-56.5

upper limit

-20.6

Variability estimate

Standard error of the mean

Dispersion value

9.1

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-52.9

Confidence interval

level

95%

sides

2-sided

lower limit

-70.7

upper limit

-35.1

Variability estimate

Standard error of the mean

Dispersion value

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-56

Confidence interval

level

95%

sides

2-sided

lower limit

-73.7

upper limit

-38.3

Variability estimate

Standard error of the mean

Dispersion value

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0109 ^[1]

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-24.2

Confidence interval

level

95%

sides

2-sided

lower limit

-42.6

upper limit

-5.7

Variability estimate

Standard error of the mean

Dispersion value

9.3

Notes
[1] - P-Value is not adjusted for multiplicity

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-50.5

Confidence interval

level

95%

sides

2-sided

lower limit

-68.4

upper limit

-32.6

Variability estimate

Standard error of the mean

Dispersion value

Secondary: Percent Change from Baseline in Apolipoprotein B (Apo B) at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Apolipoprotein B (Apo B) at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	6.7 ( 5.1 )	-19.9 ( 5.1 )	-35.2 ( 5.1 )	-38.8 ( 4.9 )	-3.8 ( 4.7 )	-20.4 ( 4.6 )	-43.2 ( 4.3 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-26.6

Confidence interval

level

95%

sides

2-sided

lower limit

-40.9

upper limit

-12.4

Variability estimate

Standard error of the mean

Dispersion value

7.2

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-42

Confidence interval

level

95%

sides

2-sided

lower limit

-56.1

upper limit

-27.9

Variability estimate

Standard error of the mean

Dispersion value

7.1

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-45.5

Confidence interval

level

95%

sides

2-sided

lower limit

-59.5

upper limit

-31.5

Variability estimate

Standard error of the mean

Dispersion value

7.1

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0132

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-16.6

Confidence interval

level

95%

sides

2-sided

lower limit

-29.7

upper limit

-3.5

Variability estimate

Standard error of the mean

Dispersion value

6.6

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-39.4

Confidence interval

level

95%

sides

2-sided

lower limit

-52

upper limit

-26.8

Variability estimate

Standard error of the mean

Dispersion value

6.4

Secondary: Percent Change from Baseline in Apo B at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Apo B at Week 24 (ITT Estimand) ^[2]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	5.9 ( 6.0 )	-15.9 ( 5.9 )	-34.5 ( 5.6 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0111

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-21.8

Confidence interval

level

95%

sides

2-sided

lower limit

-38.4

upper limit

-5.1

Variability estimate

Standard error of the mean

Dispersion value

8.4

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-40.4

Confidence interval

level

95%

sides

2-sided

lower limit

-56.7

upper limit

-24

Variability estimate

Standard error of the mean

Dispersion value

8.2

Secondary: Percent Change from Baseline in Non High Density Lipoprotein Cholesterol (non-HDL-C) at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Non High Density Lipoprotein Cholesterol (non-HDL-C) at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	8.0 ( 5.4 )	-31.3 ( 5.4 )	-45.8 ( 5.3 )	-50.6 ( 5.2 )	-1.1 ( 5.8 )	-24.8 ( 5.7 )	-52.0 ( 5.3 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-39.3

Confidence interval

level

95%

sides

2-sided

lower limit

-54.4

upper limit

-24.3

Variability estimate

Standard error of the mean

Dispersion value

7.6

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-53.8

Confidence interval

level

95%

sides

2-sided

lower limit

-68.8

upper limit

-38.9

Variability estimate

Standard error of the mean

Dispersion value

7.6

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-58.5

Confidence interval

level

95%

sides

2-sided

lower limit

-73.4

upper limit

-43.7

Variability estimate

Standard error of the mean

Dispersion value

7.5

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0042

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-23.7

Confidence interval

level

95%

sides

2-sided

lower limit

-39.7

upper limit

-7.7

Variability estimate

Standard error of the mean

Dispersion value

8.1

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-50.9

Confidence interval

level

95%

sides

2-sided

lower limit

-66.4

upper limit

-35.4

Variability estimate

Standard error of the mean

Dispersion value

7.8

Secondary: Percent Change from Baseline in non-HDL-C at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in non-HDL-C at Week 24 (ITT Estimand) ^[3]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	10.4 ( 7.0 )	-20.2 ( 6.7 )	-44.3 ( 6.4 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0021

