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The purpose of this study is to determine if bempedoic acid (ETC-1002) 180mg added to PCSK9 inhibitor (evolocumab) therapy is effective and safe in patients with elevated LDL cholesterol.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| bempedoic acid | Experimental | Bempedoic acid 180mg tablet taken orally, once daily plus evolocumab (Repatha) 420mg injection once monthly |
|
| placebo | Placebo Comparator | Matching placebo tablet taken orally, once daily plus evolocumab (Repatha) 420mg injection once monthly |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| bempedoic acid 180mg | Drug | Daily bempedoic acid 180mg tablet in addition to monthly PCSK9i (evolocumab) background therapy |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the average of the last two non-missing values within Month -1 (Screening Visit 4) and Day 1 (Treatment Visit 1) values (including unscheduled assessments). If only one value was available, then that single value was used at Baseline. Percent change from Baseline was analyzed using analysis of covariance (ANCOVA), with treatment group as a factor and Baseline as a covariate. Missing data were imputed using last observation carried forward (LOCF) (only post-Baseline values were carried forward). | Baseline; Month 2 |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline in LDL-C at Month 1 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the average of the last two non-missing values within Month -1 (Screening Visit 4) and Day 1 (Treatment Visit 1) values (including unscheduled assessments). If only one value was available, then that single value was used at Baseline. Percent change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Ron Haberman, MD | Esperion Therapeutics, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| L-MARC Research Center | Louisville | Kentucky | 40213 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27892461 | Background | Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, Birch CM, Smith BK, Filippov S, Groot PHE, Steinberg GR, Lalwani ND. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016 Nov 28;7:13457. doi: 10.1038/ncomms13457. | |
| 24222016 | Background |
| Label | URL |
|---|---|
| World Health Organization Fact Sheet No. 317 | View source |
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170 participants were screened; out of 170, 59 participants were randomized. One participant never received study medication and withdrew from the study due to the Sponsor's decision.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Plus Evolocumab | Participants received a matching oral placebo tablet taken once a day, plus evolocumab 420 milligrams (mg) injected over 9 minutes once a month as background therapy. |
| FG001 | Bempedoic Acid Plus Evolocumab | Participants received a bempedoic acid 180 mg tablet orally once a day (with or without food), plus evolocumab 420 mg injected once a month over 9 minutes as background therapy. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety population included all randomized participants who received at least 1 dose of study medication. Participants in this group were included in the treatment group that they received, regardless of their randomized treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo Plus Evolocumab | Participants received a matching oral placebo tablet taken once a day, plus evolocumab 420 milligrams (mg) injected over 9 minutes once a month as background therapy. |
| BG001 | Bempedoic Acid Plus Evolocumab |
| 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 Cholesterol (LDL-C) at Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the average of the last two non-missing values within Month -1 (Screening Visit 4) and Day 1 (Treatment Visit 1) values (including unscheduled assessments). If only one value was available, then that single value was used at Baseline. Percent change from Baseline was analyzed using analysis of covariance (ANCOVA), with treatment group as a factor and Baseline as a covariate. Missing data were imputed using last observation carried forward (LOCF) (only post-Baseline values were carried forward). | Modified Intent-to-Treat (mITT) Population: all randomized participants with a Baseline lipid value and at least 1 post-Baseline lipid value who received investigational medicinal product (IMP) within 2 days before the lipid measurement and evolocumab 420 mg within 30 days plus or minus 3 days before the lipid measurement | Posted | Least Squares Mean | Standard Error | percent change | Baseline; Month 2 |
|
up to Month 2 (until 30 days after last dose)
