Homozygous Familial Hypercholesterolemia
Conditions
Keywords
hypercholesterolemia, familial hypercholesterolemia, homozygous familial hypercholesterolemia
Brief summary
A study to determine the safety, tolerability, and efficacy of evolocumab (AMG 145) in patients with homozygous familial hypercholesterolemia (HoFH).
Detailed description
Study Masking: Part A: Open Label Part B: Double Blind
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
12 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Males and females ≥ 12 to ≤ 80 years of age * Diagnosis of homozygous familial hypercholesterolemia * Stable lipid-lowering therapies for at least 4 weeks * LDL cholesterol ≥ 130 mg/dl (3.4 mmol/L) * Triglyceride ≤ 400 mg/dL (4.5 mmol/L) * Bodyweight of ≥ 40 kg at screening.
Exclusion criteria
* LDL or plasma apheresis within 8 weeks prior to randomization * New York Heart Association (NYHA) class III or IV or last known left ventricular ejection fraction \< 30% * Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months of randomization * Planned cardiac surgery or revascularization * Uncontrolled cardiac arrhythmia * Uncontrolled hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C was quantified using the ultracentrifugation method. |
| Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | Baseline and Week 12 | LDL-C was quantified using the ultracentrifugation method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12 | Baseline and Weeks 6 and 12 | LDL-C was quantified using the ultracentrifugation method. |
| Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 | Baseline and Week 12 | LDL-C was quantified using the ultracentrifugation method. |
| Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | Baseline and Week 12 | — |
| Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 | Baseline and Week 12 | — |
| Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 | Baseline and Week 12 | — |
| Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 | Baseline and Week 12 | — |
| Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 | Baseline and Week 12 | — |
| Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 | Baseline and Week 12 | — |
| Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 | Baseline and Week 12 | — |
| Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12 | Baseline and Weeks 6 and 12 | — |
| Part A: Change From Baseline in LDL-C at Week 12 | Baseline and Week 12 | LDL-C was quantified using the ultracentrifugation method. |
| Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12 | Baseline and Weeks 6 and 12 | — |
Countries
Belgium, Canada, Czechia, France, Hong Kong, Italy, Lebanon, Netherlands, New Zealand, South Africa, Spain, United States
Participant flow
Recruitment details
Male and female adults and adolescents ages ≥ 12 to ≤ 65 years (≥ 12 to ≤ 80 years in Part B) with a diagnosis of homozygous familial hypercholesterolemia (HoFH) were eligible for this study. The first participant enrolled on 05 April 2012 and the last participant enrolled on 08 November 2013.
Pre-assignment details
Part A was an open-label, single-arm, multicenter pilot study. Part B was a double-blind, randomized, placebo-controlled, multicenter study with expanded enrollment. In Part B participants were randomized in a 1:2 allocation stratified on the basis of screening low-density lipoprotein cholesterol (LDL-C) (\< 420 mg/dL vs ≥ 420 mg/dL).
