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Clinical Trial Results:
A Double-blind, Randomized, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc-conjugated Small Interfering RNA [siRNA]) in Subjects With Elevated Lipoprotein(a)

Summary
EudraCT number	2019-003688-23
Trial protocol	DK NL
Global end of trial date	08 Nov 2022

Results information
Results version number	v1(current)
This version publication date	10 Aug 2023
First version publication date	10 Aug 2023
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

20180109

ISRCTN number

US NCT number

NCT04270760

WHO universal trial number (UTN)

Sponsor organisation name

Amgen Inc.

Sponsor organisation address

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

Public contact

Study Director, Amgen Inc., +1 8665726436, medinfo@amgen.com

Scientific contact

Study Director, Amgen Inc., +1 8665726436, medinfo@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

16 Dec 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Nov 2022

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial was to evaluate the effect of olpasiran administered subcutaneously (SC) once every 12 weeks (Q12W) compared with placebo, on percent change from Baseline in lipoprotein(a) (Lp[a]) after 36 weeks of treatment.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation Good Clinical Practice regulations/guidelines.

Background therapy

Participants remained on standard of care per their local guidelines during the Treatment Period and Extended Safety Follow-up Period.

Evidence for comparator

Actual start date of recruitment

28 Jul 2020

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

14 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 43

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

Iceland: 11

Country: Number of subjects enrolled

Netherlands: 30

Country: Number of subjects enrolled

Canada: 26

Country: Number of subjects enrolled

United States: 142

Country: Number of subjects enrolled

Japan: 19

Worldwide total number of subjects

281

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)

163

From 65 to 84 years

118

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 34 centers in Australia, Denmark, Iceland, the Netherlands, Canada, the United States, and Japan between 28 July 2020 and 08 November 2022.

Screening details

The Treatment Period was 48 weeks with investigational product (IP) administered SC Q12W or every 24 weeks (Q24W). After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Group 1: Olpasiran 10 mg Q12W

Arm description

Participants were administered SC olpasiran 10 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36. After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Olpasiran

Investigational medicinal product code

AMG 890

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered via SC injection.

Group 2: Olpasiran 75 mg Q12W

Arm description

Participants were administered SC olpasiran 75 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36. After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Olpasiran

Investigational medicinal product code

AMG 890

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered via SC injection.

Group 3: Olpasiran 225 mg Q12W

Arm description

Participants were administered SC olpasiran 225 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36. After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Olpasiran

Investigational medicinal product code

AMG 890

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered via SC injection.

Group 4: Olpasiran 225 mg Q24W

Arm description

Participants were administered SC olpasiran 225 mg Q24W for 48 weeks with doses at Day 1 and Week 24. After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Olpasiran

Investigational medicinal product code

AMG 890

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered via SC injection.

Group 5: Placebo Q12W

Arm description

Participants were administered SC placebo Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36. After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered via SC injection.

Number of subjects in period 1	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W
Started	58	58	56	55	54
Entered Extended Safety Follow-up Period	57	57	54	55	53
Completed	57	55	52	55	53
Not completed	1	3	4	0	1
Adverse event, serious fatal	-	-	-	-	1
Consent withdrawn by subject	-	1	3	-	-
Lost to follow-up	1	2	1	-	-

Baseline characteristics

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Reporting group title

Group 1: Olpasiran 10 mg Q12W

Reporting group description

Reporting group title

Group 2: Olpasiran 75 mg Q12W

Reporting group description

Reporting group title

Group 3: Olpasiran 225 mg Q12W

Reporting group description

Reporting group title

Group 4: Olpasiran 225 mg Q24W

Reporting group description

Reporting group title

Group 5: Placebo Q12W

Reporting group description

Reporting group values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W	Total
Number of subjects	58	58	56	55	54	281
Age Categorical
Units:
18 - 64 years	31	35	37	31	29	163
65 - 74 years	19	17	18	19	17	90
75 - 84 years	8	6	1	5	8	28
Age Continuous
Units: Years
arithmetic mean (standard deviation)	63.4 ± 9.5	61.3 ± 9.2	59.7 ± 10.1	61.8 ± 9.4	63.4 ± 8.9	-
Sex: Female, Male
Units:
Female	12	23	15	22	18	90
Male	46	35	41	33	36	191
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	0	0	2	2	6
Not Hispanic or Latino	56	58	56	53	52	275
Unknown or Not Reported	0	0	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
Asian	6	5	5	5	3	24
Black or African American	0	1	2	1	2	6
White	52	52	47	49	48	248
Other	0	0	2	0	1	3