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-30.6

Confidence interval

level

95%

sides

2-sided

lower limit

-49.8

upper limit

-11.4

Variability estimate

Standard error of the mean

Dispersion value

9.7

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-54.6

Confidence interval

level

95%

sides

2-sided

lower limit

-73.4

upper limit

-35.8

Variability estimate

Standard error of the mean

Dispersion value

9.5

Secondary: Percentage of Participants with >= 30% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Top of page

End point title

Percentage of Participants with >= 30% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percentage of Participants
number (not applicable)	11.3	68.1	73.9	71.4	15.5	57.9	86.8

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

19.4

Confidence interval

level

95%

sides

2-sided

lower limit

5.1

upper limit

72.8

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

23.9

Confidence interval

level

95%

sides

2-sided

lower limit

6.4

upper limit

89.2

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

22.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

80.5

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0007

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

8.5

Confidence interval

level

95%

sides

2-sided

lower limit

2.5

upper limit

29.2

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

42.3

Confidence interval

level

95%

sides

2-sided

lower limit

10.4

upper limit

172.3

Secondary: Percentage of Participants with >= 50% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Top of page

End point title

Percentage of Participants with >= 50% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percentage of Participants
number (not applicable)	5.2	28.6	53.7	60.6	12.3	24.6	63.2

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.01

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

53.5

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

24.8

Confidence interval

level

95%

sides

2-sided

lower limit

4.7

upper limit

129.9

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

36.1

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

194.7

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3185

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

8.2

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.5

Confidence interval

level

95%

sides

2-sided

lower limit

3.9

upper limit

54.2

Secondary: Percentage of Participants with Calculated LDL-C < 50 mg/dL (1.30 mmol/L) at Week 16 (ITT Estimand)

Top of page

End point title

Percentage of Participants with Calculated LDL-C < 50 mg/dL (1.30 mmol/L) at Week 16 (ITT Estimand)

End point description

Percentage of Participants with Calculated LDL-C < 50 milligrams/deciliter (mg/dL) [1.30 Millimoles per liter (mmol/L)] at Week 16 (ITT Estimand)

End point type

Secondary

End point timeframe

Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percentage of Participants
number (not applicable)	5.1	22.8	29.7	40.8	9.3	13.2	39.5

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0718

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

4.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

26.5

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0048

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

2.1

upper limit

62.1

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0015

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.8

upper limit

76.8

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.527

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

8.4

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0047

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

31.7

Secondary: Percent Change from Baseline in Calculated LDL-C at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Calculated LDL-C at Week 24 (ITT Estimand) ^[4]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	14.8 ( 8.3 )	-17.7 ( 8.0 )	-39.7 ( 7.7 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0059

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-32.5

Confidence interval

level

95%

sides

2-sided

lower limit

-55.5

upper limit

-9.6

Variability estimate

Standard error of the mean

Dispersion value

11.5

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-54.5

Confidence interval

level

95%

sides

2-sided

lower limit

-77

upper limit

-32

Variability estimate

Standard error of the mean

Dispersion value

11.3

Secondary: Percent Change from Baseline in Total Cholesterol (TC) at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Total Cholesterol (TC) at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	6.1 ( 4.0 )	-31.0 ( 4.0 )	-40.3 ( 4.0 )	-45.4 ( 3.9 )	-0.4 ( 4.5 )	-22.6 ( 4.4 )	-46.8 ( 4.1 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-37.1

