Primary Hyperlipidemia and Mixed Dyslipidemia
Conditions
Keywords
Raised cholesterol, Cholesterol, Elevated Cholesterol, Hyperlipidemias, Dyslipidemias, Lipid Metabolism Disorders, Metabolic Diseases
Brief summary
This is a randomized, double-blind, placebo-controlled trial to evaluate the effect of evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics.
Interventions
BIOLOGICALEvolocumab
Administered by subcutaneous injection
DRUGAtorvastatin
Administered by mouth
Administered by subcutaneous injection
Administered by mouth
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Fasting LDL-C at screening ≥ 100 mg/dL and ≤ 190 mg/dL * Fasting triglycerides ≤ 150 mg/dL * Body mass index (BMI) between 18.0 and 32.0 kg/m\^2 * Framingham cardiac risk score 10% or less
Exclusion criteria
* Treatment with a lipid-regulating drug or over the counter supplement in the last 3 months prior to screening * History of coronary heart disease (CHD) or CHD equivalent * Uncontrolled hypertension * Diabetes mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR) | Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration. | The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in LDL-C at Day 50 | Baseline and Day 50 | LDL-C was measured using ultrcentrifugation. |
| Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR) | Baseline and Day 50 | The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate. |
| Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR) | Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration. | The fractional catabolic rate (the percentage of lipoprotein(a) (Lp\[a\]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism. |
| Percent Change From Baseline in Lipoprotein(a) Production Rate (PR) | Baseline and Day 50 | The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism. |
Countries
Australia
Participant flow
Recruitment details
This study was conducted at 2 centers in Australia. The first participant was enrolled on 08 July 2014, and the last participant enrolled on 15 December 2014.
Pre-assignment details
Participants who met eligibility criteria underwent an initial 4 week run-in period of dietary stabilization before randomization. Randomization was stratified based on screening low-density lipoprotein (LDL-C) concentration (\< 130 mg/dL vs ≥ 130 mg/dL)
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks. | 21 |
| Atorvastatin Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks. | 22 |
| Evolocumab Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks. | 22 |
| Evolocumab and Atorvastatin Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks. | 20 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Sponsor Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Evolocumab and Atorvastatin | Evolocumab | Atorvastatin |
|---|---|---|---|---|---|
| Age, Continuous | 33.9 years STANDARD_DEVIATION 12.7 | 32.2 years STANDARD_DEVIATION 10.5 | 31.0 years STANDARD_DEVIATION 9.8 | 33.5 years STANDARD_DEVIATION 11.6 | 30.4 years STANDARD_DEVIATION 7.4 |
| LDL-C Concentration | 118.1 mg/dL STANDARD_DEVIATION 18.1 | 119.1 mg/dL STANDARD_DEVIATION 20.2 | 116.5 mg/dL STANDARD_DEVIATION 23.7 | 118.2 mg/dL STANDARD_DEVIATION 18.4 | 123.2 mg/dL STANDARD_DEVIATION 21.3 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 7 participants | 3 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 3 participants | 3 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Mixed Race | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 19 participants | 73 participants | 14 participants | 20 participants | 20 participants |
| Screening LDL-C Level < 130 mg/dL | 9 participants | 35 participants | 8 participants | 9 participants | 9 participants |
| Screening LDL-C Level ≥ 130 mg/dL | 12 participants | 50 participants | 12 participants | 13 participants | 13 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 21 Participants | 85 Participants | 20 Participants | 22 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 21 | 12 / 22 | 14 / 22 | 10 / 20 |
| serious Total, serious adverse events | 0 / 21 | 0 / 22 | 0 / 22 | 1 / 20 |
Outcome results
Primary
Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)
The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
Time frame: Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.
Population: Efficacy Analysis Set including all randomized and dosed participants who completed baseline and Day 50 measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR) | -5.07 percent change | Standard Error 26.06 |
| Atorvastatin | Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR) | 74.13 percent change | Standard Error 24.84 |
| Evolocumab | Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR) | 83.70 percent change | Standard Error 26.06 |
| Evolocumab and Atorvastatin | Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR) | 310.48 percent change | Standard Error 26.68 |
Comparison: The superiority of evolocumab monotherapy to placebo was tested using a 2-sided p-value at a significance level of 0.05.p-value: 0.01895% CI: [15.73, 161.8]ANCOVA
Comparison: The treatment effect of evolocumab plus atorvastatin compared with placebo plus atorvastatin was estimated and a nominal p-value is provided.p-value: <0.00195% CI: [164.02, 308.69]ANCOVA
Comparison: To assess whether the treatment effect of evolocumab compared with placebo depended on being administered alone or combined with atorvastatin, the interaction was tested, i.e., the difference between the treatment difference versus the respective placebo group for the evolocumab+atorvastatin group and the evolocumab group was calculated.p-value: 0.00595% CI: [44.8, 250.38]ANCOVA
Secondary
Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)
The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate.