End points

Top of page

Reporting group title

Group 1: Olpasiran 10 mg Q12W

Reporting group description

Reporting group title

Group 2: Olpasiran 75 mg Q12W

Reporting group description

Reporting group title

Group 3: Olpasiran 225 mg Q12W

Reporting group description

Reporting group title

Group 4: Olpasiran 225 mg Q24W

Reporting group description

Reporting group title

Group 5: Placebo Q12W

Reporting group description

Primary: Percentage Change From Baseline in Lp(a) at Week 36

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End point title

Percentage Change From Baseline in Lp(a) at Week 36

End point description

Least squares mean is from the repeated measures linear effects model which includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit. Participants in the FAS with data available at each time point. FAS: includes all randomized participants who received at least one dose of IP.

End point type

Primary

End point timeframe

Baseline and Week 36

End point values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W
Number of subjects analysed	57	57	53	53	51
Units: Percentage Change in Lp(a)
least squares mean (standard error)	-66.91 ± 1.78	-93.78 ± 1.78	-97.53 ± 1.82	-96.89 ± 1.85	3.60 ± 1.89

Group 1 versus (vs) Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

< 0.001 ^[2]

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-70.51

Confidence interval

level

95%

sides

2-sided

lower limit

-75.12

upper limit

-65.9

Variability estimate

Standard error of the mean

Dispersion value

2.35

Notes
[1] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.
[2] - Adjusted p-value is reported based on the Hochberg procedure to control the type I error for multiple comparisons. Each individual adjusted p-value is compared to 0.05 to determine statistical significance.

Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

< 0.001 ^[4]

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-101.13

Confidence interval

level

95%

sides

2-sided

lower limit

-105.79

upper limit

-96.47

Variability estimate

Standard error of the mean

Dispersion value

2.38

Notes
[3] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.
[4] - Adjusted p-value is reported based on the Hochberg procedure to control the type I error for multiple comparisons. Each individual adjusted p-value is compared to 0.05 to determine statistical significance.

Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

^[5]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-100.49

Confidence interval

level

95%

sides

2-sided

lower limit

-105.16

upper limit

-95.82

Variability estimate

Standard error of the mean

Dispersion value

2.38

Notes
[5] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[6]

P-value

< 0.001 ^[7]

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-97.38

Confidence interval

level

95%

sides

2-sided

lower limit

-101.98

upper limit

-92.77

Variability estimate

Standard error of the mean

Dispersion value

2.35

Notes
[6] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.
[7] - Adjusted p-value is reported based on the Hochberg procedure to control the type I error for multiple comparisons. Each individual adjusted p-value is compared to 0.05 to determine statistical significance.

Secondary: Percentage Change From Baseline in Lp(a) at Week 48

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End point title

Percentage Change From Baseline in Lp(a) at Week 48

End point description

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W
Number of subjects analysed	57	57	54	53	51
Units: Percentage Change in Lp(a)
least squares mean (standard error)	-64.89 ± 2.17	-92.54 ± 2.17	-97.29 ± 2.22	-82.36 ± 2.25	3.59 ± 2.30

Group 1 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[8]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-68.47

Confidence interval

level

95%

sides

2-sided

lower limit

-74.27

upper limit

-62.67

Variability estimate

Standard error of the mean

Dispersion value

2.96

Notes
[8] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[9]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-96.12

Confidence interval

level

95%

sides

2-sided

lower limit

-101.92

upper limit

-90.33

Variability estimate

Standard error of the mean

Dispersion value

2.96

Notes
[9] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[10]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-100.88

Confidence interval

level

95%

sides

2-sided

lower limit

-106.74

upper limit

-95.02

Variability estimate

Standard error of the mean

Dispersion value

2.99

Notes
[10] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

^[11]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-85.94

Confidence interval

level

95%

sides

2-sided

lower limit

-91.83

upper limit

-80.06

Variability estimate

Standard error of the mean

Dispersion value

Notes
[11] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

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End point title

Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

End point description

End point type

Secondary

End point timeframe

Baseline; Week 36 and Week 48

End point values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W
Number of subjects analysed	57	57	54	53	51
Units: Percentage Change in LDL-C
least squares mean (standard error)
Week 36 (n = 57, 57, 53, 53, 51)	-17.425 ± 4.258	-16.284 ± 4.259	-16.733 ± 4.389	-18.462 ± 4.428	6.234 ± 4.520
Week 48 (n = 57, 57, 54, 52, 51)	-14.743 ± 4.419	-11.481 ± 4.418	-17.308 ± 4.532	-16.908 ± 4.608	10.113 ± 4.688