Confidence interval

level

95%

sides

2-sided

lower limit

-48.4

upper limit

-25.8

Variability estimate

Standard error of the mean

Dispersion value

5.7

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-46.4

Confidence interval

level

95%

sides

2-sided

lower limit

-57.5

upper limit

-35.2

Variability estimate

Standard error of the mean

Dispersion value

5.6

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-51.5

Confidence interval

level

95%

sides

2-sided

lower limit

-62.5

upper limit

-40.4

Variability estimate

Standard error of the mean

Dispersion value

5.6

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0006

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-22.2

Confidence interval

level

95%

sides

2-sided

lower limit

-34.6

upper limit

-9.8

Variability estimate

Standard error of the mean

Dispersion value

6.2

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-46.4

Confidence interval

level

95%

sides

2-sided

lower limit

-58.4

upper limit

-34.4

Variability estimate

Standard error of the mean

Dispersion value

6.1

Secondary: Percent Change from Baseline in Total Cholesterol at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Total Cholesterol at Week 24 (ITT Estimand) ^[5]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	8.5 ( 5.1 )	-19.9 ( 4.9 )	-40.8 ( 4.7 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-28.4

Confidence interval

level

95%

sides

2-sided

lower limit

-42.6

upper limit

-14.3

Variability estimate

Standard error of the mean

Dispersion value

7.1

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean Difference

Point estimate

-49.3

Confidence interval

level

95%

sides

2-sided

lower limit

-63.2

upper limit

-35.4

Variability estimate

Standard error of the mean

Dispersion value

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Fasting Triglycerides at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	8.1 ( 4.5 )	-38.0 ( 4.2 )	-47.7 ( 4.0 )	-53.4 ( 3.9 )	-6.9 ( 4.7 )	-32.1 ( 4.5 )	-52.8 ( 4.1 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-46.1

Confidence interval

level

95%

sides

2-sided

lower limit

-57.8

upper limit

-34.3

Variability estimate

Standard error of the mean

Dispersion value

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-55.8

Confidence interval

level

95%

sides

2-sided

lower limit

-67.3

upper limit

-44.3

Variability estimate

Standard error of the mean

Dispersion value

5.9

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-61.5

Confidence interval

level

95%

sides

2-sided

lower limit

-72.9

upper limit

-50

Variability estimate

Standard error of the mean

Dispersion value

5.8

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-25.2

Confidence interval

level

95%

sides

2-sided

lower limit

-38

upper limit

-12.4

Variability estimate

Standard error of the mean

Dispersion value

6.5

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-45.9

Confidence interval

level

95%

sides

2-sided

lower limit

-58.4

upper limit

-33.5

Variability estimate

Standard error of the mean

Dispersion value

6.3

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Fasting Triglycerides at Week 24 (ITT Estimand) ^[6]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	-6.1 ( 5.4 )	-23.2 ( 5.1 )	-51.3 ( 4.8 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0228

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-17.1

Confidence interval

level

95%

sides

2-sided

lower limit

-31.8

upper limit

-2.4

Variability estimate

Standard error of the mean

Dispersion value

7.5

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-45.3

Confidence interval

level

95%

sides

2-sided

lower limit

-59.6

upper limit

-31

Variability estimate

Standard error of the mean

Dispersion value

7.3

Secondary: Percent Change from Baseline in Lipoprotein a [Lp(a)] at Week 16 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Lipoprotein a [Lp(a)] at Week 16 (ITT Estimand)

End point description

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Group A: Placebo SC QW (DBTP)	Group A: Evinacumab 300mg SC Q2W (DBTP)	Group A: Evinacumab 300mg SC QW (DBTP)	Group A: Evinacumab 450mg SC QW (DBTP)	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	39	39	42	40	33	35	38
Units: Percent Change
least squares mean (standard error)	0.3 ( 3.9 )	-10.3 ( 4.1 )	-11.6 ( 4.0 )	-8.9 ( 4.0 )	0.8 ( 3.7 )	-15.7 ( 3.7 )	-15.7 ( 3.3 )

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC Q2W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0635

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-10.6

Confidence interval

level

95%

sides

2-sided

lower limit

-21.8

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

5.7

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 300mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0314

