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| ID | Type | Description | Link |
|---|---|---|---|
| FLOREY | Other Identifier | Amgen |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 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 | Active Comparator | 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 | Experimental | 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 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evolocumab | Biological | Administered by subcutaneous injection |
|
| 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. |
| 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) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| MD | Amgen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Adelaide | South Australia | 5000 | Australia | ||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27941065 | Background | 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. | |
| 29566128 | Background | 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. |
| Label | URL |
|---|---|
| AmgenTrials clinical trials website | View source |
Not provided
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)
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The full analysis set includes all randomized participants who received any study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | Atorvastatin |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Efficacy Analysis Set including all randomized and dosed participants who completed baseline and Day 50 measurements. | Posted | Least Squares Mean | Standard Error | percent change | 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. |
|
From first dose of study drug until day 73
Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Liver injury | Hepatobiliary disorders | MedDRA 17.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA 17.1 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Amgen Inc. | 866-572-6436 |
Not provided
| ID | Term |
|---|---|
| D006937 | Hypercholesterolemia |
| D006949 | Hyperlipidemias |
| D050171 | Dyslipidemias |
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
| ID | Term |
|---|---|
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C577155 | evolocumab |
| D000069059 | Atorvastatin |
| ID | Term |
|---|---|
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
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| Atorvastatin | Drug | Administered by mouth |
|
|
| Placebo to Evolocumab | Drug | Administered by subcutaneous injection |
|
| Placebo to Atorvastatin | Drug | Administered by mouth |
|
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 |
| Nedlands |
| Western Australia |
| 6009 |
| Australia |
| 29880491 | Background | 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. |
| 30897995 | Derived | 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. |
| Sponsor Decision |
|
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.
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Screening LDL-C Level | Number | participants |
|
| LDL-C Concentration | LDL-C was measured using ultracentrifugation | Mean | Standard Deviation | mg/dL |
|
| 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. |
| OG001 | 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. |
| OG002 | 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. |
| OG003 | 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. |
|
|
|
| Secondary | Percent Change From Baseline in LDL-C at Day 50 | LDL-C was measured using ultrcentrifugation. | Efficacy Analysis Set with available data at both time points | Posted | Least Squares Mean | Standard Error | percent change | Baseline and Day 50 |
|
|
|
|
| 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. | Efficacy Analysis Set | Posted | Least Squares Mean | Standard Error | percent change | Baseline and Day 50 |
|
|
|
|
| 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. | Efficacy Analysis Set with available data | Posted | Least Squares Mean | Standard Error | percent change | 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 | 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. | Efficacy Analysis Set with available data | Posted | Least Squares Mean | Standard Error | percent change | Baseline and Day 50 |
|
|
|
|
| 0 |
| 21 |
| 5 |
| 21 |
| EG001 | 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. | 0 | 22 | 12 | 22 |
| EG002 | 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. | 0 | 22 | 14 | 22 |
| EG003 | 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. | 1 | 20 | 10 | 20 |
| Nausea | Gastrointestinal disorders | MedDRA 17.1 | Systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA 17.1 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 17.1 | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA 17.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 17.1 | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA 17.1 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 17.1 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 17.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 17.1 | Systematic Assessment |
|
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
| D006538 |
| Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| ANCOVA |
Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. |
| <0.001 |
| LS Mean Treatment Difference |
| -37.95 |
| Standard Error of the Mean |
| 4.31 |
| 2-Sided |
| 95 |
| -46.55 |
| -29.34 |
| Superiority or Other |
| ANCOVA | Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. | 0.003 | Treatment Effect | 19.20 | Standard Error of the Mean | 6.15 | 2-Sided | 95 | 6.93 | 31.47 | Superiority or Other |
| ANCOVA |
Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. |
| 0.002 |
| LS Mean Treatment Difference |
| -32.66 |
| Standard Error of the Mean |
| 10.31 |
| 2-Sided |
| 95 |
| -53.19 |
| -12.13 |
| Superiority or Other |
| ANCOVA | Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. | 0.28 | Treatment Effect | -16.01 | Standard Error of the Mean | 14.65 | 2-Sided | 95 | -45.18 | 13.16 | Superiority or Other |
|
The treatment effect of evolocumab plus atorvastatin compared with placebo plus atorvastatin was estimated and a nominal p-value is provided. |
| ANCOVA |
Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. |
| 0.003 |
| LS Mean Treatment Difference |
| 39.06 |
| Standard Error of the Mean |
| 12.76 |
| 2-Sided |
| 95 |
| 13.52 |
| 64.59 |
| Superiority or Other |
| 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. | ANCOVA | Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. | 0.030 | Treatment Effect | 41.18 | Standard Error of the Mean | 18.50 | 2-Sided | 95 | 4.15 | 78.20 | Superiority or Other |
| ANCOVA |
Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. |
| 0.039 |
| LS Mean Treatment Difference |
| 23.28 |
| Standard Error of the Mean |
| 11.05 |
| 2-Sided |
| 95 |
| 1.16 |
| 45.40 |
| Superiority or Other |
| ANCOVA | Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level. | <0.001 | Treatment Effect | 62.72 | Standard Error of the Mean | 16.02 | 2-Sided | 95 | 30.65 | 94.79 | Superiority or Other |