Imaging of Coronary Plaques in Participants Treated With Evolocumab

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03570697
• Collaborator: (none)
• Enrollment: 164
• Locations: 33
• Arms: 2
• Actual Duration (Months): 26.1
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To evaluate the effect of evolocumab on fibrous cap thickness (FCT) in participants with non-ST-elevation acute coronary syndrome (NSTE-ACS) who are taking maximally tolerated statin therapy.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease (CAD)	Drug: Evolocumab; Drug: Placebo; Drug: Statin therapy	Phase 3

Detailed Description

This study seeks to identify morphologic changes, such as increase in FCT in atherosclerotic plaques associated with treatment with evolocumab and maximally tolerated statin therapy with or without additional lipid-modifying medication in patients presenting with NSTE-ACS using optical coherence tomography (OCT; primary, secondary, and exploratory endpoints).

Study Design

• Study Type: Interventional
• Actual Enrollment: 164 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: This is a double-blind study. Treatment assignment will be blinded to all subjects, site personnel, and Amgen
• Primary Purpose: Treatment
• Official Title: High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS)
• Actual Study Start Date: Nov 19, 2018
• Actual Primary Completion Date: Dec 18, 2020
• Actual Study Completion Date: Jan 21, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Evolocumab Participants receive evolocumab subcutaneous injection once every month (QM) for 48 weeks. As prescribed and provided by the investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation.	Drug: Evolocumab; Participants will receive evolocumab (AMG 145) subcutaneous monthly.; Other Names: Repatha, AMG 145, EvoMab ; Drug: Statin therapy; high-intensity statin treatment with atorvastatin ≥ 40 mg daily or equivalent as background therapy Investigators will up-titrate statin therapy to the maximally tolerated dose, in accordance with local guidelines, prior to randomization.
Placebo Comparator: Placebo Participants receive placebo subcutaneous injection QM for 48 weeks. As prescribed and provided by the Investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation.	Drug: Placebo; Participants will receive matching placebo subcutaneous monthly.; Drug: Statin therapy; high-intensity statin treatment with atorvastatin ≥ 40 mg daily or equivalent as background therapy Investigators will up-titrate statin therapy to the maximally tolerated dose, in accordance with local guidelines, prior to randomization.

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Minimum FCT [Baseline, week 50]

   Absolute change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.

Secondary Outcome Measures

1. Percent Change From Baseline in Minimum FCT [Baseline, week 50]

   Percent change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.

2. Absolute Change From Baseline in Mean Minimum FCT [Baseline, week 50]

   Absolute change from baseline in mean minimum FCT for all images assessed in an individual participant as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.

3. Absolute Change From Baseline in the Maximum Lipid Arc [Baseline, week 50]

   Absolute change from baseline in the maximum lipid arc in a matched segment of artery as determined by OCT. Lower value of lipid arc indicates a better situation.

4. Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques [Baseline, week 50]

   Absolute change from baseline in minimum FCT in lipid rich plaques as determined by OCT. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Higher value of FCT indicates a better situation

5. Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques [Baseline, week 50]

   Absolute change from baseline in maximum lipid arc in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid arc indicates a better situation.

6. Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques [Baseline, week 50]

   Absolute change from baseline in lipid core length in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid core length indicates a better situation.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Provided informed consent prior to initiation of any study-specific activities/procedures.

• Age greater than or equal to 18 years at screening

• Clinical indication for coronary angiography during admission due to NSTE-ACS with interventional treatment of culprit plaque

• An eligible low-density lipoprotein cholesterol (LDL-C) level via local lab assessment based on statin use at screening

No statin use: greater than or equal to 130 mg/dL Low- or moderate-intensity statin use greater than or equal to 80 mg/dL High-intensity statin use greater than or equal to 60 mg/dL

• On maximally tolerated statin therapy in accordance with standard of care per local guidelines prior to randomization.