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-11.9

Confidence interval

level

95%

sides

2-sided

lower limit

-22.8

upper limit

-1.1

Variability estimate

Standard error of the mean

Dispersion value

5.5

Week 16

Comparison groups

Group A: Placebo SC QW (DBTP) v Group A: Evinacumab 450mg SC QW (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0923

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-9.2

Confidence interval

level

95%

sides

2-sided

lower limit

-19.9

upper limit

1.5

Variability estimate

Standard error of the mean

Dispersion value

5.5

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0017

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-16.5

Confidence interval

level

95%

sides

2-sided

lower limit

-26.8

upper limit

-6.2

Variability estimate

Standard error of the mean

Dispersion value

5.3

Week 16

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0009

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-16.5

Confidence interval

level

95%

sides

2-sided

lower limit

-26.2

upper limit

-6.8

Variability estimate

Standard error of the mean

Dispersion value

4.9

Secondary: Percent Change from Baseline in Lipoprotein (a) [Lp(a)] at Week 24 (ITT Estimand)

Top of page

End point title

Percent Change from Baseline in Lipoprotein (a) [Lp(a)] at Week 24 (ITT Estimand) ^[7]

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only applicable to those patients receiving IV route of study treatment administration

End point values	Group B: Placebo IV Q4W (DBTP)	Group B: Evinacumab 5mg/kg IV Q4W (DBTP)	Group B: Evinacumab 15mg/kg IV Q4W (DBTP)
Number of subjects analysed	33	35	38
Units: Percent Change
least squares mean (standard error)	-1.4 ( 4.1 )	-17.5 ( 4.0 )	-16.0 ( 3.7 )

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0054

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-16.1

Confidence interval

level

95%

sides

2-sided

lower limit

-27.4

upper limit

-4.7

Variability estimate

Standard error of the mean

Dispersion value

5.8

Week 24

Comparison groups

Group B: Placebo IV Q4W (DBTP) v Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0085

Method

Regression, Linear

Parameter type

Adjusted Mean Difference

Point estimate

-14.6

Confidence interval

level

95%

sides

2-sided

lower limit

-25.4

upper limit

-3.7

Variability estimate

Standard error of the mean

Dispersion value

5.5

Adverse events

Top of page

Timeframe for reporting adverse events

From day of first treatment until the end of study

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

DB Evinacumab 5 mg

Reporting group description

Group B: Evinacumab 5mg/kg IV Q4W (DBTP)

Reporting group title

DB Placebo IV Q4W (DBTP)

Reporting group description

Group B: Placebo IV Q4W (DBTP)

Reporting group title

DB Placebo IV Q4W (OLTP)

Reporting group description

Group B: DB Placebo IV Q4W (OLTP)

Reporting group title

DB Evinacumab 15 mg

Reporting group description

Group B: Evinacumab 15mg/kg IV Q4W (DBTP)

Reporting group title

DB Evinacumab 5 mg/kg IV Q4W (OLTP)

Reporting group description

Group B: DB Evinacumab 5mg/kg IV Q4W (OLTP)

Reporting group title

DB Evinacumab 15 mg/kg IV Q4W (OLTP)

Reporting group description

Group B: DB Evinacumab 15mg/kg IV Q4W (OLTP)

Reporting group title

DB Placebo SC QW (DBTP)

Reporting group description

Group A: Placebo SC QW (DBTP)

Reporting group title

DB Evinacumab 300 mg SC Q2W (DBTP)

Reporting group description

Group A: Evinacumab 300mg SC Q2W (DBTP)

Reporting group title

DB Evinacumab 300 mg SC QW (DBTP)

Reporting group description

Group A: Evinacumab 300mg SC QW (DBTP)

Reporting group title

DB Evinacumab 450 mg SC QW (DBTP)

Reporting group description

Group A: Evinacumab 450mg SC QW (DBTP)