Week 36: Group 1 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[12]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-23.659

Confidence interval

level

95%

sides

2-sided

lower limit

-35.176

upper limit

-12.143

Variability estimate

Standard error of the mean

Dispersion value

5.874

Notes
[12] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[13]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-22.518

Confidence interval

level

95%

sides

2-sided

lower limit

-34.036

upper limit

-11

Variability estimate

Standard error of the mean

Dispersion value

5.875

Notes
[13] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[14]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-22.967

Confidence interval

level

95%

sides

2-sided

lower limit

-34.656

upper limit

-11.278

Variability estimate

Standard error of the mean

Dispersion value

5.962

Notes
[14] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

^[15]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-24.696

Confidence interval

level

95%

sides

2-sided

lower limit

-36.399

upper limit

-12.993

Variability estimate

Standard error of the mean

Dispersion value

5.969

Notes
[15] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[16]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-21.594

Confidence interval

level

95%

sides

2-sided

lower limit

-33.59

upper limit

-9.598

Variability estimate

Standard error of the mean

Dispersion value

6.118

Notes
[16] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 1 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

108

Analysis specification

Pre-specified

Analysis type

^[17]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-24.856

Confidence interval

level

95%

sides

2-sided

lower limit

-36.853

upper limit

-12.859

Variability estimate

Standard error of the mean

Dispersion value

6.119

Notes
[17] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[18]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-27.421

Confidence interval

level

95%

sides

2-sided

lower limit

-39.565

upper limit

-15.277

Variability estimate

Standard error of the mean

Dispersion value

6.194

Notes
[18] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

104

Analysis specification

Pre-specified

Analysis type

^[19]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-27.021

Confidence interval

level

95%

sides

2-sided

lower limit

-39.24

upper limit

-14.801

Variability estimate

Standard error of the mean

Dispersion value

6.232

Notes
[19] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Secondary: Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

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End point title

Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

End point description

End point type

Secondary

End point timeframe

Baseline; Week 36 and Week 48

End point values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W	Group 5: Placebo Q12W
Number of subjects analysed	57	57	54	53	52
Units: Percentage Change in ApoB
least squares mean (standard error)
Week 36 (n = 57, 57, 54, 53, 52)	-11.496 ± 2.886	-9.302 ± 2.885	-10.241 ± 2.960	-11.378 ± 3.012	7.394 ± 3.066
Week 48 (n = 57, 57, 54, 53, 52)	-7.748 ± 3.307	-4.768 ± 3.305	-7.218 ± 3.393	-9.548 ± 3.443	12.292 ± 3.501

Week 36: Group 1 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

^[20]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-18.89

Confidence interval

level

95%

sides

2-sided

lower limit

-26.303

upper limit

-11.477

Variability estimate

Standard error of the mean

Dispersion value

3.779

Notes
[20] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

^[21]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-16.696

Confidence interval

level

95%

sides

2-sided

lower limit

-24.107

upper limit

-9.284

Variability estimate

Standard error of the mean

Dispersion value

3.778

Notes
[21] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

^[22]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-17.635

Confidence interval

level

95%

sides

2-sided

lower limit

-25.139

upper limit

-10.131

Variability estimate

Standard error of the mean

Dispersion value

3.825

Notes
[22] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 36: Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 36.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[23]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-18.772

Confidence interval

level

95%

sides

2-sided

lower limit

-26.303

upper limit

-11.241

Variability estimate

Standard error of the mean

Dispersion value

3.839

Notes
[23] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 1 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 1 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 1: Olpasiran 10 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

^[24]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-20.04

Confidence interval

level

95%

sides

2-sided

lower limit

-28.757

upper limit

-11.323

Variability estimate

Standard error of the mean

Dispersion value

4.443

Notes
[24] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 2 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 2 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 2: Olpasiran 75 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

^[25]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-17.06

Confidence interval

level

95%

sides

2-sided

lower limit

-25.774

upper limit

-8.345

Variability estimate

Standard error of the mean

Dispersion value

4.442

Notes
[25] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 3 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 3 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 3: Olpasiran 225 mg Q12W v Group 5: Placebo Q12W

Number of subjects included in analysis

106

Analysis specification

Pre-specified

Analysis type

^[26]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-19.509

Confidence interval

level

95%

sides

2-sided

lower limit

-28.336

upper limit

-10.682

Variability estimate

Standard error of the mean

Dispersion value

4.5

Notes
[26] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Week 48: Group 4 vs Group 5

Statistical analysis description

Treatment difference = percentage change in Group 4 - percentage change in Group 5 from Baseline at Week 48.