• Tolerates placebo run-in injection at screening

• Meets all the following criteria at the qualifying coronary angiogram:

Angiographic evidence of coronary artery disease (CAD) with greater than or equal to 20% reduction of lumen diameter by angiographic visual estimation, in addition to the culprit plaque.

Left main coronary artery must not have a greater than 50% reduction in lumen diameter by visual angiographic estimation.

Targeted vessel:

May not be the culprit vessel for the current or a previous myocardial infarction (MI).

Has not undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), and may not be a bypass graft.

May not be a candidate for PCI or CABG currently or over the next 12 months, in the opinion of the investigator.

Must be accessible by the optical coherence tomography (OCT) catheter.

Targeted segment:

Must have up to 50% but not greater than 50% reduction in lumen diameter by visual angiographic estimation and must be at least 40 mm in length.

Must contain at least 1 image with a fibrous cap thickness (FCT) of less than or equal to 120 μm and at least 1 image with a lipid arc of greater than 90° as determined by the imaging core laboratory Distal plaques of up to 50% stenosis by visual angiographic estimation are permitted, provided that such stenosis is not a target for PCI or CABG.

Exclusion Criteria:

• ST-segment elevation myocardial infarction (STEMI) or left bundle branch block (LBBB).

• Acute coronary syndromes (ACS) likely to be caused by a non-atherosclerotic process, in the opinion of the investigator (ie, type 2 myocardial infarction, which is characterized by an imbalance between myocardial oxygen demand and supply).

• Clinically significant heart disease which in the opinion of the investigator is likely to require coronary bypass surgery, PCI (does not apply to PCI of non-STEMI (NSTEMI) during initial screening angiogram), surgical or percutaneous valve repair and/or replacement during the course of the study.

• Any cardiac surgery within 6 weeks prior to screening.

• Triglycerides greater than or equal to 400 mg/dL (4.5 mmol/L) at screening.

• Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m^2 at screening.

• Malignancy except non-melanoma skin cancers, cervical, or breast ductal carcinoma in situ within the last 5 years.

• Intolerant to statins as determined by principal investigator.

• Previously received or receiving evolocumab or any other therapy to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9).

• Previously received a cholesterol ester transfer protein (CETP) inhibitor (ie, anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide, or has undergone LDL-apheresis in the last 12 months prior to LDL-C screening.

• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

• Baseline OCT does not meet OCT imaging criteria as determined by the imagine core laboratory technical standards.

• Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product. (Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine or serum pregnancy test.)

• Female subjects of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an additional 15 weeks after the last dose of investigational product.

• Female subject who has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal.

• Known sensitivity to any of the products or components (eg, carboxymethylcellulose) to be administered during dosing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles	Los Angeles	California	United States	90095
2	Medstar Heart and Vascular Institute	Washington	District of Columbia	United States	20010
3	Midwest Cardiovascular Research And Education Foundation	Elkhart	Indiana	United States	46514
4	Saint Louis University Hospital	Saint Louis	Missouri	United States	63110
5	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
6	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
7	Royal North Shore Hospital	St Leonards	New South Wales	Australia	2065
8	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
9	Monash Medical Centre	Clayton	Victoria	Australia	3168
10	The Northern Hospital	Epping	Victoria	Australia	3076
11	Fakultni nemocnice Brno	Brno		Czechia	625 00
12	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
13	Charite Universitätsmedizin Berlin Campus Benjamin Franklin	Berlin		Germany	12203
14	Universitäres Herzzentrum Hamburg GmbH	Hamburg		Germany	20246
15	Deutsches Herzzentrum München des Freistaates Bayern	München		Germany	80636
16	Allami Szivkorhaz Balatonfured	Balatonfured		Hungary	8230
17	Semmelweis Egyetem	Budapest		Hungary	1122
18	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest		Hungary	1134
19	Pecsi Tudomanyegyetem Klinikai Kozpont	Pecs		Hungary	7624
20	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII	Bergamo		Italy	24127
21	Azienda Ospedaliera Santa Croce e Carle	Cuneo		Italy	12100
22	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
23	IRCCS Centro Cardiologico Monzino	Milano		Italy	20138
24	Azienda Ospedaliera Universitaria Federico II	Napoli		Italy	80131
25	Azienda Ospedaliera San Giovanni Addolorata	Roma		Italy	00184
26	IRCCS Istituto Clinico Humanitas	Rozzano MI		Italy	20089
27	Noordwest Ziekenhuisgroep	Alkmaar		Netherlands	1815 JD
28	Vrjie Universiteit Medisch Centrum	Amsterdam		Netherlands	1081 HV
29	Onze Lieve Vrouwe Gasthuis	Amsterdam		Netherlands	1091 AC
30	Radboud Universitair Medisch Centrum	Nijmegen		Netherlands	6525 GA
31	Canisius-Wilhelmina Ziekenhuis	Nijmegen		Netherlands	6532 SZ
32	Elisabeth-TweeSteden Ziekenhuis	Tilburg		Netherlands	5042 AD
33	Isala Klinieken	Zwolle		Netherlands	8025 AB

