Hypercholesterolemia
Conditions
Keywords
Cholesterol, High Cholesterol, Elevated Cholesterol, Raised Cholesterol
Brief summary
This study will evaluate whether low-density lipoprotein (LDL-C) lowering with evolocumab (AMG 145) results in greater change from baseline in percent atheroma volume (PAV) at week 78 than placebo in adults with coronary artery disease taking lipid lowering therapy.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
DRUGPlacebo
Administered by subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Clinical indication for coronary angiography * Subjects already taking statin therapy, niacin or ezetimibe at screening must have been on a stable dose for at least 4 weeks prior to screening LDL-C. Subjects not taking lipid-regulating therapy must enter the study via a lipid stabilization period. Subjects who are intolerant to statins must meet statin intolerance entry criteria * Fasting LDL-C ≥ 80 mg/dL (2.07 mmol/L) with or without additional risk factors, or, LDL-C ≥ 60 -\< 80 mg/dL (1.55-2.07 mmol/L) in the presence of one major or three minor risk factors Subjects must meet the following criteria at the qualifying coronary catheterization procedure: * Evidence of coronary heart disease (at least one lesion in a native coronary artery that has \> 20% reduction in lumen diameter) or prior percutaneous intervention (PCI) * Left main coronary artery \< 50% reduction in lumen diameter by visual estimation * Target coronary artery for IVUS must be accessible to the IVUS catheter, must not have a \> 50% reduction in lumen diameter within the target segment (and at least 40 mm in length); cannot have undergone prior PCI or coronary artery bypass graft (CABG) and is not a candidate for intervention over the next 18 months. It may not be a bypass graft, bypassed vessel or culprit vessel for previous myocardial infarction (MI).
Exclusion criteria
* Coronary artery bypass graft surgery \< 6 weeks prior to the qualifying IVUS * New York Heart Association (NYHA) III or IV heart failure, or last known left ventricular ejection fraction less than 30% * Uncontrolled cardiac arrhythmia that is not controlled by medications in the 3 months prior to randomization * Known hemorrhagic stroke * Uncontrolled hypertension at randomization * Fasting Triglycerides ≥ 400 mg/dL (4.5 mmol/L) at screening * Type 1 diabetes or poorly controlled type 2 diabetes (hemoglobin A1c \[HbA1c\] \> 9%) at screening. * Moderate to severe renal dysfunction (estimated glomerular filtration rate \[eGFR\] \< 30 ml/min/1.73m²) at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Atheroma Volume at Week 78 | Baseline and week 78 | Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Atheroma Volume at Week 78 | Baseline and week 78 | Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants. |
| Percentage of Participants With Regression in Percent Atheroma Volume | Baseline and week 78 | Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma. Regression in PAV was defined as any reduction from baseline in PAV. |
| Percentage of Participants With Regression in Total Atheroma Volume | Baseline and week 78 | Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants. Regression in TAV was defined as any reduction from baseline in TAV. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, Czechia, Denmark, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Malaysia, Mexico, Netherlands, Norway, Philippines, Poland, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 163 centers in 30 countries in Europe, North America, Asia Pacific, and Latin America. The first participant was enrolled on 18 April 2013 and the last participant enrolled on 12 January 2015.
Pre-assignment details
Participants who met all entry criteria were randomized 1:1 to receive evolocumab 420 mg once monthly (QM) subcutaneous (SC) or placebo QM SC for 76 weeks. Randomization was stratified by region.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo to evolocumab administered by subcutaneous injection once a month for 76 weeks. | 486 |
| Evolocumab Participants received 420 mg evolocumab administered by subcutaneous injection once a month for 76 weeks. | 484 |
| Total | 970 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 3 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Sponsor Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 8 |
Baseline characteristics
| Characteristic | Evolocumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 9.6 | 59.8 years STANDARD_DEVIATION 9.2 | 59.8 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 58 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 450 Participants | 912 Participants | 462 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 14 participants | 31 participants | 17 participants |
| Race/Ethnicity, Customized Black or African American | 4 participants | 9 participants | 5 participants |
| Race/Ethnicity, Customized Multiple | 7 participants | 13 participants | 6 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 5 participants | 3 participants |
| Race/Ethnicity, Customized White | 456 participants | 909 participants | 453 participants |
| Sex: Female, Male Female | 135 Participants | 270 Participants | 135 Participants |
| Sex: Female, Male Male | 349 Participants | 700 Participants | 351 Participants |
| Stratification Factor: Geographical Region Asia Pacific | 51 participants | 101 participants | 50 participants |
| Stratification Factor: Geographical Region Europe | 332 participants | 664 participants | 332 participants |
| Stratification Factor: Geographical Region Latin America | 15 participants | 31 participants | 16 participants |
| Stratification Factor: Geographical Region North America | 86 participants | 174 participants | 88 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 120 / 484 | 114 / 484 |
| serious Total, serious adverse events | 142 / 484 | 135 / 484 |
Outcome results
Primary
Change From Baseline in Percent Atheroma Volume at Week 78
Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma.
Time frame: Baseline and week 78
Population: Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Percent Atheroma Volume at Week 78 | 0.053 percent atheroma volume | Standard Error 0.189 |
| Evolocumab | Change From Baseline in Percent Atheroma Volume at Week 78 | -0.955 percent atheroma volume | Standard Error 0.19 |
p-value: <0.000195% CI: [-1.375, -0.64]ANCOVA
Secondary
Change From Baseline in Total Atheroma Volume at Week 78
Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants.
Time frame: Baseline and week 78
Population: Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Atheroma Volume at Week 78 | -0.910 mm³ | Standard Error 1.214 |
| Evolocumab | Change From Baseline in Total Atheroma Volume at Week 78 | -5.799 mm³ | Standard Error 1.216 |
p-value: <0.000195% CI: [-7.247, -2.531]ANCOVA
Secondary
Percentage of Participants With Regression in Percent Atheroma Volume
Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. The extent of atherosclerosis was expressed as percent atheroma volume (PAV) in a ≥ 40 mm segment of one targeted (imaged) coronary artery, calculated as the percentage of the total vessel volume occupied by atheroma. Regression in PAV was defined as any reduction from baseline in PAV.
Time frame: Baseline and week 78
Population: Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Regression in Percent Atheroma Volume | 47.3 percentage of participants |
| Evolocumab | Percentage of Participants With Regression in Percent Atheroma Volume | 64.3 percentage of participants |
p-value: <0.000195% CI: [10.3, 23.5]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Regression in Total Atheroma Volume
Intravascular ultrasound (IVUS) was used to visualize the extent of atherosclerotic plaques in the coronary artery lumen. Total atheroma volume (TAV) in a ≥ 40 mm segment of the targeted coronary artery was calculated as the average plaque area over the number of images that were evaluated by IVUS multiplied by the median vessel length to compensate for differences in segment length between participants. Regression in TAV was defined as any reduction from baseline in TAV.
Time frame: Baseline and week 78
Population: Randomized participants who received at least 1 dose of study drug, with a baseline IVUS and an IVUS measurement conducted after week 52 (IVUS analysis set)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Regression in Total Atheroma Volume | 48.9 percentage of participants |
| Evolocumab | Percentage of Participants With Regression in Total Atheroma Volume | 61.5 percentage of participants |
p-value: 0.000295% CI: [5.8, 19.1]Cochran-Mantel-Haenszel