Participants by arm
| Arm | Count |
|---|---|
| Part A: Evolocumab Participants received open-label evolocumab 420 mg subcutaneously (SC) once a month (QM) for 12 weeks. | 8 |
| Part B: Placebo Participants received double-blind placebo subcutaneously once a month for 12 weeks. | 17 |
| Part B: Evolocumab Participants received double-blind evolocumab 420 mg subcutaneously once a month for 12 weeks. | 33 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part B: Evolocumab | Total | Part A: Evolocumab | Part B: Placebo |
|---|---|---|---|---|
| Age, Continuous | 30.3 years STANDARD_DEVIATION 12.4 | 31.6 years STANDARD_DEVIATION 12.7 | 34.3 years STANDARD_DEVIATION 12.4 | 32.8 years STANDARD_DEVIATION 13.7 |
| Apolipoprotein B/Apolipoprotein A1 Ratio Part A | NA ratio | 2.800 ratio STANDARD_DEVIATION 0.729 | 2.800 ratio STANDARD_DEVIATION 0.729 | NA ratio |
| Apolipoprotein B/Apolipoprotein A1 Ratio Part B | 2.098 ratio STANDARD_DEVIATION 1.046 | 2.084 ratio STANDARD_DEVIATION 1.011 | NA ratio | 2.053 ratio STANDARD_DEVIATION 0.967 |
| Apolipoprotein B Concentration Part A | NA mg/dL | 269.1 mg/dL STANDARD_DEVIATION 53 | 269.1 mg/dL STANDARD_DEVIATION 53 | NA mg/dL |
| Apolipoprotein B Concentration Part B | 208.3 mg/dL STANDARD_DEVIATION 68.4 | 208.4 mg/dL STANDARD_DEVIATION 71.4 | NA mg/dL | 208.6 mg/dL STANDARD_DEVIATION 79.5 |
| LDL-C Concentration Part A | NA mg/dL | 441.7 mg/dL STANDARD_DEVIATION 113.3 | 441.7 mg/dL STANDARD_DEVIATION 113.3 | NA mg/dL |
| LDL-C Concentration Part B | 356.0 mg/dL STANDARD_DEVIATION 134.5 | 349.4 mg/dL STANDARD_DEVIATION 137.2 | NA mg/dL | 335.8 mg/dL STANDARD_DEVIATION 146 |
| Lipoprotein(a) Concentration Part A | NA nmol/L | 246.5 nmol/L | 246.5 nmol/L | NA nmol/L |
| Lipoprotein(a) Concentration Part B | 76.0 nmol/L | 100.5 nmol/L | NA nmol/L | 127.5 nmol/L |
| Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration Part A | NA mg/dL | 470.6 mg/dL STANDARD_DEVIATION 117.8 | 470.6 mg/dL STANDARD_DEVIATION 117.8 | NA mg/dL |
| Non-High-Density Lipoprotein Cholesterol (non-HDL-C) Concentration Part B | 374.9 mg/dL STANDARD_DEVIATION 136.9 | 369.7 mg/dL STANDARD_DEVIATION 139.6 | NA mg/dL | 358.9 mg/dL STANDARD_DEVIATION 149.1 |
| Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration Part A | NA ng/mL | 598.6 ng/mL STANDARD_DEVIATION 121.1 | 598.6 ng/mL STANDARD_DEVIATION 121.1 | NA ng/mL |
| Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Concentration Part B | 640.3 ng/mL STANDARD_DEVIATION 207.5 | 651.4 ng/mL STANDARD_DEVIATION 197.7 | NA ng/mL | 674.2 ng/mL STANDARD_DEVIATION 180 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 2 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 32 participants | 57 participants | 8 participants | 17 participants |
| Race/Ethnicity, Customized Other | 3 participants | 3 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 29 participants | 53 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 16 Participants | 26 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 17 Participants | 32 Participants | 6 Participants | 9 Participants |
| Stratification Factor: Low-Density Lipoprotein Cholesterol (LDL-C) Level < 420 mg/dL | 21 participants | 32 participants | 0 participants | 11 participants |
| Stratification Factor: Low-Density Lipoprotein Cholesterol (LDL-C) Level ≥ 420 mg/dL | 12 participants | 18 participants | 0 participants | 6 participants |
| Stratification Factor: Low-Density Lipoprotein Cholesterol (LDL-C) Level Missing | 0 participants | 8 participants | 8 participants | 0 participants |
| Total Cholesterol/HDL-C Ratio Part A | NA ratio | 15.988 ratio STANDARD_DEVIATION 5.107 | 15.988 ratio STANDARD_DEVIATION 5.107 | NA ratio |
| Total Cholesterol/HDL-C Ratio Part B | 11.972 ratio STANDARD_DEVIATION 6.387 | 12.014 ratio STANDARD_DEVIATION 6.395 | NA ratio | 12.101 ratio STANDARD_DEVIATION 6.619 |
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 | 4 / 8 | 10 / 16 | 11 / 33 |
| serious Total, serious adverse events | 0 / 8 | 0 / 16 | 0 / 33 |
Outcome results
Primary
Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C was quantified using the ultracentrifugation method.