Comparison groups

Group 4: Olpasiran 225 mg Q24W v Group 5: Placebo Q12W

Number of subjects included in analysis

105

Analysis specification

Pre-specified

Analysis type

^[27]

P-value

< 0.001

Method

Repeated measures linear effects model

Parameter type

Treatment difference

Point estimate

-21.839

Confidence interval

level

95%

sides

2-sided

lower limit

-30.7

upper limit

-12.979

Variability estimate

Standard error of the mean

Dispersion value

4.517

Notes
[27] - Includes treatment group, stratification factors, scheduled visit and the interaction of treatment group with scheduled visit as covariates.

Secondary: Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48

Top of page

End point title

Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48 ^[28]

End point description

Pharmacokinetic blood draws were collected at one timepoint during the 6-12 and 24-72 hour flexible time windows and at Week 48. Lower limit of quantification (LLOQ) = 0.400 ng/mL. Values below the LLOQ were set to zero. Participants in the FAS with data available at each time point. FAS: includes all randomized participants who received at least one dose of IP.

End point type

Secondary

End point timeframe

Pre-dose and 1, 3, 6-12, and 24-72 hours post-dose on Day 1 and Week 24; Week 48

Notes
[28] - 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: Serum Olpasiran concentration data are reported for Olpasiran arms only as pre-specified.

End point values	Group 1: Olpasiran 10 mg Q12W	Group 2: Olpasiran 75 mg Q12W	Group 3: Olpasiran 225 mg Q12W	Group 4: Olpasiran 225 mg Q24W
Number of subjects analysed	55	56	49	52
Units: ng/mL
arithmetic mean (standard deviation)
Day 1: Pre-dose (n = 54, 52, 47, 51)	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00	0.00 ± 0.00
Day 1: 1 Hour Post-dose (n = 52, 44, 45, 46)	12.3 ± 6.9	67.1 ± 47.4	220 ± 218	275 ± 450
Day 1: 3 Hours Post-dose (n = 53, 44, 44, 48)	18 ± 9.85	80.3 ± 43.2	291 ± 273	324 ± 383
Day 1: 6-12 Hours Post-dose (n = 8, 9, 8, 16)	18.6 ± 10.1	61.7 ± 36	420 ± 432	329 ± 191
Day 1: 24-72 Hours Post-dose (n = 11, 12, 9, 17)	0.995 ± 0.946	20.4 ± 13.2	63.2 ± 59.7	103 ± 47.3
Week 24: Pre-dose (n = 55, 56, 49, 52)	0.00 ± 0.00	0.0315 ± 0.134	0.498 ± 1.88	0.0645 ± 0.22
Week 24: 1 Hour Post-dose (n = 52, 48, 48, 45)	12.4 ± 7.23	73.6 ± 43.6	204 ± 144	253 ± 247
Week 24: 3 Hours Post-dose (n = 53, 49, 46, 48)	16.3 ± 9.2	96.3 ± 63.5	278 ± 193	332 ± 255
Week 24: 6-12 Hours Post-dose (n = 8, 10, 7, 15)	17.2 ± 10.2	76.3 ± 54.7	271 ± 229	315 ± 191
Week 24: 24-72 Hours Post-dose (n = 7, 9, 8, 16)	1.27 ± 1.82	17.3 ± 18.9	99 ± 59.1	96.3 ± 50.3
Week 48 (n = 52, 50, 48, 51)	0.00 ± 0.00	0.0599 ± 0.168	0.533 ± 0.592	0.127 ± 0.693

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment Period: Median duration was 11.07 months. Extended Safety Follow-up Period: Median duration was 8.56 months.

Adverse event reporting additional description

FAS: includes all randomized participants who received at least one dose of IP. For safety analysis FAS was used based on actual treatment received.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Treatment Period: Olpasiran 225 mg Q12W

Reporting group description

Group 3: Participants were administered SC olpasiran 225 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36.