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Apr 19, 2018
• Statistical Analysis Plan - Jan 15, 2021

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Nicholls SJ, Nissen SE, Prati F, Windecker S, Kataoka Y, Puri R, Hucko T, Kassahun H, Liao J, Somaratne R, Butters J, Di Giovanni G, Jones S, Psaltis PJ. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovasc Diagn Ther. 2021 Feb;11(1):120-129. doi: 10.21037/cdt-20-684.
• Pharmacoeconomic Review Report: Icosapent Ethyl (Vascepa): (HLS Therapeutics Inc.): Indication: Prevention of cardiovascular events in statin-treated patients [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Aug. Available from http://www.ncbi.nlm.nih.gov/books/NBK566010/

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03570697
• Other Study ID Numbers: 20160184; 2017-003236-37
• First Posted: Jun 27, 2018
• Last Update Posted: May 3, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Amgen: Optical coherence tomography (OCT); Intravascular ultrasound (IVUS); Coronary angiography; Coronary artery disease; Cardiovascular events; Coronary atherosclerotic plaques; Lipid-lowering therapy; Statin; Maximally tolerated statin therapy
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Evolocumab

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 23 research centers in Australia (2), Czech Republic (2), Germany (2), Hungary (4), Italy (6), and the Netherlands (7), from November 2018 to December 2019.
Pre-assignment Detail	Participants were randomized 1:1 into 2 treatment groups: evolocumab 420 mg subcutaneously (SC) monthly (QM) or placebo SC QM. Randomization was stratified by current statin use (> 4 weeks or ≤ 4 weeks) at screening.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Period Title: Overall Study
STARTED	82	82
Received at Least 1 Dose of Study Drug	81	80
COMPLETED	76	79
NOT COMPLETED	6	3

Baseline Characteristics

Arm/Group Title	Placebo	Evolocumab	Total
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Total of all reporting groups
Overall Participants	82	82	164
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.4 (9.4)	61.1 (10.0)	60.8 (9.6)
Sex: Female, Male (Count of Participants)
Female	26 31.7%	20 24.4%	46 28%
Male	56 68.3%	62 75.6%	118 72%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 1.2%	4 4.9%	5 3%
Not Hispanic or Latino	81 98.8%	78 95.1%	159 97%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 1.2%	1 1.2%	2 1.2%
White	80 97.6%	79 96.3%	159 97%
Other, Not Specified	1 1.2%	2 2.4%	3 1.8%
Stratification Factor: Statin Use at Screening (Count of Participants)
> 4 weeks of statin use	20 24.4%	19 23.2%	39 23.8%
≤ 4 weeks of statin use	62 75.6%	63 76.8%	125 76.2%
Minimum Fibrous Cap Thickness (FCT) (µm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [µm]	54.6 (15.1)	56.6 (17.8)	55.6 (16.5)

