Coronary Artery Disease (CAD)
Conditions
Keywords
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
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.
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).
Interventions
DRUGEvolocumab
Participants will receive evolocumab (AMG 145) subcutaneous monthly.
DRUGPlacebo
Participants will receive matching placebo subcutaneous monthly.
DRUGStatin 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.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
This is a double-blind study. Treatment assignment will be blinded to all subjects, site personnel, and Amgen
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
Countries
Australia, Czechia, Germany, Hungary, Italy, Netherlands, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation. | 82 |
| Evolocumab Evolocumab 420 mg SC injection QM for 48 weeks. Background maximally tolerated statin therapy for the duration of the study participation. | 82 |
| Total | 164 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 2 |
Baseline characteristics
| Characteristic | Evolocumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 10 | 60.8 years STANDARD_DEVIATION 9.6 | 60.4 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 5 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 159 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Minimum Fibrous Cap Thickness (FCT) | 56.6 µm STANDARD_DEVIATION 17.8 | 55.6 µm STANDARD_DEVIATION 16.5 | 54.6 µm STANDARD_DEVIATION 15.1 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 79 Participants | 159 Participants | 80 Participants |
| Sex: Female, Male Female | 20 Participants | 46 Participants | 26 Participants |
| Sex: Female, Male Male | 62 Participants | 118 Participants | 56 Participants |
| Stratification Factor: Statin Use at Screening ≤ 4 weeks of statin use | 63 Participants | 125 Participants | 62 Participants |
| Stratification Factor: Statin Use at Screening > 4 weeks of statin use | 19 Participants | 39 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 82 | 0 / 82 |
| other Total, other adverse events | 30 / 81 | 31 / 80 |
| serious Total, serious adverse events | 16 / 81 | 13 / 80 |
Outcome results
Primary
Absolute Change From Baseline in Minimum FCT
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Minimum FCT | 21.5 µm | Standard Error 5.2 |
| Evolocumab | Absolute Change From Baseline in Minimum FCT | 42.7 µm | Standard Error 5.1 |
p-value: 0.01595% CI: [4.7, 37.7]ANCOVA
Secondary
Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques | -3.33 mm | Standard Error 0.64 |
| Evolocumab | Absolute Change From Baseline in Lipid Core Length in Lipid Rich Plaques | -5.76 mm | Standard Error 0.61 |
p-value: 0.00395% CI: [-4.04, -0.82]ANCOVA
Secondary
Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques | -31.9 degrees | Standard Error 8.1 |
| Evolocumab | Absolute Change From Baseline in Maximum Lipid Arc in Lipid Rich Plaques | -61.9 degrees | Standard Error 7.9 |
p-value: 0.00595% CI: [-50.5, -9.5]ANCOVA
Secondary
Absolute Change From Baseline in Mean Minimum FCT
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Mean Minimum FCT | 29.78 µm | Standard Error 6.88 |
| Evolocumab | Absolute Change From Baseline in Mean Minimum FCT | 62.29 µm | Standard Error 5.95 |
p-value: 0.00395% CI: [12.67, 52.35]ANCOVA
Secondary
Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques | 24.6 μm | Standard Error 5.5 |
| Evolocumab | Absolute Change From Baseline in Minimum FCT in Lipid Rich Plaques | 40.6 μm | Standard Error 5.5 |
p-value: 0.03695% CI: [1.1, 31]ANCOVA
Secondary
Absolute Change From Baseline in the Maximum Lipid Arc
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in the Maximum Lipid Arc | -31.4 degrees | Standard Error 9 |
| Evolocumab | Absolute Change From Baseline in the Maximum Lipid Arc | -57.5 degrees | Standard Error 7.4 |
p-value: 0.03295% CI: [-49.6, -2.4]ANCOVA
Secondary
Percent Change From Baseline in Minimum FCT
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
Population: Full Analysis Set: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Minimum FCT | 44.30 percent change | Standard Error 11.76 |
| Evolocumab | Percent Change From Baseline in Minimum FCT | 81.76 percent change | Standard Error 10.94 |
p-value: 0.04195% CI: [1.63, 73.31]ANCOVA