Reporting group title

Treatment Period: Olpasiran 75 mg Q12W

Reporting group description

Group 2: Participants were administered SC olpasiran 75 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36.

Reporting group title

Treatment Period: Olpasiran 10 mg Q12W

Reporting group description

Group 1: Participants were administered SC olpasiran 10 mg Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36.

Reporting group title

Extended Safety Follow-up Period: Olpasiran 75 mg Q12W

Reporting group description

Group 2: After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Reporting group title

Extended Safety Follow-up Period: Olpasiran 225 mg Q12W

Reporting group description

Group 3: After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Reporting group title

Extended Safety Follow-up Period: Olpasiran 225 mg Q24W

Reporting group description

Group 4: After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Reporting group title

Extended Safety Follow-up Period: Olpasiran 10 mg Q12W

Reporting group description

Group 1: After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Reporting group title

Extended Safety Follow-up: Placebo Q12W

Reporting group description

Group 5: After Week 48 there was an Extended Safety Follow-up Period without further dosing with IP for a minimum of 24 weeks.

Reporting group title

Treatment Period: Olpasiran 225 mg Q24W

Reporting group description

Group 4: Participants were administered SC olpasiran 225 mg Q24W for 48 weeks with doses at Day 1 and Week 24.

Reporting group title

Treatment Period: Placebo Q12W

Reporting group description

Group 5: Participants were administered SC placebo Q12W for 48 weeks with doses at Day 1, Week 12, Week 24, and Week 36.

Serious adverse events	Treatment Period: Olpasiran 225 mg Q12W	Treatment Period: Olpasiran 75 mg Q12W	Treatment Period: Olpasiran 10 mg Q12W	Extended Safety Follow-up Period: Olpasiran 75 mg Q12W	Extended Safety Follow-up Period: Olpasiran 225 mg Q12W	Extended Safety Follow-up Period: Olpasiran 225 mg Q24W	Extended Safety Follow-up Period: Olpasiran 10 mg Q12W	Extended Safety Follow-up: Placebo Q12W	Treatment Period: Olpasiran 225 mg Q24W	Treatment Period: Placebo Q12W
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 56 (10.71%)	3 / 58 (5.17%)	3 / 58 (5.17%)	2 / 57 (3.51%)	6 / 54 (11.11%)	5 / 55 (9.09%)	4 / 57 (7.02%)	4 / 53 (7.55%)	4 / 55 (7.27%)	8 / 54 (14.81%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastrointestinal cancer metastatic
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 54 (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
Breast cancer stage IV
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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
Malignant melanoma stage I
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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 carcinoma
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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
Metastases to pancreas
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 54 (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
Prostate cancer recurrent
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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
Hypertension
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Iliac artery occlusion
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
General disorders and administration site conditions
Injection site urticaria
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	1 / 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
Non-cardiac chest pain
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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
Injection site reaction
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Psychiatric disorders
Depression
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Product issues
Device inappropriate shock delivery
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Rib fracture
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Hip fracture
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Femur fracture
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Traumatic haematoma
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	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
Angina pectoris
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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 / 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
Angina unstable
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	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
Bradycardia
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Atrial flutter
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Cerebrovascular accident
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Ischaemic stroke
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 54 (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
Syncope
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (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
Partial seizures
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Seizure
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (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
Eye disorders
Cataract
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Gastrointestinal disorders
Rectal haemorrhage
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Diarrhoea
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Colitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 54 (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
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinoma
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Ureterolithiasis
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Musculoskeletal and connective tissue disorders
Cervical spinal stenosis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	0 / 55 (0.00%)	0 / 54 (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
Fistula
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Osteoarthritis
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	2 / 54 (3.70%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	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
Cellulitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Campylobacter infection
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (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
COVID-19 pneumonia
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Abdominal abscess
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Diverticulitis intestinal perforated
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Influenza
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Pneumonia
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
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 / 2
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 / 1
Diverticulitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	0 / 54 (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 tract infection
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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
Vestibular neuronitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Metabolism and nutrition disorders
Obesity
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (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

