Hypercholesterolemia
Conditions
Keywords
Cholesterol, High Cholesterol, Elevated Cholesterol, Raised Cholesterol
Brief summary
To evaluate the efficacy, safety, and tolerability of 52 weeks of subcutaneous (SC) evolocumab (AMG 145) compared with placebo when added to assigned background lipid-lowering therapy.
Detailed description
Eligible participants with screening central laboratory low-density lipoprotein cholesterol (LDL-C) values ≥ 75 mg/dL (1.9 mmol/L) were instructed to follow National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP) Therapeutic Lifestyle Changes (TLC) diet and were assigned to 1 of the following 4 background lipid-lowering therapies for a 4-week stabilization period based upon their screening LDL-C and its distance from the individual's required goal as stipulated by their NCEP ATP III risk category: 1. no drug therapy required - diet alone 2. low dose drug therapy required - diet plus atorvastatin 10 mg orally (PO) once daily (QD) 3. high dose drug therapy required - diet plus atorvastatin 80 mg PO QD 4. maximal drug therapy required - diet plus atorvastatin 80 mg PO QD plus ezetimibe 10 mg PO QD. If the participant met entry criteria at the end of the lipid stabilization period they were randomized 2:1 to receive evolocumab 420 mg or placebo subcutaneously once a month for 52 weeks in addition to their background therapy.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection once a month
BIOLOGICALPlacebo
Administered by subcutaneous injection once a month
DRUGAtorvastatin
Background lipid lowering therapy: 10 mg or 80 mg atorvastatin orally once daily.
DRUGEzetimibe
Background lipid lowering therapy: ezetimibe 10 mg orally once a day
OTHERDiet Only
Diet only, no lipid lowering background drug given
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 80 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent. * Fasting LDL-C ≥ 75 mg/dL and meeting the following LDL-C values on background lipid-lowering therapy: * \< 100 mg/dL for subjects with diagnosed coronary heart disease (CHD) or CHD risk equivalent * \< 130 mg/dL for subjects without diagnosed CHD or CHD risk equivalent * OR on maximal background lipid-lowering therapy defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD * Fasting triglycerides ≤ 400 mg/dL
Exclusion criteria
* New York Heart Association (NYHA) II-IV heart failure, or last known left ventricular ejection fraction \< 30% * Uncontrolled cardiac arrhythmia * Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization, type 1 diabetes, newly diagnosed or poorly controlled type 2 diabetes * Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C at Week 52 | Baseline and Week 52 | Cholesterol was measured by means of ultracentrifugation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52 | Baseline and Week 52 | — |
| Change From Baseline in LDL-C at Week 52 | Baseline and Week 52 | Cholesterol was measured by means of ultracentrifugation. |
| Percentage of Participants With an LDL-C Response at Week 52 | Week 52 | An LDL-C response is defined as LDL-C level \< 70 mg/dL (1.8 mmol/L) at Week 52. |
| Percent Change From Baseline in LDL-C at Week 12 | Baseline and Week 12 | Cholesterol was measured by means of ultracentrifugation. |
| Percent Change From Baseline in Total Cholesterol at Week 12 | Baseline and Week 12 | — |
| Percent Change From Baseline in Total Cholesterol at Week 52 | Baseline and Week 52 | — |
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52 | Baseline and Week 52 | Cholesterol was measured by means of ultracentrifugation. |
| Percent Change From Baseline in Apolipoprotein B at Week 52 | Baseline and Week 52 | — |
| Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52 | Baseline and Week 52 | — |
| Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52 | Baseline and Week 52 | — |
| Percent Change From Baseline in Lipoprotein(a) at Week 52 | Baseline and Week 52 | — |
| Percent Change From Baseline in Triglycerides at Week 52 | Baseline and Week 52 | — |
| Percent Change From Week 12 to Week 52 in LDL-C | Week 12 and Week 52 | Cholesterol was measured by means of ultracentrifugation. |
| Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52 | Baseline and Week 52 | — |
Countries
Australia, Austria, Belgium, Canada, Czechia, Denmark, Hungary, South Africa, United States
Participant flow
Recruitment details
Adults with fasting low-density lipoprotein cholesterol (LDL-C) ≥ 75 mg/dL and triglycerides ≤ 400 mg/dL were eligible. The first patient enrolled on 5 January 2012 and the last patient enrolled on 12 October 2012. All patients were counseled on the National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes diet.
