Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled trial to evaluate the effect of evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics.

Official Title
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Double-blind, Randomized, Placebo-controlled, Single Site Study to Evaluate the Effects of Evolocumab (AMG 145) Treatment, Alone and in Combination With Atorvastatin, on Lipoprotein Kinetics

Conditions
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Primary Hyperlipidemia and Mixed Dyslipidemia

Intervention / Treatment
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* Biological: Evolocumab
* Drug: Atorvastatin
* Drug: Placebo to Evolocumab
* Drug: Placebo to Atorvastatin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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. | Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>Drug: Placebo to Atorvastatin<br>* Administered by mouth<br>|
| Active Comparator: Atorvastatin<br>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. | Drug: Atorvastatin<br>* Administered by mouth<br>* Other names: LIPITOR®;Drug: Placebo to Evolocumab<br>* Administered by subcutaneous injection<br>|
| Experimental: Evolocumab<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Placebo to Atorvastatin<br>* Administered by mouth<br>|
| Experimental: Evolocumab and Atorvastatin<br>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. | Biological: Evolocumab<br>* Administered by subcutaneous injection<br>* Other names: Repatha;Drug: Atorvastatin<br>* Administered by mouth<br>* Other names: LIPITOR®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in LDL-C at Day 50 | LDL-C was measured using ultrcentrifugation. | Baseline and Day 50 | 
| 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. | Baseline and Day 50 | 
| 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. | 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. | 
| 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. | Baseline and Day 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Raised cholesterol, Cholesterol, Elevated Cholesterol, Hyperlipidemias, Dyslipidemias, Lipid Metabolism Disorders, Metabolic Diseases