A Study of LY3015014 in Participants With High Cholesterol

Study Overview
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Brief Summary
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This study is designed to define the amount and duration of cholesterol lowering and to assess the safety and tolerability of different dose regimens of LY3015014 in participants with high cholesterol. The study will also investigate how the body processes the drug and how the drug affects the body. Participants will remain on a stable diet and will continue taking cholesterol-lowering medications (statins with or without ezetimibe). After signing the informed consent document, the participant will complete a screening/run-in period that will last at most 8 weeks. Then, the treatment period will last approximately 16 weeks. After the treatment period, the participants will complete a follow-up period lasting approximately 8 weeks for a total study duration ranging from approximately 25 to 32 weeks.

Official Title
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A Phase 2 Efficacy and Safety Dose-Ranging Study of LY3015014 in Patients With Primary Hypercholesterolemia

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: LY3015014
* Drug: Placebo
* Drug: Statin
* Drug: Ezetimibe


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20 mg LY3015014 Q4W<br>20 milligrams (mg) LY3015014 given subcutaneously (SC) once every 4 weeks (Q4W) for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: LY3015014<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|
| Experimental: 120 mg LY3015014 Q4W<br>120 mg LY3015014 given SC Q4W for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: LY3015014<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|
| Experimental: 300 mg LY3015014 Q4W<br>300 mg LY3015014 given SC Q4W for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: LY3015014<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|
| Experimental: 100 mg LY3015014 Q8W<br>100 mg LY3015014 given SC once every 8 weeks (Q8W) for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: LY3015014<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|
| Experimental: 300 mg LY3015014 Q8W<br>300 mg LY3015014 given SC Q8W for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: LY3015014<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|
| Placebo Comparator: Placebo Q4W<br>Placebo given SC Q4W for 16 weeks. Participants will remain on stable diet and physician-prescribed statin therapy, if tolerated, with or without ezetimibe. | Drug: Placebo<br>* Administered SC<br>Drug: Statin<br>* Administered orally<br>* Other names: pitavastatin;Drug: Ezetimibe<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) | 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. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in LDL-C, Total Cholesterol (TC), High-Density Lipoprotein Cholesterol (HDL-C), Triglycerides (TG), Non-HDL-C | 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. | Baseline, Week 16 | 
| Percentage Change From Baseline in Apolipoprotein A1 (Apo A1), Apolipoprotein B (Apo B) | 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. | Baseline, Week 16 | 
| Percentage Change From Baseline in Lipoprotein(a) [Lp(a)] | 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. | Baseline, Week 16 | 
| Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) | 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. | Baseline, Week 16 | 
| 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 | 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. | Baseline, Week 16 | 
| Percentage Change From Baseline in Free Proprotein Convertase Subtilisin/Kexin Type 9 Antibody (PCSK9) Levels | 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. | Baseline, Week 16 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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low density lipoprotein, heterozygous familial hypercholesterolemia, polygenic hypercholesterolemia