Hypercholesterolemia, Familial
Conditions
Keywords
Heterozygous Familial Hypercholesterolemia, Proprotein convertase subtilisin/kexin type 9 (PCSK9)
Brief summary
The primary objective of this study was to evaluate the effect of 12 weeks of subcutaneous evolocumab (AMG 145), compared with placebo, on percent change from baseline in LDL-C in adults with heterozygous familial hypercholesterolemia (HeFH).
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
BIOLOGICALPlacebo
d 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 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female ≥ 18 to ≤ 75 years of age * Diagnosis of heterozygous familial hypercholesterolemia by having met the diagnostic criteria outlined by the Simon Broome Register Group (Scientific Steering Committee 1991) * On an approved statin, with or without ezetimibe, with stable dose(s) for at least 4 weeks * Fasting Low-Density Lipoprotein Cholesterol (LDL-C) ≥ 100 mg/dL * Fasting triglycerides ≤ 400 mg/dL
Exclusion criteria
* Homozygous familial hypercholesterolemia * Low-Density Lipoprotein (LDL) or plasma apheresis within 12 months prior to randomization * New York Heart Association (NYHA) III or IV heart failure, or 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 (HbA1c \> 8.5%) * Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C was measured using ultracentrifugation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in LDL-C at Week 12 | Baseline and Week 12 | LDL-C was measured using ultracentrifugation. |
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C) at Week 12 | Baseline and Week 12 | — |
| Percent Change From Baseline in Apolipoprotein B at Week 12 | Baseline and Week 12 | — |
| Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | Baseline and Week 12 | — |
| Percent Change From Baseline in Apolipoprotein B /Apolipoprotein A-1 Ratio at Week 12 | Baseline and Week 12 | — |
Participant flow
Recruitment details
Men and women 18 to to 75 years of age, with a diagnosis of heterozygous familial hypercholesterolemia, fasting low-density lipoprotein cholesterol (LDL-C) of ≥ 100 mg/dL, and fasting triglycerides ≤ 400 mg/dL were eligible for this study. The first patient was enrolled on 02 August 2011 and the last patient was enrolled on 20 February 2012.
Pre-assignment details
Randomization was stratified on the basis of screening LDL-C level (\< 130 mg/dL \[3.4 mmol/L\] or ≥ 130 mg/dL) and ezetimibe use at baseline (yes or no).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneous injection once every 4 weeks for 12 weeks. | 56 |
| Evolocumab 350 mg Participants received 350 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks. | 55 |
| Evolocumab 420 mg Participants received 420 mg evolocumab by subcutaneous injection once every 4 weeks for 12 weeks. | 56 |
| Total | 167 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Other | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Evolocumab 350 mg | Placebo | Total | Evolocumab 420 mg |
|---|---|---|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 13.6 | 49.3 years STANDARD_DEVIATION 11.3 | 49.6 years STANDARD_DEVIATION 12.7 | 51.8 years STANDARD_DEVIATION 13 |
| Apolipoprotein B/Apolipoprotein A1 Ratio | 0.901 ratio STANDARD_DEVIATION 0.286 | 0.899 ratio STANDARD_DEVIATION 0.277 | 0.899 ratio STANDARD_DEVIATION 0.274 | 0.867 ratio STANDARD_DEVIATION 0.264 |
| Apolipoprotein B Concentration | 120.9 mg/dL STANDARD_DEVIATION 29.3 | 125.2 mg/dL STANDARD_DEVIATION 30.3 | 121.8 mg/dL STANDARD_DEVIATION 29 | 119.3 mg/dL STANDARD_DEVIATION 27.6 |
| LDL-C Concentration | 156.8 mg/dL STANDARD_DEVIATION 46.1 | 160.8 mg/dL STANDARD_DEVIATION 44 | 155.7 mg/dL STANDARD_DEVIATION 42.3 | 149.5 mg/dL STANDARD_DEVIATION 36.3 |
| Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration | 178.0 mg/dL STANDARD_DEVIATION 51.7 | 182.7 mg/dL STANDARD_DEVIATION 52.6 | 177.2 mg/dL STANDARD_DEVIATION 49.4 | 171.0 mg/dL STANDARD_DEVIATION 43.6 |
| Race/Ethnicity, Customized Asian | 1 participants | 3 participants | 7 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 0 participants | 4 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Mixed Race | 0 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 55 participants | 54 participants | 165 participants | 56 participants |
| Race/Ethnicity, Customized Other | 3 participants | 4 participants | 7 participants | 0 participants |
| Race/Ethnicity, Customized White | 48 participants | 48 participants | 148 participants | 52 participants |
| Sex: Female, Male Female | 25 Participants | 32 Participants | 78 Participants | 21 Participants |
| Sex: Female, Male Male | 30 Participants | 24 Participants | 89 Participants | 35 Participants |
| Stratification Factor: Baseline Use Of Ezetimibe No | 19 participants | 20 participants | 59 participants | 20 participants |
| Stratification Factor: Baseline Use Of Ezetimibe Yes | 36 participants | 36 participants | 108 participants | 36 participants |
| Stratification Factor: LDL-C Level < 130 mg/dL | 17 participants | 19 participants | 55 participants | 19 participants |
| Stratification Factor: LDL-C Level ≥ 130 mg/dL | 38 participants | 37 participants | 112 participants | 37 participants |
| Total Cholesterol/HDL-C Ratio | 5.119 ratio STANDARD_DEVIATION 1.923 | 4.895 ratio STANDARD_DEVIATION 1.79 | 4.956 ratio STANDARD_DEVIATION 1.795 | 4.857 ratio STANDARD_DEVIATION 1.688 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 56 | 22 / 55 | 19 / 56 |
| serious Total, serious adverse events | 0 / 56 | 0 / 55 | 2 / 56 |
Outcome results
Primary
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C was measured using ultracentrifugation.