Treatment-emergent adverse events (TEAEs) and serious TEAEs, defined as those events that began or worsened after the first dose of investigational medicinal product (IMP) until 30 days after the last dose of IMP, were reported for the Safety Population.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Plus Evolocumab | Participants received a matching oral placebo tablet taken once a day, plus evolocumab 420 milligrams (mg) injected over 9 minutes once a month as background therapy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Influenza | Infections and infestations | MedDRA 20.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspepsia | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Esperion Therapeutics, Inc. | 1-833-377-7633 | medinfo@esperion.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 5, 2017 | Mar 12, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 25, 2018 | Mar 12, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006937 | Hypercholesterolemia |
| ID | Term |
|---|---|
| D006949 | Hyperlipidemias |
| D050171 | Dyslipidemias |
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
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| ID | Term |
|---|---|
| C581236 | 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid |
| C577155 | evolocumab |
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| placebo | Other | Daily matching placebo tablet in addition to monthly PCSK9i (evolocumab) background therapy |
|
| evolocumab | Drug | Monthly PCSK9i (evolocumab) background therapy |
|
|
| Baseline; Month 1 |
| Absolute Change From Baseline in LDL-C at Month 1 and Month 2 | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the average of the Screening Visit 4 and the Day 1 value. If only 1 value is available, then that single value is used as Baseline. Change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis at Month 1. Missing Month 2 data were handled by LOCF. | Baseline; Month 1 and Month 2 |
| Percent Change From Baseline in Lipid Profile Parameters at Month 1 and Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline apolipoprotein B (apoB) is defined as the Day 1 value. Baseline total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) are defined as the average of the Month -1 (Screening Visit 4) and the Day 1 (Treatment Visit 1) values. If a missing value presented at Month -1 or Day 1, then the last non-missing value prior to the first dose of double-blind study medication (including unscheduled assessments) within Month -1 and Day 1 was used to compute the Baseline measurements. Percent change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis at Month 1. Missing Month 2 data were handled by LOCF. | Baseline; Month 1 and Month 2 |
| Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) at Month 1 and Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the Day 1 value. Percent change from Baseline was analyzed using a non-parametric approach. Missing Month 2 data were handled by LOCF. Observed data were used for analysis at Month 1. | Baseline; Month 1 and Month 2 |
| Number of Participants With Any Treatment-emergent Adverse Event (AE) and Treatment-emergent Serious Adverse Event (SAE) | Treatment-emergent AEs (TEAEs) and SAEs (TESAEs) were reported and defined as any AE that began or worsened after the first dose of investigational medicinal product. | up to Month 2 (until 30 days after last dose) |
| Number of Participants With Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) >3x the Upper Limit of Normal (ULN) at Month 1 and Month 2 | The number of participants with ALT or AST >3x ULN was measured. | Month 1 and Month 2 |
| Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a. Epub 2013 Nov 12. No abstract available. |
| 11535564 | Background | Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W; Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001 Sep 4;104(10):1108-13. doi: 10.1161/hc3501.095214. |
| 12672737 | Background | Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003 Apr 2;289(13):1681-90. doi: 10.1001/jama.289.13.1681. |
Participants received a bempedoic acid 180 mg tablet orally once a day (with or without food), plus evolocumab 420 mg injected over 9 minutes once a month as background therapy.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Baseline Low-Density Lipoprotein Cholesterol (L-DLC) Values | Baseline LDL-C is defined as the average of the Month -1 (Screening Visit 4) and Day 1 values. If only 1 value was available, then that single value was used as Baseline. | Mean | Standard Deviation | milligrams per deciliter (mg/dL) |
|