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

Non-serious adverse events	Treatment Period: Olpasiran 225 mg Q12W	Treatment Period: Olpasiran 75 mg Q12W	Treatment Period: Olpasiran 10 mg Q12W	Extended Safety Follow-up Period: Olpasiran 75 mg Q12W	Extended Safety Follow-up Period: Olpasiran 225 mg Q12W	Extended Safety Follow-up Period: Olpasiran 225 mg Q24W	Extended Safety Follow-up Period: Olpasiran 10 mg Q12W	Extended Safety Follow-up: Placebo Q12W	Treatment Period: Olpasiran 225 mg Q24W	Treatment Period: Placebo Q12W
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 56 (66.07%)	40 / 58 (68.97%)	35 / 58 (60.34%)	25 / 57 (43.86%)	21 / 54 (38.89%)	17 / 55 (30.91%)	18 / 57 (31.58%)	17 / 53 (32.08%)	36 / 55 (65.45%)	29 / 54 (53.70%)
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 56 (1.79%)	1 / 58 (1.72%)	0 / 58 (0.00%)	2 / 57 (3.51%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	0 / 55 (0.00%)	3 / 54 (5.56%)
occurrences all number	1	1	0	3	0	0	1	0	0	4
Fall
subjects affected / exposed	1 / 56 (1.79%)	3 / 58 (5.17%)	2 / 58 (3.45%)	1 / 57 (1.75%)	0 / 54 (0.00%)	2 / 55 (3.64%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	1 / 54 (1.85%)
occurrences all number	1	3	2	1	0	2	0	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	3 / 56 (5.36%)	2 / 58 (3.45%)	4 / 58 (6.90%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	2 / 55 (3.64%)	2 / 54 (3.70%)
occurrences all number	3	3	4	1	0	0	0	1	2	2
Nervous system disorders
Headache
subjects affected / exposed	6 / 56 (10.71%)	7 / 58 (12.07%)	6 / 58 (10.34%)	1 / 57 (1.75%)	2 / 54 (3.70%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	6 / 55 (10.91%)	4 / 54 (7.41%)
occurrences all number	7	9	9	1	2	1	0	0	8	6
Areflexia
subjects affected / exposed	0 / 56 (0.00%)	3 / 58 (5.17%)	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	0 / 54 (0.00%)
occurrences all number	0	5	0	0	1	0	0	0	0	0
Dizziness
subjects affected / exposed	2 / 56 (3.57%)	3 / 58 (5.17%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	1 / 53 (1.89%)	1 / 55 (1.82%)	2 / 54 (3.70%)
occurrences all number	2	3	0	0	0	1	0	1	1	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	3 / 58 (5.17%)	2 / 57 (3.51%)	1 / 54 (1.85%)	0 / 55 (0.00%)	1 / 57 (1.75%)	1 / 53 (1.89%)	1 / 55 (1.82%)	0 / 54 (0.00%)
occurrences all number	0	1	3	2	1	0	1	1	1	0
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	3 / 56 (5.36%)	3 / 58 (5.17%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	4 / 55 (7.27%)	0 / 54 (0.00%)
occurrences all number	5	3	0	0	0	0	0	0	4	0
Injection site bruising
subjects affected / exposed	5 / 56 (8.93%)	4 / 58 (6.90%)	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	0 / 55 (0.00%)	4 / 54 (7.41%)
occurrences all number	6	5	0	0	0	0	0	0	0	6
Fatigue
subjects affected / exposed	3 / 56 (5.36%)	8 / 58 (13.79%)	6 / 58 (10.34%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	2 / 57 (3.51%)	1 / 53 (1.89%)	2 / 55 (3.64%)	3 / 54 (5.56%)
occurrences all number	3	11	8	1	0	0	2	1	4	4
Oedema peripheral
subjects affected / exposed	1 / 56 (1.79%)	1 / 58 (1.72%)	2 / 58 (3.45%)	1 / 57 (1.75%)	2 / 54 (3.70%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	3 / 55 (5.45%)	0 / 54 (0.00%)
occurrences all number	1	1	3	1	2	0	0	0	3	0
Non-cardiac chest pain
subjects affected / exposed	1 / 56 (1.79%)	2 / 58 (3.45%)	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	2 / 57 (3.51%)	0 / 53 (0.00%)	4 / 55 (7.27%)	1 / 54 (1.85%)
occurrences all number	1	2	2	0	0	1	2	0	4	1
Injection site pruritus
subjects affected / exposed	0 / 56 (0.00%)	0 / 58 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	3 / 55 (5.45%)	0 / 54 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	4	0
Injection site pain
subjects affected / exposed	1 / 56 (1.79%)	3 / 58 (5.17%)	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	5 / 55 (9.09%)	2 / 54 (3.70%)
occurrences all number	2	4	2	0	0	0	0	0	6	2
Immune system disorders
Immunisation reaction
subjects affected / exposed	2 / 56 (3.57%)	4 / 58 (6.90%)	8 / 58 (13.79%)	0 / 57 (0.00%)	2 / 54 (3.70%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	4 / 55 (7.27%)	5 / 54 (9.26%)
