A Study of LY3015014 in Participants With High Cholesterol

• LY3015014 (Drug): Administered SC
• Placebo (Drug): Administered SC
• Statin (Drug), also known as atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin: Administered orally
• Ezetimibe (Drug): Administered orally

Primary outcomes

• Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) [Baseline, Week 16]: Least square (LS) Means was calculated using analysis of covariance (ANCOVA) adjusted for disease classification, statin dose, baseline LDL-C measurement. Percent change from baseline response is the dependent variable.

Secondary outcomes

• Percentage Change From Baseline in LDL-C, Total Cholesterol (TC), High-Density Lipoprotein Cholesterol (HDL-C), Triglycerides (TG), Non-HDL-C [Baseline, Week 16]: LS Mean was calculated using mixed model repeated measures (MMRM) analysis with baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included in the model. Percent change from baseline response is the dependent variable.
• Percentage Change From Baseline in Apolipoprotein A1 (Apo A1), Apolipoprotein B (Apo B) [Baseline, Week 16]: LS Mean was calculated using MMRM analysis with baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included in the model. Percent change from baseline response is the dependent variable.
• Percentage Change From Baseline in Lipoprotein(a) [Lp(a)] [Baseline, Week 16]: Data was log-transformed for MMRM analysis, with change from baseline as the dependent variable, and baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included as independent variables. Percentage change from baseline in the original scale was then back-calculated from the log-transformed MMRM analysis.
• Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) [Baseline, Week 16]: LS Mean was calculated using MMRM analysis with baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included in the model. Percent change from baseline response is the dependent variable.
• Number of Participants Who Develop Treatment Emergent Anti-LY3015014 Antibodies [Baseline through Week 24]
• Percentage Change From Baseline in Total Proprotein Convertase Subtilisin/Kexin Type 9 Antibody (PCSK9) Levels [Baseline, Week 16]: LS Mean was calculated using MMRM analysis with baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included in the model. Percent change from baseline response is the dependent variable.
• Percentage Change From Baseline in Free Proprotein Convertase Subtilisin/Kexin Type 9 Antibody (PCSK9) Levels [Baseline, Week 16]: LS Mean was calculated using MMRM analysis with baseline measurement, disease classification, statin dose, treatment, visit, and treatment by visit interaction included in the model. Percent change from baseline response is the dependent variable.
• Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady-State (AUC,ss) for LY3015014 [Week 12-16 (Q4W) - Predose, Week 8-16 (Q8W) - Predose]
• Number of Participants With an Injection Site Reaction [Baseline through Week 24]

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* Diagnosed with high low density lipoprotein (LDL) cholesterol
* Are on stable daily dose of a statin or have a history of statin intolerance
* Men with a partner who can become pregnant must agree to use barrier protection during sexual intercourse to prevent pregnancies
* Women who cannot become pregnant, or women who are not pregnant or breast feeding and agree to use a reliable method of birth control to prevent pregnancies

Exclusion Criteria:

* Have high cholesterol due to another disease or have a rare and serious form of hereditary high cholesterol
* Have had recent heart attack, stroke, blood clot or heart surgery, have planned heart or blood vessel surgery, or has a heart that does not pump sufficiently well
* Have poorly controlled high blood pressure
* Have diabetes that requires an injectable medication (including insulin), or have diabetes that is poorly controlled
* Have thyroid blood test that is outside normal range
* Have a history of adrenal gland disorder
* Have a history of vitamin E deficiency or fat malabsorption syndrome
* Have poor kidney function
* Have active liver or gall bladder disease, history of hepatitis or liver blood tests that are high
* Have a history of muscle disease including muscle damage from a medicine or muscle blood test that is high
* Are anemic (low red blood cell counts)
* Have a history of allergy or intolerance to other antibody medications
* Have a history of human immunodeficiency virus infection (HIV) infection
* Are likely to have a major operation or be hospitalized during the study
* Have chronic alcohol or drug abuse or dependency
* Have or suspected to have any cancer or malignant tumor
* Have an active serious infection
* Have started or stopped taking a statin or ezetimibe medication, or changed statin dose regimen recently
* Are on a statin regimen other than daily dosing (for example, an every-other-day statin regimen)
* Have recently used simvastatin (highest dose level), fibrates, bile acid binders, niacin, probucol, or over-the-counter/health food preparations to lower cholesterol (such as red yeast rice, fish oil, omega 3 fatty acid)
* Have undergone LDL apheresis in the past 1 year
* Have recently used steroids, cyclosporine or isotretinoin
* Have recently used an immunosuppressive therapy
* Have recently received treatment with another antibody medication
* Are currently using medications injected into the skin , except for single injections (for example flu vaccines) or injections into muscles
* Are currently on a prescription or over-the-counter medicine for weight loss or are on a very low carbohydrate diet