Pre-assignment details
Patients were assigned to 1 of 4 background lipid-lowering regimens for a 4-12 week stabilization period: diet alone, diet and 10 mg atorvastatin daily, diet and 80 mg atorvastatin daily, or diet, 80 mg atorvastatin and 10 mg ezetimibe daily. Patients meeting criteria were randomized 2:1 to evolocumab or placebo, stratified by background therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy. | 303 |
| Evolocumab Participants received evolocumab 420 mg subcutaneously once a month for 52 weeks in addition to background lipid-lowering therapy. | 602 |
| Total | 905 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 2 | 11 |
| Overall Study | Other | 5 | 10 |
| Overall Study | Withdrawal by Subject | 9 | 11 |
Baseline characteristics
| Characteristic | Evolocumab | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 55.9 years STANDARD_DEVIATION 10.9 | 56.1 years STANDARD_DEVIATION 10.7 | 56.6 years STANDARD_DEVIATION 10.3 |
| Apolipoprotein B/Apolipoprotein A-1 Ratio | 0.593 ratio STANDARD_DEVIATION 0.17 | 0.590 ratio STANDARD_DEVIATION 1.7 | 0.586 ratio STANDARD_DEVIATION 0.17 |
| Apolipoprotein B Concentration | 87.0 mg/dL STANDARD_DEVIATION 16.3 | 87.2 mg/dL STANDARD_DEVIATION 16.3 | 87.5 mg/dL STANDARD_DEVIATION 16.3 |
| Background Therapy Diet + Atorvastatin 10 mg | 256 participants | 385 participants | 129 participants |
| Background Therapy Diet + Atorvastatin 80 mg | 146 participants | 219 participants | 73 participants |
| Background Therapy Diet + Atorvastatin 80 mg + Ezetimibe 10 mg | 126 participants | 189 participants | 63 participants |
| Background Therapy Diet Only | 74 participants | 112 participants | 38 participants |
| High-density Lipoprotein Cholesterol (HDL-C) Concentration | 52.6 mg/dL STANDARD_DEVIATION 15.5 | 52.9 mg/dL STANDARD_DEVIATION 15.7 | 53.5 mg/dL STANDARD_DEVIATION 16.1 |
| Lipoprotein(a) Concentration | 84.0 nmol/L STANDARD_DEVIATION 98.5 | 85.8 nmol/L STANDARD_DEVIATION 102 | 89.3 nmol/L STANDARD_DEVIATION 108.6 |
| Low-density Lipoprotein Cholesterol (LDL-C) Concentration | 104.2 mg/dL STANDARD_DEVIATION 22.1 | 104.1 mg/dL STANDARD_DEVIATION 22 | 104.0 mg/dL STANDARD_DEVIATION 21.6 |
| Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) Concentration | 124.2 mg/dL STANDARD_DEVIATION 25.6 | 124.6 mg/dL STANDARD_DEVIATION 26.1 | 125.6 mg/dL STANDARD_DEVIATION 26.9 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 41 participants | 57 participants | 16 participants |
| Race/Ethnicity, Customized Black or African American | 53 participants | 76 participants | 23 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 33 participants | 50 participants | 17 participants |
| Race/Ethnicity, Customized Mixed Race | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 569 participants | 855 participants | 286 participants |
| Race/Ethnicity, Customized Other | 26 participants | 39 participants | 13 participants |
| Race/Ethnicity, Customized White | 478 participants | 727 participants | 249 participants |
| Sex: Female, Male Female | 312 Participants | 474 Participants | 162 Participants |
| Sex: Female, Male Male | 290 Participants | 431 Participants | 141 Participants |
| Total Cholesterol | 176.8 mg/dL STANDARD_DEVIATION 27.5 | 177.6 mg/dL STANDARD_DEVIATION 27.4 | 179.1 mg/dL STANDARD_DEVIATION 27.2 |
| Total Cholesterol/High Density Lipoprotein-Cholesterol (HDL-C) Ratio | 3.597 ratio STANDARD_DEVIATION 1.04 | 3.599 ratio STANDARD_DEVIATION 1.06 | 3.603 ratio STANDARD_DEVIATION 1.11 |
| Triglycerides Concentration | 119.8 mg/dL STANDARD_DEVIATION 63.2 | 122.5 mg/dL STANDARD_DEVIATION 64.1 | 127.8 mg/dL STANDARD_DEVIATION 65.8 |
| Very Low-density Lipoprotein Cholesterol (VLDL-C) Concentration | 20.0 mg/dL STANDARD_DEVIATION 11.4 | 20.5 mg/dL STANDARD_DEVIATION 12.1 | 21.5 mg/dL STANDARD_DEVIATION 13.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 76 / 302 | 177 / 599 |
| serious Total, serious adverse events | 13 / 302 | 33 / 599 |
Outcome results
Primary
Percent Change From Baseline in LDL-C at Week 52
Cholesterol was measured by means of ultracentrifugation.
Time frame: Baseline and Week 52
Population: Full Analysis Set (all randomized subjects who received at least 1 dose of study drug).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in LDL-C at Week 52 | 6.83 percent change | Standard Error 1.75 |
| Evolocumab | Percent Change From Baseline in LDL-C at Week 52 | -50.14 percent change | Standard Error 1.24 |
Comparison: The null hypothesis was that there was no mean difference in the percent change from Baseline at Week 52 in LDL-C between evolocumab 420 mg and placebo, and the alternative hypothesis was that a mean difference did exist.p-value: <0.00195% CI: [-61.08, -52.85]Repeated measures linear effects model
Secondary
Change From Baseline in LDL-C at Week 52
Cholesterol was measured by means of ultracentrifugation.