Serious adverse events	DB Evinacumab 5 mg	DB Placebo IV Q4W (DBTP)	DB Placebo IV Q4W (OLTP)	DB Evinacumab 15 mg	DB Evinacumab 5 mg/kg IV Q4W (OLTP)	DB Evinacumab 15 mg/kg IV Q4W (OLTP)	DB Placebo SC QW (DBTP)	DB Evinacumab 300 mg SC Q2W (DBTP)	DB Evinacumab 300 mg SC QW (DBTP)	DB Evinacumab 450 mg SC QW (DBTP)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 36 (5.56%)	1 / 33 (3.03%)	4 / 31 (12.90%)	6 / 37 (16.22%)	3 / 32 (9.38%)	2 / 33 (6.06%)	3 / 39 (7.69%)	2 / 39 (5.13%)	4 / 42 (9.52%)	4 / 40 (10.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	1	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Acquired hydrocele
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 37 (2.70%)	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	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	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal motility disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Gallbladder polyp
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Urinary bladder polyp
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Joint effusion
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	DB Evinacumab 5 mg	DB Placebo IV Q4W (DBTP)	DB Placebo IV Q4W (OLTP)	DB Evinacumab 15 mg	DB Evinacumab 5 mg/kg IV Q4W (OLTP)	DB Evinacumab 15 mg/kg IV Q4W (OLTP)	DB Placebo SC QW (DBTP)	DB Evinacumab 300 mg SC Q2W (DBTP)	DB Evinacumab 300 mg SC QW (DBTP)	DB Evinacumab 450 mg SC QW (DBTP)
Total subjects affected by non serious adverse events
subjects affected / exposed	23 / 36 (63.89%)	18 / 33 (54.55%)	19 / 31 (61.29%)	24 / 37 (64.86%)	22 / 32 (68.75%)	24 / 33 (72.73%)	20 / 39 (51.28%)	27 / 39 (69.23%)	26 / 42 (61.90%)	22 / 40 (55.00%)
Vascular disorders
Hypertension
subjects affected / exposed	3 / 36 (8.33%)	1 / 33 (3.03%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	3	1	1	0	0	0	0	1	0	1
General disorders and administration site conditions
Influenza like illness
subjects affected / exposed	3 / 36 (8.33%)	3 / 33 (9.09%)	1 / 31 (3.23%)	1 / 37 (2.70%)	3 / 32 (9.38%)	4 / 33 (12.12%)	0 / 39 (0.00%)	2 / 39 (5.13%)	0 / 42 (0.00%)	3 / 40 (7.50%)
occurrences all number	3	3	1	2	4	5	0	2	0	8
Fatigue
subjects affected / exposed	4 / 36 (11.11%)	2 / 33 (6.06%)	3 / 31 (9.68%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 33 (0.00%)	3 / 39 (7.69%)	0 / 39 (0.00%)	2 / 42 (4.76%)	4 / 40 (10.00%)
occurrences all number	4	2	3	1	2	0	3	0	2	15
Asthenia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	3 / 37 (8.11%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences all number	0	0	1	3	0	0	1	0	1	0
Chest pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	3 / 31 (9.68%)	2 / 37 (5.41%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	3 / 42 (7.14%)	1 / 40 (2.50%)
occurrences all number	1	0	3	2	1	0	0	1	4	1
Injection site bruising
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	2 / 39 (5.13%)	1 / 39 (2.56%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	0	0	11	1	2	1
Injection site erythema
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	2 / 39 (5.13%)	1 / 42 (2.38%)	4 / 40 (10.00%)
occurrences all number	10	0	0	0	0	0	4	2	4	26
Injection site haematoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	2 / 39 (5.13%)	0 / 39 (0.00%)	3 / 42 (7.14%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	5	0
Injection site haemorrhage
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	1 / 39 (2.56%)	3 / 42 (7.14%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	1	6	3	0
Injection site pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	2 / 39 (5.13%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	0	0	0	6	2	1
Injection site reaction
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	2 / 39 (5.13%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	2
Oedema peripheral
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	1 / 42 (2.38%)	3 / 40 (7.50%)
occurrences all number	0	0	0	0	0	0	1	0	1	3
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	2 / 40 (5.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	1 / 31 (3.23%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 33 (0.00%)	2 / 39 (5.13%)	1 / 39 (2.56%)	3 / 42 (7.14%)	2 / 40 (5.00%)