Participant flow

Outcome results

• Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) (Primary), Least squares mean, Percentage change: Placebo Q4W 7.6 +/- 2.27; 20 mg LY3015014 Q4W -14.9 +/- 2.39; 120 mg LY3015014 Q4W -40.5 +/- 2.31; 300 mg LY3015014 Q4W -50.5 +/- 2.30; 100 mg LY3015014 Q8W -14.9 +/- 2.35; 300 mg LY3015014 Q8W -37.1 +/- 2.44
• Percentage Change From Baseline in LDL-C, Total Cholesterol (TC), High-Density Lipoprotein Cholesterol (HDL-C), Triglycerides (TG), Non-HDL-C (Secondary), Least squares mean, Percentage change: Placebo Q4W 5.9 +/- 2.13; 20 mg LY3015014 Q4W -18.0 +/- 2.18; 120 mg LY3015014 Q4W -46.4 +/- 2.15; 300 mg LY3015014 Q4W -56.5 +/- 2.14; 100 mg LY3015014 Q8W -18.4 +/- 2.14; 300 mg LY3015014 Q8W -42.2 +/- 2.21
• Percentage Change From Baseline in Apolipoprotein A1 (Apo A1), Apolipoprotein B (Apo B) (Secondary), Least squares mean, Percentage change: Placebo Q4W 0.3 +/- 1.40; 20 mg LY3015014 Q4W 2.4 +/- 1.43; 120 mg LY3015014 Q4W 6.5 +/- 1.41; 300 mg LY3015014 Q4W 6.2 +/- 1.41; 100 mg LY3015014 Q8W 3.8 +/- 1.43; 300 mg LY3015014 Q8W 5.8 +/- 1.44
• Percentage Change From Baseline in Lipoprotein(a) [Lp(a)] (Secondary), Least squares mean, Percentage Change: Placebo Q4W -0.31 +/- 0.0436; 20 mg LY3015014 Q4W -16.63 +/- 0.0442; 120 mg LY3015014 Q4W -19.02 +/- 0.0427; 300 mg LY3015014 Q4W -37.29 +/- 0.0420; 100 mg LY3015014 Q8W -7.54 +/- 0.0427; 300 mg LY3015014 Q8W -21.01 +/- 0.0437
• Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) (Secondary), Least squares mean, Percentage change: Placebo Q4W 0.5 +/- 0.70; 20 mg LY3015014 Q4W -0.2 +/- 0.72; 120 mg LY3015014 Q4W 1.6 +/- 0.69; 300 mg LY3015014 Q4W -0.3 +/- 0.70; 100 mg LY3015014 Q8W -0.3 +/- 0.70; 300 mg LY3015014 Q8W -0.7 +/- 0.72
• Number of Participants Who Develop Treatment Emergent Anti-LY3015014 Antibodies (Secondary), Number, Participants: Placebo Q4W 4; 20 mg LY3015014 Q4W 6; 120 mg LY3015014 Q4W 10; 300 mg LY3015014 Q4W 5; 100 mg LY3015014 Q8W 4; 300 mg LY3015014 Q8W 3
• Percentage Change From Baseline in Total Proprotein Convertase Subtilisin/Kexin Type 9 Antibody (PCSK9) Levels (Secondary), Least squares mean, Percentage change: Placebo Q4W 14.6 +/- 13.66; 20 mg LY3015014 Q4W 9.1 +/- 14.00; 120 mg LY3015014 Q4W 86.4 +/- 13.65; 300 mg LY3015014 Q4W 130.6 +/- 13.63; 100 mg LY3015014 Q8W 21.8 +/- 13.63; 300 mg LY3015014 Q8W 41.0 +/- 13.63
• Percentage Change From Baseline in Free Proprotein Convertase Subtilisin/Kexin Type 9 Antibody (PCSK9) Levels (Secondary), Least squares mean, Percentage change: Placebo Q4W 9.9 +/- 5.59; 20 mg LY3015014 Q4W -16.3 +/- 5.81; 120 mg LY3015014 Q4W -36.6 +/- 5.67; 300 mg LY3015014 Q4W -68.0 +/- 5.71; 100 mg LY3015014 Q8W -4.4 +/- 5.80; 300 mg LY3015014 Q8W -35.2 +/- 5.72
• Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady-State (AUC,ss) for LY3015014 (Secondary), Geometric mean, μg∙hr/mL: 20 mg LY3015014 Q4W 1590 +/- 29.2; 120 mg LY3015014 Q4W 9670 +/- 29.9; 300 mg LY3015014 Q4W 27300 +/- 26.3; 100 mg LY3015014 Q8W 7800 +/- 28.5; 300 mg LY3015014 Q8W 26600 +/- 32.2
• Number of Participants With an Injection Site Reaction (Secondary), Number, Participants: Placebo Q4W 26; 20 mg LY3015014 Q4W 42; 120 mg LY3015014 Q4W 57; 300 mg LY3015014 Q4W 51; 100 mg LY3015014 Q8W 36; 300 mg LY3015014 Q8W 41

Adverse events

Serious adverse events by term

Other adverse events by term

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern Time (UTC/GMT - 5 hours, EST), Study director, Eli Lilly and Company