occurrences all number	3	6	11	0	3	0	0	0	8	6
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 56 (5.36%)	0 / 58 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 54 (0.00%)	1 / 55 (1.82%)	1 / 57 (1.75%)	0 / 53 (0.00%)	2 / 55 (3.64%)	2 / 54 (3.70%)
occurrences all number	3	0	0	1	0	1	1	0	2	2
Diarrhoea
subjects affected / exposed	3 / 56 (5.36%)	3 / 58 (5.17%)	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	4 / 54 (7.41%)
occurrences all number	3	3	2	0	0	1	0	0	1	4
Constipation
subjects affected / exposed	1 / 56 (1.79%)	0 / 58 (0.00%)	3 / 58 (5.17%)	0 / 57 (0.00%)	0 / 54 (0.00%)	1 / 55 (1.82%)	0 / 57 (0.00%)	0 / 53 (0.00%)	2 / 55 (3.64%)	2 / 54 (3.70%)
occurrences all number	2	0	3	0	0	1	0	0	2	2
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 56 (1.79%)	1 / 58 (1.72%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	3 / 53 (5.66%)	0 / 55 (0.00%)	2 / 54 (3.70%)
occurrences all number	1	1	1	0	1	0	0	3	0	2
Nausea
subjects affected / exposed	2 / 56 (3.57%)	1 / 58 (1.72%)	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 54 (0.00%)	2 / 55 (3.64%)	0 / 57 (0.00%)	1 / 53 (1.89%)	3 / 55 (5.45%)	1 / 54 (1.85%)
occurrences all number	2	1	2	0	0	3	0	1	3	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	3 / 58 (5.17%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	3 / 53 (5.66%)	0 / 55 (0.00%)	1 / 54 (1.85%)
occurrences all number	0	1	3	2	0	0	0	3	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 56 (5.36%)	3 / 58 (5.17%)	2 / 58 (3.45%)	1 / 57 (1.75%)	1 / 54 (1.85%)	1 / 55 (1.82%)	0 / 57 (0.00%)	1 / 53 (1.89%)	2 / 55 (3.64%)	1 / 54 (1.85%)
occurrences all number	3	4	2	1	1	1	0	1	3	1
Back pain
subjects affected / exposed	7 / 56 (12.50%)	5 / 58 (8.62%)	6 / 58 (10.34%)	1 / 57 (1.75%)	1 / 54 (1.85%)	1 / 55 (1.82%)	3 / 57 (5.26%)	0 / 53 (0.00%)	1 / 55 (1.82%)	3 / 54 (5.56%)
occurrences all number	7	5	6	1	1	1	3	0	1	3
Myalgia
subjects affected / exposed	4 / 56 (7.14%)	1 / 58 (1.72%)	3 / 58 (5.17%)	0 / 57 (0.00%)	0 / 54 (0.00%)	0 / 55 (0.00%)	2 / 57 (3.51%)	0 / 53 (0.00%)	4 / 55 (7.27%)	4 / 54 (7.41%)
occurrences all number	4	1	4	0	0	0	2	0	4	6
Pain in extremity
subjects affected / exposed	0 / 56 (0.00%)	1 / 58 (1.72%)	2 / 58 (3.45%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	3 / 55 (5.45%)	1 / 54 (1.85%)
occurrences all number	0	1	2	1	0	0	1	0	3	1
Infections and infestations
COVID-19
subjects affected / exposed	7 / 56 (12.50%)	8 / 58 (13.79%)	1 / 58 (1.72%)	11 / 57 (19.30%)	14 / 54 (25.93%)	10 / 55 (18.18%)	8 / 57 (14.04%)	10 / 53 (18.87%)	4 / 55 (7.27%)	6 / 54 (11.11%)
occurrences all number	7	9	1	12	14	10	8	10	4	6
Gastroenteritis
subjects affected / exposed	0 / 56 (0.00%)	4 / 58 (6.90%)	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	1 / 53 (1.89%)	2 / 55 (3.64%)	1 / 54 (1.85%)
occurrences all number	0	4	2	0	1	0	0	1	2	1
Nasopharyngitis
subjects affected / exposed	4 / 56 (7.14%)	2 / 58 (3.45%)	2 / 58 (3.45%)	1 / 57 (1.75%)	0 / 54 (0.00%)	2 / 55 (3.64%)	3 / 57 (5.26%)	0 / 53 (0.00%)	1 / 55 (1.82%)	1 / 54 (1.85%)
occurrences all number	4	2	2	1	0	2	3	0	1	1
Sinusitis
subjects affected / exposed	0 / 56 (0.00%)	3 / 58 (5.17%)	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	2 / 55 (3.64%)	0 / 54 (0.00%)
occurrences all number	0	4	0	1	0	0	0	0	2	0
Upper respiratory tract infection
subjects affected / exposed	2 / 56 (3.57%)	3 / 58 (5.17%)	4 / 58 (6.90%)	2 / 57 (3.51%)	0 / 54 (0.00%)	1 / 55 (1.82%)	2 / 57 (3.51%)	1 / 53 (1.89%)	1 / 55 (1.82%)	2 / 54 (3.70%)
occurrences all number	2	3	4	2	0	1	4	1	1	2
Urinary tract infection
subjects affected / exposed	2 / 56 (3.57%)	4 / 58 (6.90%)	3 / 58 (5.17%)	4 / 57 (7.02%)	1 / 54 (1.85%)	0 / 55 (0.00%)	0 / 57 (0.00%)	0 / 53 (0.00%)	1 / 55 (1.82%)	1 / 54 (1.85%)
occurrences all number	2	4	3	5	1	0	0	0	1	1
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	1 / 56 (1.79%)	3 / 58 (5.17%)	3 / 58 (5.17%)	1 / 57 (1.75%)	0 / 54 (0.00%)	0 / 55 (0.00%)	1 / 57 (1.75%)	0 / 53 (0.00%)	2 / 55 (3.64%)	2 / 54 (3.70%)
occurrences all number	1	3	3	1	0	0	1	0	2	2

