A Study of LY3015014 in Healthy Participants With Elevated Low Density Lipoprotein Cholesterol

Study Overview
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Brief Summary
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This is a study in otherwise healthy Japanese and non-Japanese participants with elevated low density lipoprotein cholesterol (LDL-C). Following single doses of LY3015014, the safety and tolerability of the drug, how the body handles the drug, and the drug's effect on the body will be evaluated. Participants will remain in the study for approximately up to 6 months.

Official Title
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A Single-Dose, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3015014 in Subjects With Elevated LDL-C

Conditions
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Hyperlipidemia

Intervention / Treatment
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* Drug: LY3015014 IV
* Drug: Placebo IV
* Drug: LY3015014 SC
* Drug: Placebo SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are overtly healthy males or females, as determined by medical history and physical examination To qualify as Japanese for the purpose of this study, the participant must be first-generation Japanese, defined as the participant's biological parents and all of the participant's biological grandparents must be of exclusive Japanese descent, and must have been born in Japan. Japanese participants have to be between the ages of 20-65, inclusive, at screening Statin naive participants, have a screening LDL-C of between 100 and 180 milligrams per deciliter (mg/dL), inclusive; for participants currently taking a statin, have a screening LDL-C of between 100 and 160 mg/dL Have serum triglycerides <400 mg/dL Additional inclusion criteria for participants in the statin-interaction cohort: At screening, must have been on a stable dose of either atorvastatin [10 to 40 mg once daily (QD)], rosuvastatin (5 to 20 mg QD), simvastatin (20 to 40 mg QD), lovastatin (40 to 80 mg QD), or pravastatin (40 to 80 mg QD) which has been well tolerated for at least 3 months Exclusion Criteria: Have known allergies to compounds related to LY3015014 or any components of the formulation, or known clinically significant hypersensitivity to biologic agents, or known allergies to acetaminophen and/or antihistamines Intend to use over-the-counter or prescription medication within 14 days prior to dosing (excluding the statins listed in Inclusion Criterion), other than estrogen/progesterone as hormone replacement therapy (HRT) and thyroid medications. Participants taking these medications should be on chronic, stable doses. Certain medications, for example vitamin supplements, may be permitted at the discretion of the investigator and the sponsor. Participants on statins may be allowed to be on a stable dose of single hypertensive agent if agreed upon by sponsor and investigator Have received any vaccine(s) within 1 month of LY3015014 dosing, or intend to during the study Have received treatment with biologic agents (such as monoclonal antibodies) within 3 months or 5 half-lives (whichever is longer) prior to dosing Have a history of atopy, or significant allergies to humanized monoclonal antibodies, or clinically significant multiple or severe drug allergies, or intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions [including, but not limited to, erythema multiforme major, linear immunoglobulin (Ig)A dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis] Additional exclusion criteria for participants in the statin-interaction cohort: Incidence of unexplained muscle pain, or incidence of frequent muscle cramp within the last 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3015014 intravenously (IV)<br>A single dose of LY3015014 up to 10.0 milligrams per kilogram (mg/kg) administered IV | Drug: LY3015014 IV<br>* Administered IV over 30-90 minutes<br>|
| Experimental: LY3015014 IV Japanese<br>Single dose of LY3015014 10.0 mg/kg administered IV to Japanese participants. Added per protocol amendment effective October, 2012. | Drug: LY3015014 IV<br>* Administered IV over 30-90 minutes<br>|
| Placebo Comparator: Placebo IV<br>Administered IV once only | Drug: Placebo IV<br>* Administered IV only over 30-90 minutes<br>|
| Experimental: LY3015014 subcutaneously (SC)<br>A single dose of LY3015014 up to 3.0 mg/kg administered SC | Drug: LY3015014 SC<br>* Administered SC<br>|
| Experimental: LY3015014 SC + Statin<br>A single dose of LY3015014 up to 3 mg/kg administered SC in addition to participant's dose of statin | Drug: LY3015014 SC<br>* Administered SC<br>|
| Placebo Comparator: Placebo SC<br>Administered SC once only | Drug: Placebo SC<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Effects | Adverse events (AEs) were considered as clinically significant effects. A summary of serious AEs (SAEs) and other nonserious AEs, regardless of causality, is located in the Reported Adverse Events module. | Baseline to study completion (up to 22 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time 0 to the Last Time Point With a Measurable Concentration of LY3015014 [AUC(0-tlast)] |  | Predose, 0, 1, 2, 4, 12, 24 hours post dose, and 3, 5, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85, 99, 113, 127 and 155 days post-dose | 
| PK: Maximum Concentration (Cmax) of LY3015014 |  | Predose, 0, 1, 2, 4, 12, 24 hours post dose, and 3, 5, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 85, 99, 113, 127 and 155 days post-dose | 
| Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) | Least Square means were calculated using mixed-effects models for repeated measures analysis. The model included factors for treatment, visits and baseline LDL-C. Percent change = (LDL value on Days 15 or 29 - LDL at baseline) / LDL at baseline *100. | Baseline, Days 15 and 29 | 
| Number of Participants With Detectable Levels of Anti-LY3015014 Antibodies |  | Days 8, 29 and 85 |