occurrences all number	0	2	1	1	2	0	2	1	3	2
Epistaxis
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	1	0	0	0	0	0	0	0	1	3
Nasal congestion
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	1 / 37 (2.70%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	2 / 42 (4.76%)	0 / 40 (0.00%)
occurrences all number	0	0	2	2	1	0	0	1	2	0
Oropharyngeal pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	2 / 32 (6.25%)	0 / 33 (0.00%)	2 / 39 (5.13%)	0 / 39 (0.00%)	4 / 42 (9.52%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	2	0	2	0	4	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	2 / 32 (6.25%)	1 / 33 (3.03%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	0	2	1	0	1	0	0
Depression
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 37 (2.70%)	1 / 32 (3.13%)	0 / 33 (0.00%)	2 / 39 (5.13%)	0 / 39 (0.00%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences all number	0	0	1	1	1	0	2	0	1	0
Insomnia
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	2 / 32 (6.25%)	0 / 33 (0.00%)	1 / 39 (2.56%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	0	1	0	2	0	1	1	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 37 (0.00%)	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	2	0	0	1	0	1	0	0
Body temperature increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	2 / 32 (6.25%)	0 / 33 (0.00%)	1 / 39 (2.56%)	2 / 39 (5.13%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	1	0	0	0	2	0	1	2	1	1
Fall
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	1 / 39 (2.56%)	0 / 39 (0.00%)	4 / 42 (9.52%)	0 / 40 (0.00%)
occurrences all number	1	0	0	0	1	0	1	0	4	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	3
Nervous system disorders
Headache
subjects affected / exposed	2 / 36 (5.56%)	6 / 33 (18.18%)	4 / 31 (12.90%)	5 / 37 (13.51%)	2 / 32 (6.25%)	4 / 33 (12.12%)	4 / 39 (10.26%)	2 / 39 (5.13%)	3 / 42 (7.14%)	4 / 40 (10.00%)
occurrences all number	3	10	4	6	2	6	7	2	5	4
Dizziness
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	0 / 31 (0.00%)	3 / 37 (8.11%)	1 / 32 (3.13%)	0 / 33 (0.00%)	5 / 39 (12.82%)	1 / 39 (2.56%)	2 / 42 (4.76%)	1 / 40 (2.50%)
occurrences all number	3	0	0	3	1	0	6	1	2	1
Lethargy
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	2 / 39 (5.13%)	2 / 42 (4.76%)	0 / 40 (0.00%)
occurrences all number	0	1	0	0	0	0	0	2	2	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	0 / 31 (0.00%)	0 / 37 (0.00%)	3 / 32 (9.38%)	1 / 33 (3.03%)	3 / 39 (7.69%)	1 / 39 (2.56%)	2 / 42 (4.76%)	3 / 40 (7.50%)
occurrences all number	1	2	0	0	4	1	5	2	3	17
Dyspepsia
subjects affected / exposed	1 / 36 (2.78%)	2 / 33 (6.06%)	1 / 31 (3.23%)	1 / 37 (2.70%)	0 / 32 (0.00%)	2 / 33 (6.06%)	1 / 39 (2.56%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	2	1	1	0	2	1	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 36 (0.00%)	2 / 33 (6.06%)	1 / 31 (3.23%)	1 / 37 (2.70%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	2	1	1	1	0	0	1	0	2
Abdominal discomfort
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	2
Abdominal pain
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	1 / 31 (3.23%)	2 / 37 (5.41%)	1 / 32 (3.13%)	0 / 33 (0.00%)	4 / 39 (10.26%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	0	1	5	1	0	4	1	0	0
Abdominal pain upper
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	3	0	0	0	1	0	0	1	0	0
Constipation
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	4 / 39 (10.26%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	2	0	0	1	0	0	1	4	0	0
Nausea
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	0 / 31 (0.00%)	3 / 37 (8.11%)	1 / 32 (3.13%)	1 / 33 (3.03%)	3 / 39 (7.69%)	4 / 39 (10.26%)	1 / 42 (2.38%)	4 / 40 (10.00%)
occurrences all number	2	0	0	3	1	1	3	4	1	21
Toothache