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in LDL-C at Week 52 | 5.1 mg/dL | Standard Error 1.9 |
| Evolocumab | Change From Baseline in LDL-C at Week 52 | -52.7 mg/dL | Standard Error 1.4 |
p-value: <0.00195% CI: [-62.3, -53.3]Repeated measures linear effects model
Secondary
Percentage of Participants With an LDL-C Response at Week 52
An LDL-C response is defined as LDL-C level \< 70 mg/dL (1.8 mmol/L) at Week 52.
Time frame: Week 52
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an LDL-C Response at Week 52 | 6.4 percentage of participants |
| Evolocumab | Percentage of Participants With an LDL-C Response at Week 52 | 82.3 percentage of participants |
p-value: <0.00195% CI: [70.8, 79.7]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52 | 4.46 percent change | Standard Error 1.5 |
| Evolocumab | Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 52 | -41.75 percent change | Standard Error 1.09 |
p-value: <0.00195% CI: [-49.79, -42.63]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Apolipoprotein B at Week 52
Time frame: Baseline and Week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B at Week 52 | 2.94 percent change | Standard Error 1.41 |
| Evolocumab | Percent Change From Baseline in Apolipoprotein B at Week 52 | -41.26 percent change | Standard Error 1.02 |
p-value: <0.00195% CI: [-47.56, -40.85]Repeated measures linear effects model
Secondary
Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52 | 0.35 percent change | Standard Error 0.9 |
| Evolocumab | Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 52 | 5.77 percent change | Standard Error 0.65 |
p-value: <0.00195% CI: [3.28, 7.56]Repeated measures linear effects model
Secondary
Percent Change From Baseline in LDL-C at Week 12
Cholesterol was measured by means of ultracentrifugation.
Time frame: Baseline and Week 12
Population: Full Analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in LDL-C at Week 12 | 3.17 percent change | Standard Error 1.31 |
| Evolocumab | Percent Change From Baseline in LDL-C at Week 12 | -54.35 percent change | Standard Error 0.96 |
p-value: <0.00195% CI: [-60.57, -54.45]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Lipoprotein(a) at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Lipoprotein(a) at Week 52 | -5.37 percent change | Standard Error 1.62 |
| Evolocumab | Percent Change From Baseline in Lipoprotein(a) at Week 52 | -27.72 percent change | Standard Error 1.19 |
p-value: <0.00195% CI: [-26.15, -18.55]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52 | 8.44 percent change | Standard Error 1.68 |
| Evolocumab | Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at Week 52 | -41.82 percent change | Standard Error 1.21 |
p-value: <0.00195% CI: [-54.25, -46.28]Repeated measures linear effects model
Secondary
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52 | 6.47 percent change | Standard Error 1.37 |
| Evolocumab | Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 52 | -30.67 percent change | Standard Error 0.99 |
p-value: <0.00195% CI: [-40.41, -33.87]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Total Cholesterol at Week 12
Time frame: Baseline and Week 12
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Total Cholesterol at Week 12 | 2.85 percent change | Standard Error 0.87 |
| Evolocumab | Percent Change From Baseline in Total Cholesterol at Week 12 | -32.30 percent change | Standard Error 0.63 |
p-value: <0.00195% CI: [-37.19, -33.11]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Total Cholesterol at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Total Cholesterol at Week 52 | 5.26 percent change | Standard Error 1.16 |
| Evolocumab | Percent Change From Baseline in Total Cholesterol at Week 52 | -28.18 percent change | Standard Error 0.84 |
p-value: <0.00195% CI: [-36.21, -30.68]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Triglycerides at Week 52
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Triglycerides at Week 52 | 8.99 percent change | Standard Error 2.39 |
| Evolocumab | Percent Change From Baseline in Triglycerides at Week 52 | -2.55 percent change | Standard Error 1.72 |
p-value: <0.00195% CI: [-17.21, -5.86]Repeated measures linear effects model
Secondary
Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52
Cholesterol was measured by means of ultracentrifugation.
Time frame: Baseline and Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52 | 31.89 percent change | Standard Error 4.69 |
| Evolocumab | Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 52 | 2.74 percent change | Standard Error 3.36 |
p-value: <0.00195% CI: [-40.23, -18.08]Repeated measures linear effects model
Secondary
Percent Change From Week 12 to Week 52 in LDL-C
Cholesterol was measured by means of ultracentrifugation.
Time frame: Week 12 and Week 52
Population: The Effect Durability Analysis Set included participants in the FAS who adhered to the scheduled study drug and had nonmissing LDL-C values at Baseline, Week 12 and Week 52.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Week 12 to Week 52 in LDL-C | 2.57 percent change | Standard Error 1.56 |
| Evolocumab | Percent Change From Week 12 to Week 52 in LDL-C | 2.44 percent change | Standard Error 1.14 |
p-value: 0.9495% CI: [-3.76, 3.48]ANCOVA