Time frame: Baseline and Week 12
Population: Part A full analysis set (all enrolled participants who received at least 1 dose of evolocumab)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -16.5 percent change | Standard Error 6.7 |
Primary
Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
LDL-C was quantified using the ultracentrifugation method.
Time frame: Baseline and Week 12
Population: Part B full analysis set (all enrolled participants who received at least 1 dose of investigational product)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | 7.88 percent change | Standard Error 5.26 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 12 | -23.05 percent change | Standard Error 3.78 |
Comparison: LDL-C lowering was analyzed by comparing evolocumab and placebo. Statistical analysis was 2-sided with a significance level of 0.05.p-value: <0.00195% CI: [-43.86, -18]Repeated measures linear effects model
Secondary
Part A: Change From Baseline in LDL-C at Week 12
LDL-C was quantified using the ultracentrifugation method.
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Change From Baseline in LDL-C at Week 12 | -70.6 mg/dL | Standard Error 32.3 |
Secondary
Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Change From Baseline in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) at Week 12 | -151.3 ng/mL | Standard Error 81.7 |
Secondary
Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12
LDL-C was quantified using the ultracentrifugation method.
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Evolocumab | Part A: Percentage of Participants With 15% or Greater Reduction in LDL-C From Baseline at Week 12 | 50.0 percentage of participants |
Secondary
Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 12 | -15.65 percent change | Standard Error 4.69 |
Secondary
Part A: Percent Change From Baseline in Apolipoprotein B at Week 12
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Percent Change From Baseline in Apolipoprotein B at Week 12 | -14.9 percent change | Standard Error 5 |
Secondary
Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12 | -16.6 percent change | Standard Error 6.5 |
Secondary
Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12
Time frame: Baseline and Week 12
Population: Part A full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part A: Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12 | -18.319 percent change | Standard Error 6.058 |
Secondary
Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12
Time frame: Baseline and Weeks 6 and 12
Population: Part B full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12 | 2.65 percent change | Standard Error 4.42 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 6 and 12 | -20.24 percent change | Standard Error 3.18 |
p-value: <0.00195% CI: [-33.72, -12.05]Repeated measures linear effects model
Secondary
Part B: Percent Change From Baseline in Apolipoprotein B at Week 12
Time frame: Baseline and Week 12
Population: Part B full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 | 3.97 percent change | Standard Error 4.74 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in Apolipoprotein B at Week 12 | -19.17 percent change | Standard Error 3.46 |
p-value: <0.00195% CI: [-34.83, -11.45]Repeated measures linear effects model
Secondary
Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12
LDL-C was quantified using the ultracentrifugation method.
Time frame: Baseline and Weeks 6 and 12
Population: Part B full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12 | 4.22 percent change | Standard Error 4.56 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in LDL-C at the Mean of Weeks 6 and 12 | -25.56 percent change | Standard Error 3.28 |
p-value: <0.00195% CI: [-40.94, -18.62]Repeated measures linear effects model
Secondary
Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12
Time frame: Baseline and Weeks 6 and 12
Population: Part B full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12 | -1.43 percent change | Standard Error 4.78 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in Lipoprotein (a) at the Mean of Weeks 6 and 12 | -12.71 percent change | Standard Error 3.53 |
p-value: 0.08895% CI: [-23.11, 0.56]Repeated measures linear effects
Secondary
Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12
Time frame: Baseline and Week 12
Population: Part B full anlaysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Evolocumab | Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 | 2.43 percent change | Standard Error 5.49 |
| Part B: Evolocumab | Part B: Percent Change From Baseline in Lipoprotein (a) at Week 12 | -9.40 percent change | Standard Error 4.07 |
p-value: 0.08895% CI: [-25.48, 1.82]Repeated measures linear effects model