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Minimum FCT
Description	Absolute change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [µm]	21.5 (5.2)	42.7 (5.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	21.2
	Confidence Interval	(2-Sided) 95%; 4.7 to 37.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.9
	Estimation Comments

2. Secondary Outcome

Title	Percent Change From Baseline in Minimum FCT
Description	Percent change from baseline in minimum FCT in a matched segment of artery as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [percent change]	44.30 (11.76)	81.76 (10.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	37.47
	Confidence Interval	(2-Sided) 95%; 1.63 to 73.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.04
	Estimation Comments

3. Secondary Outcome

Title	Absolute Change From Baseline in Mean Minimum FCT
Description	Absolute change from baseline in mean minimum FCT for all images assessed in an individual participant as determined by OCT. Minimum FCT for a participant is defined as the minimum of all minimum FCT measurements within each individual frame across all frames of that participant. Higher value of FCT indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [µm]	29.78 (6.88)	62.29 (5.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	32.51
	Confidence Interval	(2-Sided) 95%; 12.67 to 52.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.52
	Estimation Comments

4. Secondary Outcome

Title	Absolute Change From Baseline in the Maximum Lipid Arc
Description	Absolute change from baseline in the maximum lipid arc in a matched segment of artery as determined by OCT. Lower value of lipid arc indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [degrees]	-31.4 (9.0)	-57.5 (7.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-26.0
	Confidence Interval	(2-Sided) 95%; -49.6 to -2.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 11.4
	Estimation Comments

5. Secondary Outcome

Title	Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques
Description	Absolute change from baseline in minimum FCT in lipid rich plaques as determined by OCT. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Higher value of FCT indicates a better situation
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [μm]	24.6 (5.5)	40.6 (5.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	16.0
	Confidence Interval	(2-Sided) 95%; 1.1 to 31.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.5
	Estimation Comments

6. Secondary Outcome

Title	Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques
Description	Absolute change from baseline in maximum lipid arc in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid arc indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [degrees]	-31.9 (8.1)	-61.9 (7.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-30.0
	Confidence Interval	(2-Sided) 95%; -50.5 to -9.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.4
	Estimation Comments

7. Secondary Outcome

Title	Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques
Description	Absolute change from baseline in lipid core length in lipid rich plaques. Lipid rich plaques are defined as minimum FCT less than 120 μm and lipid arc greater than 90° in at least 3 consecutive images as determined by OCT. Lower value of lipid core length indicates a better situation.
Time Frame	Baseline, week 50

Outcome Measure Data

Analysis Population Description

Full Analysis Set: all participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.	Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
Measure Participants	81	80
Least Squares Mean (Standard Error) [mm]	-3.33 (0.64)	-5.76 (0.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Evolocumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-2.43
	Confidence Interval	(2-Sided) 95%; -4.04 to -0.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.81
	Estimation Comments