Time frame: Baseline and Week 12
Population: Full analysis set; Missing ultracentrifugation (UC) LDL-C data at Week 12 were imputed using last observation carried forward (LOCF) and calculated LDL-C.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 1.12 percent change | Standard Error 2.88 |
| Evolocumab 350 mg | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -42.70 percent change | Standard Error 2.93 |
| Evolocumab 420 mg | Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -55.24 percent change | Standard Error 2.88 |
Comparison: The null hypothesis was that there was no mean difference in the percent change from baseline at Week 12 in LDL-C between evolocumab and placebo.p-value: <0.00195% CI: [-51.56, -36.09]ANCOVA
Comparison: The null hypothesis was that there was no mean difference in the percent change from baseline at Week 12 in LDL-C between evolocumab and placebo.p-value: <0.00195% CI: [-64.06, -48.67]ANCOVA
Secondary
Absolute Change From Baseline in LDL-C at Week 12
LDL-C was measured using ultracentrifugation.
Time frame: Baseline and Week 12
Population: Full analysis set; LOCF imputation was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in LDL-C at Week 12 | 4.2 mg/dL | Standard Error 5.2 |
| Evolocumab 350 mg | Absolute Change From Baseline in LDL-C at Week 12 | -61.3 mg/dL | Standard Error 5.4 |
| Evolocumab 420 mg | Absolute Change From Baseline in LDL-C at Week 12 | -80.5 mg/dL | Standard Error 5.2 |
p-value: <0.00195% CI: [-79.6, -51.4]ANCOVA
p-value: <0.00195% CI: [-98.8, -70.7]ANCOVA
Secondary
Percent Change From Baseline in Apolipoprotein B /Apolipoprotein A-1 Ratio at Week 12
Time frame: Baseline and Week 12
Population: Full analysis set; LOCF imputation was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B /Apolipoprotein A-1 Ratio at Week 12 | -4.10 percent change | Standard Error 2.53 |
| Evolocumab 350 mg | Percent Change From Baseline in Apolipoprotein B /Apolipoprotein A-1 Ratio at Week 12 | -38.02 percent change | Standard Error 2.58 |
| Evolocumab 420 mg | Percent Change From Baseline in Apolipoprotein B /Apolipoprotein A-1 Ratio at Week 12 | -48.74 percent change | Standard Error 2.53 |
p-value: <0.00195% CI: [-40.72, -27.11]ANCOVA
p-value: <0.00195% CI: [-51.41, -37.86]ANCOVA
Secondary
Percent Change From Baseline in Apolipoprotein B at Week 12
Time frame: Baseline and Week 12
Population: Full analysis set; LOCF imputation was used
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Apolipoprotein B at Week 12 | 2.86 percent change | Standard Error 2.61 |
| Evolocumab 350 mg | Percent Change From Baseline in Apolipoprotein B at Week 12 | -31.89 percent change | Standard Error 2.66 |
| Evolocumab 420 mg | Percent Change From Baseline in Apolipoprotein B at Week 12 | -43.34 percent change | Standard Error 2.61 |
p-value: <0.00195% CI: [-41.77, -27.74]ANCOVA
p-value: <0.00195% CI: [-53.18, -39.23]ANCOVA
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C) at Week 12
Time frame: Baseline and Week 12
Population: Full analysis set; LOCF imputation was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C) at Week 12 | 2.48 percent change | Standard Error 2.8 |
| Evolocumab 350 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C) at Week 12 | -39.31 percent change | Standard Error 2.86 |
| Evolocumab 420 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (HDL-C) at Week 12 | -50.98 percent change | Standard Error 2.8 |
p-value: <0.00195% CI: [-49.32, -34.26]ANCOVA
p-value: <0.00195% CI: [-60.95, -45.97]ANCOVA
Secondary
Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12
Time frame: Baseline and Week 12
Population: Full analysis set; LOCF imputaton was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | 2.98 percent change | Standard Error 2.73 |
| Evolocumab 350 mg | Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | -33.69 percent change | Standard Error 2.79 |
| Evolocumab 420 mg | Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | -42.03 percent change | Standard Error 2.73 |
p-value: <0.00195% CI: [-44.01, -29.32]ANCOVA
p-value: <0.00195% CI: [-52.32, -37.7]ANCOVA