Time frame: Baseline and Day 50
Population: Efficacy Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR) | -3.80 percent change | Standard Error 7.4 |
| Atorvastatin | Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR) | -3.27 percent change | Standard Error 7.05 |
| Evolocumab | Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR) | -20.45 percent change | Standard Error 7.4 |
| Evolocumab and Atorvastatin | Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR) | -35.93 percent change | Standard Error 7.57 |
p-value: 0.1195% CI: [-37.37, 4.08]ANCOVA
p-value: 0.00295% CI: [-53.19, -12.13]ANCOVA
p-value: 0.2895% CI: [-45.18, 13.16]ANCOVA
Secondary
Percent Change From Baseline in LDL-C at Day 50
LDL-C was measured using ultrcentrifugation.
Time frame: Baseline and Day 50
Population: Efficacy Analysis Set with available data at both time points
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in LDL-C at Day 50 | -0.65 percent change | Standard Error 3.09 |
| Atorvastatin | Percent Change From Baseline in LDL-C at Day 50 | -45.25 percent change | Standard Error 2.86 |
| Evolocumab | Percent Change From Baseline in LDL-C at Day 50 | -57.79 percent change | Standard Error 3.15 |
| Evolocumab and Atorvastatin | Percent Change From Baseline in LDL-C at Day 50 | -83.19 percent change | Standard Error 3.24 |
p-value: <0.00195% CI: [-65.91, -48.38]ANCOVA
p-value: <0.00195% CI: [-46.55, -29.34]ANCOVA
p-value: 0.00395% CI: [6.93, 31.47]ANCOVA
Secondary
Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)
The fractional catabolic rate (the percentage of lipoprotein(a) (Lp\[a\]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
Time frame: Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.
Population: Efficacy Analysis Set with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR) | 7.49 percent change | Standard Error 9.17 |
| Atorvastatin | Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR) | 25.52 percent change | Standard Error 8.92 |
| Evolocumab | Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR) | 5.37 percent change | Standard Error 9.81 |
| Evolocumab and Atorvastatin | Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR) | 64.57 percent change | Standard Error 9.23 |
Comparison: The superiority of evolocumab monotherapy to placebo was tested using a 2-sided p-value at a significance level of 0.05.p-value: 0.8795% CI: [-28.94, 24.7]ANCOVA
Comparison: The treatment effect of evolocumab plus atorvastatin compared with placebo plus atorvastatin was estimated and a nominal p-value is provided.p-value: 0.00395% CI: [13.52, 64.59]ANCOVA
Comparison: To assess whether the treatment effect of evolocumab compared with placebo depended on being administered alone or combined with atorvastatin, the interaction was tested, i.e., the difference between the treatment difference versus the respective placebo group for the evolocumab+atorvastatin group and the evolocumab group was calculated.p-value: 0.0395% CI: [4.15, 78.2]ANCOVA
Secondary
Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)
The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
Time frame: Baseline and Day 50
Population: Efficacy Analysis Set with available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Lipoprotein(a) Production Rate (PR) | 3.52 percent change | Standard Error 7.94 |
| Atorvastatin | Percent Change From Baseline in Lipoprotein(a) Production Rate (PR) | -6.88 percent change | Standard Error 7.72 |
| Evolocumab | Percent Change From Baseline in Lipoprotein(a) Production Rate (PR) | -35.91 percent change | Standard Error 8.49 |
| Evolocumab and Atorvastatin | Percent Change From Baseline in Lipoprotein(a) Production Rate (PR) | 16.40 percent change | Standard Error 7.99 |
p-value: 0.03995% CI: [1.16, 45.4]ANCOVA
p-value: 0.00195% CI: [-62.66, -16.21]ANCOVA
p-value: <0.00195% CI: [30.65, 94.79]ANCOVA