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Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody (FLOREY)

Primary Purpose

Primary Hyperlipidemia and Mixed Dyslipidemia

Status
Completed
Phase
Phase 3
Locations
Australia
Study Type
Interventional
Intervention
Evolocumab
Atorvastatin
Placebo to Evolocumab
Placebo to Atorvastatin
Sponsored by
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Hyperlipidemia and Mixed Dyslipidemia focused on measuring Raised cholesterol, Cholesterol, Elevated Cholesterol, Hyperlipidemias, Dyslipidemias, Lipid Metabolism Disorders, Metabolic Diseases

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Research Site
  • Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Experimental

Experimental

Arm Label

Placebo

Atorvastatin

Evolocumab

Evolocumab and Atorvastatin

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Percent Change From Baseline in LDL-C at Day 50
LDL-C was measured using ultrcentrifugation.
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.
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.
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.

Full Information

First Posted
July 8, 2014
Last Updated
September 6, 2018
Sponsor
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT02189837
Brief Title
Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody
Acronym
FLOREY
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
July 8, 2014 (Actual)
Primary Completion Date
February 13, 2015 (Actual)
Study Completion Date
March 5, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Hyperlipidemia and Mixed Dyslipidemia
Keywords
Raised cholesterol, Cholesterol, Elevated Cholesterol, Hyperlipidemias, Dyslipidemias, Lipid Metabolism Disorders, Metabolic Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
89 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Atorvastatin
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Evolocumab
Arm Type
Experimental
Arm Description
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.
Arm Title
Evolocumab and Atorvastatin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Evolocumab
Other Intervention Name(s)
AMG 145, Repatha
Intervention Description
Administered by subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Other Intervention Name(s)
LIPITOR®
Intervention Description
Administered by mouth
Intervention Type
Drug
Intervention Name(s)
Placebo to Evolocumab
Intervention Description
Administered by subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Placebo to Atorvastatin
Intervention Description
Administered by mouth
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)
Description
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.
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in LDL-C at Day 50
Description
LDL-C was measured using ultrcentrifugation.
Time Frame
Baseline and Day 50
Title
Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)
Description
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
Title
Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)
Description
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.
Title
Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)
Description
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

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Facility Name
Research Site
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia

12. IPD Sharing Statement

Citations:
PubMed Identifier
27941065
Citation
Watts GF, Chan DC, Dent R, Somaratne R, Wasserman SM, Scott R, Burrows S, R Barrett PH. Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism. Circulation. 2017 Jan 24;135(4):338-351. doi: 10.1161/CIRCULATIONAHA.116.025080. Epub 2016 Dec 9.
Results Reference
background
PubMed Identifier
29566128
Citation
Watts GF, Chan DC, Somaratne R, Wasserman SM, Scott R, Marcovina SM, Barrett PHR. Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics. Eur Heart J. 2018 Jul 14;39(27):2577-2585. doi: 10.1093/eurheartj/ehy122. Erratum In: Eur Heart J. 2019 Jan 1;40(1):58.
Results Reference
background
PubMed Identifier
29880491
Citation
Chan DC, Watts GF, Somaratne R, Wasserman SM, Scott R, Barrett PHR. Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1644-1655. doi: 10.1161/ATVBAHA.118.310882. Epub 2018 Jun 7.
Results Reference
background
PubMed Identifier
30897995
Citation
Chan DC, Watts GF, Coll B, Wasserman SM, Marcovina SM, Barrett PHR. Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy. J Am Heart Assoc. 2019 Apr 2;8(7):e011781. doi: 10.1161/JAHA.118.011781.
Results Reference
derived
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website

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Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody

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