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 37 (0.00%)	1 / 32 (3.13%)	1 / 33 (3.03%)	2 / 39 (5.13%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	2	0	1	1	2	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	2 / 33 (6.06%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	1	0	1	0	2	0	0	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	5 / 36 (13.89%)	4 / 33 (12.12%)	2 / 31 (6.45%)	2 / 37 (5.41%)	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 39 (0.00%)	4 / 39 (10.26%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	5	5	3	2	1	0	0	5	3	2
Arthralgia
subjects affected / exposed	2 / 36 (5.56%)	3 / 33 (9.09%)	3 / 31 (9.68%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 33 (0.00%)	1 / 39 (2.56%)	3 / 39 (7.69%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	2	3	3	1	2	0	1	3	1	3
Back pain
subjects affected / exposed	3 / 36 (8.33%)	2 / 33 (6.06%)	2 / 31 (6.45%)	2 / 37 (5.41%)	3 / 32 (9.38%)	0 / 33 (0.00%)	5 / 39 (12.82%)	3 / 39 (7.69%)	4 / 42 (9.52%)	2 / 40 (5.00%)
occurrences all number	3	2	4	2	3	0	6	3	5	2
Musculoskeletal pain
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	2 / 39 (5.13%)	1 / 42 (2.38%)	3 / 40 (7.50%)
occurrences all number	0	1	1	0	0	0	0	2	2	4
Muscle spasms
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 39 (2.56%)	2 / 39 (5.13%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	0	0	1	0	0	0	1	4	4	1
Pain in extremity
subjects affected / exposed	3 / 36 (8.33%)	0 / 33 (0.00%)	1 / 31 (3.23%)	2 / 37 (5.41%)	0 / 32 (0.00%)	0 / 33 (0.00%)	2 / 39 (5.13%)	2 / 39 (5.13%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	3	0	1	2	0	0	2	2	1	4
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 36 (8.33%)	2 / 33 (6.06%)	5 / 31 (16.13%)	6 / 37 (16.22%)	4 / 32 (12.50%)	3 / 33 (9.09%)	6 / 39 (15.38%)	4 / 39 (10.26%)	4 / 42 (9.52%)	4 / 40 (10.00%)
occurrences all number	4	2	7	6	4	4	7	5	5	6
Gastroenteritis
subjects affected / exposed	0 / 36 (0.00%)	1 / 33 (3.03%)	0 / 31 (0.00%)	0 / 37 (0.00%)	2 / 32 (6.25%)	2 / 33 (6.06%)	0 / 39 (0.00%)	0 / 39 (0.00%)	1 / 42 (2.38%)	2 / 40 (5.00%)
occurrences all number	0	1	0	0	3	2	0	0	1	3
Bronchitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	3 / 32 (9.38%)	1 / 33 (3.03%)	0 / 39 (0.00%)	1 / 39 (2.56%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	3	1	0	1	0	1
Cystitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	2 / 31 (6.45%)	1 / 37 (2.70%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	2 / 42 (4.76%)	0 / 40 (0.00%)
occurrences all number	0	0	2	1	0	0	0	0	2	0
Influenza
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 37 (2.70%)	0 / 32 (0.00%)	2 / 33 (6.06%)	0 / 39 (0.00%)	2 / 39 (5.13%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences all number	0	0	1	1	0	2	0	2	1	0
Oral herpes
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	1 / 31 (3.23%)	0 / 37 (0.00%)	2 / 32 (6.25%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	0	1	0	2	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	1 / 37 (2.70%)	0 / 32 (0.00%)	3 / 33 (9.09%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	0	0	0	1	0	4	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	1 / 31 (3.23%)	1 / 37 (2.70%)	2 / 32 (6.25%)	0 / 33 (0.00%)	0 / 39 (0.00%)	2 / 39 (5.13%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	1	0	1	1	2	0	0	2	0	1
Upper respiratory tract infection
subjects affected / exposed	1 / 36 (2.78%)	0 / 33 (0.00%)	2 / 31 (6.45%)	1 / 37 (2.70%)	3 / 32 (9.38%)	3 / 33 (9.09%)	0 / 39 (0.00%)	0 / 39 (0.00%)	2 / 42 (4.76%)	2 / 40 (5.00%)
occurrences all number	1	0	2	1	4	3	0	0	2	2
Urinary tract infection
subjects affected / exposed	2 / 36 (5.56%)	0 / 33 (0.00%)	2 / 31 (6.45%)	0 / 37 (0.00%)	6 / 32 (18.75%)	3 / 33 (9.09%)	4 / 39 (10.26%)	5 / 39 (12.82%)	5 / 42 (11.90%)	4 / 40 (10.00%)
occurrences all number	3	0	2	0	8	7	7	6	6	6
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	3 / 36 (8.33%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 39 (0.00%)	0 / 39 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0	0	0
Diabetes mellitus
subjects affected / exposed	0 / 36 (0.00%)	0 / 33 (0.00%)	0 / 31 (0.00%)	0 / 37 (0.00%)	1 / 32 (3.13%)	0 / 33 (0.00%)	2 / 39 (5.13%)	1 / 39 (2.56%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences all number	0	0	0	0	1	0	2	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jun 2017