| Baseline Total Cholesterol (TC) and Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) Values | Baseline TC and non-HDL-C are defined as the average of the Month -1 (Screening Visit 4) and the Day 1 (Treatment Visit 1) values. If a missing value presented at Month -1 or Day 1, then the last non-missing value prior to the first dose of double-blind study medication (including unscheduled assessments) within Month -1 and Day 1 was used to compute the Baseline measurements. | Mean | Standard Deviation | mg/dL |
|
| Baseline Apolipoprotein B (apoB) Values | Baseline values are defined as the Day 1 value. If a missing value presented at Day 1, then the last non-missing value prior to the first dose of double-blind study medication (including unscheduled assessments) within Month -1 and Day 1 was used to compute the Baseline measurements. | Only those participants with data available were analyzed. | Mean | Standard Deviation | mg/dL |
|
| Baseline High-Sensitivity C-Reactive Protein (hs-CRP) Values | Baseline values are defined as the Day 1 value. If a missing value presented at Day 1, then the last non-missing value prior to the first dose of double-blind study medication (including unscheduled assessments) within Month -1 and Day 1 was used to compute the Baseline measurements. | Only those participants with data available were analyzed. | Median | Inter-Quartile Range | milligrams per Liter |
|
| Title |
|---|
| Description |
|---|
| OG000 | Placebo Plus Evolocumab | Participants received a matching oral placebo tablet taken once a day, plus evolocumab 420 milligrams (mg) injected over 9 minutes once a month as background therapy. |
| OG001 | Bempedoic Acid Plus Evolocumab | Participants received a bempedoic acid 180 mg tablet orally once a day (with or without food), plus evolocumab 420 mg injected over 9 minutes once a month as background therapy. |
|
|
|
| Secondary | Percent Change From Baseline in LDL-C at Month 1 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the average of the last two non-missing values within Month -1 (Screening Visit 4) and Day 1 (Treatment Visit 1) values (including unscheduled assessments). If only one value was available, then that single value was used at Baseline. Percent change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis. | Modified Intent-to-Treat Population. Only those participants with data available were analyzed. | Posted | Least Squares Mean | Standard Error | percent change | Baseline; Month 1 |
|
|
|
|
| Secondary | Absolute Change From Baseline in LDL-C at Month 1 and Month 2 | Change from Baseline is calculated as the post-Baseline value minus the Baseline value. Baseline is defined as the average of the Screening Visit 4 and the Day 1 value. If only 1 value is available, then that single value is used as Baseline. Change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis at Month 1. Missing Month 2 data were handled by LOCF. | Modified Intent-to-Treat Population. Only those participants with data available were analyzed. | Posted | Least Squares Mean | Standard Error | milligrams per deciliter (mg/dL) | Baseline; Month 1 and Month 2 |
|
|
|
|
| Secondary | Percent Change From Baseline in Lipid Profile Parameters at Month 1 and Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline apolipoprotein B (apoB) is defined as the Day 1 value. Baseline total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) are defined as the average of the Month -1 (Screening Visit 4) and the Day 1 (Treatment Visit 1) values. If a missing value presented at Month -1 or Day 1, then the last non-missing value prior to the first dose of double-blind study medication (including unscheduled assessments) within Month -1 and Day 1 was used to compute the Baseline measurements. Percent change from Baseline was analyzed using ANCOVA, with treatment group as a factor and Baseline as a covariate. Observed data were used for analysis at Month 1. Missing Month 2 data were handled by LOCF. | mITT Population | Posted | Least Squares Mean | Standard Error | percent change | Baseline; Month 1 and Month 2 |
|
|
|
|
| Secondary | Percent Change From Baseline in High-sensitivity C-reactive Protein (Hs-CRP) at Month 1 and Month 2 | Percent change from Baseline is calculated as the ([post-Baseline value minus the Baseline value] divided by the Baseline value ) x 100. Baseline is defined as the Day 1 value. Percent change from Baseline was analyzed using a non-parametric approach. Missing Month 2 data were handled by LOCF. Observed data were used for analysis at Month 1. | Modified Intent-to-Treat Population. Only those participants with data available were analyzed. | Posted | Median | Inter-Quartile Range | percent change | Baseline; Month 1 and Month 2 |
|
|
|
|