More information

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Were there any global substantial amendments to the protocol? Yes

25 Nov 2020

Protocol amendment 1 was implemented to: - provide pandemic related guidance, - clarify the upper dosage limit for niacin and fish oil exclusion criteria, - modify exclusion criteria to include inherited or acquired known bleeding disorders.

01 Apr 2021

Protocol amendment 2 was implemented to: - update the number of participants from 240 to 290 and the participants per treatment from 48 to 58, - update the details of the planned interim analysis.

02 May 2022

Protocol amendment 3 was implemented to: - reduce the Extended Safety Follow-up Period from ≥ 40 weeks to a minimum of 24 weeks follow-up and removed the requirement for the participant's Lp(a) to return to 80% of Baseline levels, - update access to individual participant treatment assignments for Amgen (or designee) team members after the Treatment Period ended, the database was locked, and the snapshot was taken for the end of Treatment Period analysis.

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 Double-blind, Randomized, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc-conjugated Small Interfering RNA [siRNA]) in Subjects With Elevated Lipoprotein(a)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Change From Baseline in Lp(a) at Week 36

Primary: Percentage Change From Baseline in Lp(a) at Week 36

Secondary: Percentage Change From Baseline in Lp(a) at Week 48

Secondary: Percentage Change From Baseline in Lp(a) at Week 48

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

Secondary: Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48

Secondary: Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: A Double-blind, Randomized, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc-conjugated Small Interfering RNA [siRNA]) in Subjects With Elevated Lipoprotein(a)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Change From Baseline in Lp(a) at Week 36

Primary: Percentage Change From Baseline in Lp(a) at Week 36

Secondary: Percentage Change From Baseline in Lp(a) at Week 48

Secondary: Percentage Change From Baseline in Lp(a) at Week 48

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

Secondary: Percentage Change From Baseline in Apolipoprotein (B) (ApoB) at Week 36 and Week 48

Secondary: Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48

Secondary: Mean Serum Olpasiran Concentrations at Day 1, Week 24 and Week 48

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Double-blind, Randomized, Placebo-controlled Phase 2 Study to Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc-conjugated Small Interfering RNA [siRNA]) in Subjects With Elevated Lipoprotein(a)