Adverse Events

Time Frame	All cause mortality reporting period is from the 1st dose of investigational product (IP) up to the end of study (EOS) date (Week 52). Adverse event (AE) reporting period is from the 1st dose of IP up to and including 30 days after the last dose of IP date or the EOS date (Week 52) whichever is earlier.
Adverse Event Reporting Description	Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug. All-cause mortality is reported for all participants randomized.
Arm/Group Title	Placebo		Evolocumab
Arm/Group Description	Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.		Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation.
All Cause Mortality
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/82 (2.4%)		0/82 (0%)
Serious Adverse Events
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/81 (19.8%)		13/80 (16.3%)
Blood and lymphatic system disorders
Normocytic anaemia	0/81 (0%)		1/80 (1.3%)
Cardiac disorders
Acute coronary syndrome	1/81 (1.2%)		1/80 (1.3%)
Acute myocardial infarction	3/81 (3.7%)		0/80 (0%)
Angina pectoris	0/81 (0%)		1/80 (1.3%)
Angina unstable	1/81 (1.2%)		0/80 (0%)
Cardiac arrest	1/81 (1.2%)		0/80 (0%)
Coronary artery disease	0/81 (0%)		1/80 (1.3%)
Coronary artery stenosis	1/81 (1.2%)		1/80 (1.3%)
Ventricular fibrillation	0/81 (0%)		1/80 (1.3%)
Gastrointestinal disorders
Abdominal wall haematoma	1/81 (1.2%)		0/80 (0%)
Colitis ulcerative	0/81 (0%)		1/80 (1.3%)
Gastrointestinal angiodysplasia	0/81 (0%)		1/80 (1.3%)
General disorders
Chest pain	1/81 (1.2%)		0/80 (0%)
Infections and infestations
Enterococcal infection	0/81 (0%)		1/80 (1.3%)
Meningitis staphylococcal	1/81 (1.2%)		0/80 (0%)
Pneumonia	0/81 (0%)		1/80 (1.3%)
Injury, poisoning and procedural complications
Carotid artery restenosis	1/81 (1.2%)		0/80 (0%)
Procedural pain	1/81 (1.2%)		0/80 (0%)
Investigations
Hepatic enzyme increased	0/81 (0%)		1/80 (1.3%)
Metabolism and nutrition disorders
Diabetic metabolic decompensation	1/81 (1.2%)		0/80 (0%)
Lactic acidosis	1/81 (1.2%)		0/80 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	0/81 (0%)		1/80 (1.3%)
Musculoskeletal chest pain	1/81 (1.2%)		0/80 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/81 (1.2%)		0/80 (0%)
Colon cancer	0/81 (0%)		1/80 (1.3%)
Nervous system disorders
Syncope	1/81 (1.2%)		0/80 (0%)
Vertebrobasilar insufficiency	0/81 (0%)		1/80 (1.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertensive crisis	1/81 (1.2%)		0/80 (0%)
Vascular disorders
Arteriosclerosis	0/81 (0%)		1/80 (1.3%)
Other (Not Including Serious) Adverse Events
	Placebo		Evolocumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/81 (37%)		31/80 (38.8%)
Cardiac disorders
Angina pectoris	7/81 (8.6%)		4/80 (5%)
Bradycardia	0/81 (0%)		2/80 (2.5%)
Gastrointestinal disorders
Abdominal pain upper	1/81 (1.2%)		2/80 (2.5%)
Diarrhoea	4/81 (4.9%)		3/80 (3.8%)
General disorders
Fatigue	2/81 (2.5%)		3/80 (3.8%)
Non-cardiac chest pain	0/81 (0%)		2/80 (2.5%)
Infections and infestations
Influenza	2/81 (2.5%)		1/80 (1.3%)
Pneumonia	0/81 (0%)		2/80 (2.5%)
Metabolism and nutrition disorders
Diabetes mellitus	0/81 (0%)		2/80 (2.5%)
Glucose tolerance impaired	2/81 (2.5%)		0/80 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/81 (0%)		2/80 (2.5%)
Muscle spasms	3/81 (3.7%)		0/80 (0%)
Myalgia	6/81 (7.4%)		5/80 (6.3%)
Nervous system disorders
Headache	2/81 (2.5%)		0/80 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/81 (3.7%)		2/80 (2.5%)
Epistaxis	0/81 (0%)		3/80 (3.8%)
Oropharyngeal pain	2/81 (2.5%)		2/80 (2.5%)
Rhinorrhoea	0/81 (0%)		2/80 (2.5%)
Skin and subcutaneous tissue disorders
Drug eruption	2/81 (2.5%)		0/80 (0%)
Rash	2/81 (2.5%)		1/80 (1.3%)
Vascular disorders
Hypertension	5/81 (6.2%)		6/80 (7.5%)
Hypotension	1/81 (1.2%)		3/80 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.