Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody
- Conditions
- Primary Hyperlipidemia and Mixed Dyslipidemia
- Interventions
- Registration Number
- NCT02189837
- Lead Sponsor
- Amgen
- Brief Summary
This is a randomized, double-blind, placebo-controlled trial to evaluate the effect of evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 89
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo to Evolocumab 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. Placebo Placebo to Atorvastatin 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. Atorvastatin 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. Atorvastatin Placebo to Evolocumab 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. Evolocumab 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. Evolocumab Placebo to Atorvastatin 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. Evolocumab and Atorvastatin Evolocumab 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. Evolocumab and Atorvastatin 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
Trial Locations
- Locations (1)
Research Site
🇦🇺Nedlands, Western Australia, Australia