| Secondary | Number of Participants With Any Treatment-emergent Adverse Event (AE) and Treatment-emergent Serious Adverse Event (SAE) | Treatment-emergent AEs (TEAEs) and SAEs (TESAEs) were reported and defined as any AE that began or worsened after the first dose of investigational medicinal product. | Safety Population: all randomized participants who received at least 1 dose of IMP. Participants in the Safety Population were included in the treatment group that they received, regardless of their randomized treatment. | Posted | Count of Participants | Participants | up to Month 2 (until 30 days after last dose) |
|
|
|
| Secondary | Number of Participants With Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) >3x the Upper Limit of Normal (ULN) at Month 1 and Month 2 | The number of participants with ALT or AST >3x ULN was measured. | Safety Population. Only those participants with available data were analyzed. | Posted | Count of Participants | Participants | Month 1 and Month 2 |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 7 |
| 30 |
| EG001 | Bempedoic Acid Plus Evolocumab | Participants received a bempedoic acid 180 mg tablet orally once a day (with or without food), plus evolocumab 420 mg injected over 9 minutes once a month as background therapy. | 0 | 28 | 1 | 28 | 8 | 28 |
| Dysphagia | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
|
| Injection site reaction | General disorders | MedDRA 20.1 | Systematic Assessment |
|
| Pyelonephritis acute | Infections and infestations | MedDRA 20.1 | Systematic Assessment |
|
| Tooth infection | Infections and infestations | MedDRA 20.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 20.1 | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA 20.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 20.1 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 20.1 | Systematic Assessment |
|
| Amnesia | Nervous system disorders | MedDRA 20.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 20.1 | Systematic Assessment |
|
| Ejaculation failure | Reproductive system and breast disorders | MedDRA 20.1 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 20.1 | Systematic Assessment |
|
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA 20.1 | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 20.1 | Systematic Assessment |
|
If the Principal Investigator plans to publish information from the study, a copy of the manuscript should be provided to the Sponsor for review before submission for publication or presentation. The Sponsor may request that that publication be withheld.
| D009750 |
| Nutritional and Metabolic Diseases |
| Month 2 |
|
|
Month 2
| ANCOVA |
| <0.001 |
| Least squares mean difference |
| -29.90 |
| Standard Error of the Mean |
| 5.606 |
| 2-Sided |
| 95 |
| -41.176 |
| -18.626 |
(Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) |
| Superiority |
| non-HDL-C at Month 1 |
|
|
| TC at Month 1 |
|
|
| apo-B at Month 2 |
|
|
| non-HDL-C at Month 2 |
|
|
| TC at Month 2 |
|
|
Apo B at Month 2
| ANCOVA |
| <0.001 |
| Least squares mean difference |
| -24.469 |
| Standard Error of the Mean |
| 4.330 |
| 2-Sided |
| 95 |
| -33.225 |
| -15.713 |
(Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) |
| Superiority |
| non-HDL-C at Month 1 | ANCOVA | <0.001 | Least squares mean difference | -31.640 | Standard Error of the Mean | 4.689 | 2-Sided | 95 | -41.116 | -22.163 | (Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) | Superiority |
| non-HDL-C at Month 2 | ANCOVA | <0.001 | Least squares mean difference | -24.246 | Standard Error of the Mean | 4.838 | 2-Sided | 95 | -33.987 | -14.505 | (Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) | Superiority |
| TC at Month 1 | ANCOVA | <0.001 | Least squares mean difference | -21.941 | Standard Error of the Mean | 3.572 | 2-Sided | 95 | -29.153 | -14.729 | (Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) | Superiority |
| TC at Month 2 | ANCOVA | <0.001 | Least squares mean difference | -17.520 | Standard Error of the Mean | 3.809 | 2-Sided | 95 | -25.201 | -9.839 | (Bempedoic acid plus evolocumab) minus (placebo plus evolocumab) | Superiority |
| hs-CRP at Month 2 |
|
|
hs-CRP at Month 2 |
| Wilcoxon rank sum test |
| 0.029 |
| Median treatment difference |
| -28.512 |
| Standard Error of the Mean |
| 12.124 |
| 2-Sided |
| 95 |
| -51.455 |
| -3.930 |
The median treatment difference (location shift) and the 95% confidence limits are from Hodges-Lehmann estimates. |
| Superiority |
| TEAEs related to evolocumab |
|
| TESAEs |
|
| TESAEs related to IMP |
|
| TESAEs related to evolocumab |
|
| Deaths |
|
| Discontinuation of IMP due to TEAE |
|
| Mild TEAEs |
|
| Moderate TEAEs |
|
| Severe TEAEs |
|
| ALT, Month 2 |
|
|
| AST, Month 1 |
|
|
| AST, Month 2 |
|
|