Amendment 1: The protocol is amended primarily to update post-dose monitoring to standardize across the evinacumab program.

29 Sep 2017

Amendment 2: Specified that enrollment of intravenous (IV) cohorts will precede enrollment of subcutaneous (SC) cohorts.

01 Mar 2018

Amendment 3: Added a 24-week open-label treatment period after the 24-week double-blind treatment period for the IV groups. The purpose of this change was to obtain long term safety information with continuous exposure of evinacumab IV for up to 48 weeks. As a result, the mandatory 24-week follow up period for the IV treatment groups was removed to allow patients to go directly into a separate OL study after completing the double-blind treatment period and open label treatment period. Patients who do not participate in the OL study would enter a 24-week follow up period.

09 Oct 2018

Amendment 4: major changes include increasing the duration of the open-label treatment period for Group B from 24 weeks to 48 weeks

11 Oct 2019

Amendment 5: The protocol was amended in response to recent nonclinical findings

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, Placebo-Controlled Study of the Safety and Efficacy of Varying Doses and Dose Regimens of Evinacumab in Patients with Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 (ITT Estimand)

Primary: Percent Change from Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Apolipoprotein B (Apo B) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Apolipoprotein B (Apo B) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Apo B at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Apo B at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Non High Density Lipoprotein Cholesterol (non-HDL-C) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Non High Density Lipoprotein Cholesterol (non-HDL-C) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in non-HDL-C at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in non-HDL-C at Week 24 (ITT Estimand)

Secondary: Percentage of Participants with >= 30% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Secondary: Percentage of Participants with >= 30% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Secondary: Percentage of Participants with >= 50% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Secondary: Percentage of Participants with >= 50% Reduction in Calculated LDL-C at Week 16 (ITT Estimand)

Secondary: Percentage of Participants with Calculated LDL-C < 50 mg/dL (1.30 mmol/L) at Week 16 (ITT Estimand)

Secondary: Percentage of Participants with Calculated LDL-C < 50 mg/dL (1.30 mmol/L) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Calculated LDL-C at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Calculated LDL-C at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Total Cholesterol (TC) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Total Cholesterol (TC) at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Total Cholesterol at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Total Cholesterol at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Fasting Triglycerides at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Lipoprotein a [Lp(a)] at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Lipoprotein a [Lp(a)] at Week 16 (ITT Estimand)

Secondary: Percent Change from Baseline in Lipoprotein (a) [Lp(a)] at Week 24 (ITT Estimand)

Secondary: Percent Change from Baseline in Lipoprotein (a) [Lp(a)] at Week 24 (ITT Estimand)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Varying Doses and Dose Regimens of Evinacumab in Patients with Persistent Hypercholesterolemia Despite Maximally Tolerated Lipid Modifying Therapy