A Study of LY2484595 in Japanese Subjects

Study Overview
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Brief Summary
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The purpose of this study is to determine if 12 weeks of treatment with LY2484595 administered as a monotherapy will significantly increase high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) in Japanese participants.

Official Title
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A Phase 2 Dose Response Study of LY2484595 in Japanese Subjects

Conditions
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Dyslipidemias

Intervention / Treatment
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* Drug: LY2484595
* Drug: Placebo
* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Low HDL-C or High LDL-C criteria as follows: Low HDL lipid criteria: HDL-C <45 milligrams per deciliter (mg/dL) (men) and <50 mg/dL (women), and LDL-C according to Japan Atherosclerosis Society (JAS) guidelines as follows: LDL-C <190 mg/dL (0-1 risk factors) LDL-C <160 mg/dL (2 risk factors) LDL-C <130 mg/dL (3+ risk factors),and Fasting Triglycerides (TG) <400 mg/dL or High LDL-C lipid criteria: HDL-C <100 mg/dL, and LDL-C according to JAS guidelines as follows: LDL-C 100-190 mg/dL (0-1 risk factors) LDL-C 100-160 mg/dL (2 risk factors) LDL-C 100-130 mg/dL (3+ risk factors), and Fasting TG <400 mg/dL Note: Subjects with diabetes regarded as 3+ risk factors Male subjects: Agree to use a reliable method of birth control during the study (and for 2 weeks following the last dose of study drug) Female subjects: 1) Women not of childbearing potential due to surgical sterilization (at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history, or menopause. Menopausal women include women with either a) spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea [for example, oral contraceptives, hormones, gonadotropin releasing hormone, anti-estrogens, selective estrogen receptor modulators (SERMs), or chemotherapy] or b) spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level greater than 40 milli-international units per milliliter (mIU/mL). or, 2) Women of child bearing potential who test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test and agree to use a reliable method of birth control during the study and for 2 weeks following the last dose of study drug Have given informed consent to participate in the study Exclusion Criteria: At screening, are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have participated within 90 days prior to screening in any clinical trials of cholesteryl ester transfer protein (CETP) inhibitors (e.g., anacetrapib or dalcetrapib) Have completed or withdrawn from this study or have completed or withdrawn from any other study investigating LY2484595 Are unable, unreliable, and/or unwilling to provide informed consent, make themselves available for the duration of the study, or will not abide by the procedures and study restrictions Have recent history of any clinically significant rash, history of any clinically severe drug-related rash, history of a chronic skin disorder (such as psoriasis, eczema or urticaria), history of significant skin hypersensitivities to household or cosmetic products, or allergens per the investigator, or presence of widespread tattoos or other skin condition that limits the assessment for rashes. Subjects who develop any rash during the Diet Lead-in/Washout Phase cannot be randomized Have or have had any clinical manifestation of coronary heart disease (CHD), such as stable or unstable angina, acute coronary syndrome, myocardial infarction, or a coronary revascularization procedure including stent placement, symptomatic carotid artery disease or symptomatic peripheral arterial disease. Subjects with a diagnosis of abdominal aortic aneurysm are excluded from this study Have systolic blood pressure (SBP) >140 millimeters of mercury (mm Hg) or diastolic blood pressure (DBP) >90 mm Hg as determined by the mean of 3 standardized measurements in the sitting position at randomization Have or have had documented hyperaldosteronism Have symptoms consistent with moderate or severe heart failure or are receiving treatment for symptomatic congestive heart failure (CHF) or known left ventricular ejection fraction (LVEF) <35%. The absence of LVEF measurement does not prohibit entry into this study Have one of the following abnormalities: QTc prolongation [Bazett's corrected QT interval (QTcB)] of >450 msec in male subjects or >470 msec in female subjects, or abnormally wide QRS complexes (resulting from bundle branch blocks, intraventricular conduction delays, or pacemakers) or atrial fibrillation on screening electrocardiogram (ECG), previous history of QTc prolongation with another medication that required discontinuation, congenital long QT syndrome, previous history of ventricular tachycardia or unexplained syncope Have family history of long QT syndrome or sudden death likely secondary to ventricular arrhythmia Have active hepatobiliary disease, serologic evidence of past or active hepatitis B or C, or past or active gallbladder disease. Subjects who have been diagnosed with Gilbert syndrome or had a cholecystectomy greater than 90 days prior to screening can be included Have aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline phosphatase (ALP), or total bilirubin >1.5 times the upper limit of normal (ULN) Have a history or presence of a chronic muscular or neuromuscular disease including prior rhabdomyolysis or drug-induced myopathy or an unexplained/documented elevation in creatine kinase (CK) ≥3 times the ULN Have a history of discontinuation from statin, change of statin, or a dose reduction of statin due to history of hypersensitivity, intolerance or adverse effect. Have a history of increased hepatic enzymes associated with use of an hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) Have a history of hypersensitivity or intolerance to drug preparations containing cholesteryl ester transfer protein (CETP) inhibitors, including but not limited to torcetrapib, anacetrapib, or dalcetrapib Have a hemoglobin A1c ≥8.0%; or use, plan to use, or are likely to require insulin during the course of the study. Diabetic subjects on an antidiabetic agent with lipid modifying effects must be on a stable dose for at least 30 days prior to screening Have a serum creatinine ≥2 mg/dL, or nephrotic syndrome, end stage renal disease and use renal replacement therapy such as hemodialysis or peritoneal dialysis Have hemoglobin <10 grams per deciliter (g/dL) in women and <11 g/dL in men Have current uncontrolled active inflammatory condition or infection which in the opinion of the investigator would influence a subject's ability to complete the study Have thyroid-stimulating hormone (TSH) levels outside normal reference range. Subjects who are clinically euthyroid, on stable thyroid replacement therapy for 60 days prior to screening, and are anticipated to remain on this dose throughout the trial period are acceptable exceptions to this criterion Are women who are lactating Have planned or are likely to require major surgery requiring anesthesia or hospitalization during the course of the study Have chronic alcohol or drug abuse or dependency Are currently under suspicion of having cancer or have had a history of cancer in the past 2 years, with the exception of excised superficial lesions such as basal cell carcinoma and squamous cell carcinoma of the skin Have history of human immunodeficiency virus (HIV) infection Have any other condition or abnormal laboratory value, which in the opinion of the investigator precludes the subject from providing informed consent Plan to use, are likely to require, or unwilling or unable to stop with adequate washout any prescription or over-the-counter (OTC) medication or health foods with the intent to treat serum lipids (LDL-C, HDL-C, triglycerides) including but not limited to these classes of drugs: statin, ezetimibe, bile acid sequestrant, eicosapentaenoic acid (EPA). Subjects taking probucol, fibrate or nicotinic agents within 8 weeks before screening are excluded from the study Are currently using, plan to use, or are likely to require during the course of the study systemic corticosteroids; or anabolic agents other than stable doses of estrogen, estrogen/progestin, or testosterone replacement therapy Are currently using, plan to use, or are likely to require during the course of the study, more than the occasional use (i.e., once every other week) of stimulant laxatives (e.g., bisacodyl), osmotic laxatives (e.g., milk of magnesia), or castor oil Use of any immunosuppressive therapy within 60 days prior to screening or are likely to require immunosuppressive therapy during the course of the study Have received treatment within 30 days prior to the time of study entry with any drug or drugs that have not received regulatory approval for any indication Have plans to adopt diets with aggressive carbohydrate restrictions for weight loss. Currently use, have used within 60 days prior to screening, or plan to use during the trial period prescriptions or OTC formulations intended for weight loss Are currently using, have used within 60 days prior to screening, plan to use, or are likely to require during the course of the study, drugs or foods that are inducers (including rifampin and carbamazepine) or moderate or strong inhibitors of cytochrome P450 3A (including, ketoconazole, erythromycin and grapefruit juice); or strong inhibitors of the organic anion transporter polypeptide 1B1 (OATP1B1) transporter (including cyclosporine and rifampin). The drugs used in topical preparations are acceptable

Ages Eligible for Study
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Minimum Age: 20 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 milligrams (mg) LY2484595<br>Administered orally once daily for 12 weeks | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: 100 mg LY2484595<br>Administered orally once daily for 12 weeks | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: 500 mg LY2484595<br>Administered orally once daily for 12 weeks | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Placebo Comparator: Placebo<br>Administered orally once daily for 12 weeks | Drug: Placebo<br>* Administered orally<br>|
| Active Comparator: 10 mg Atorvastatin<br>Administered orally once daily for 12 weeks | Drug: Placebo<br>* Administered orally<br>Drug: Atorvastatin<br>* Administered orally<br>|
| Experimental: 100 mg LY2484595 + 10 mg Atorvastatin<br>Administered orally once daily for 12 weeks | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>Drug: Atorvastatin<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to 12 Weeks in High Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) With LY2484595 and Placebo | Percent change from baseline = 100*(post-baseline assessment - baseline assessment)/baseline assessment. Higher values in the percent change from baseline represented an improvement for HDL-C and lower values in the percent change from baseline represented an improvement for LDL-C. Least Squares (LS) mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) With LY2484595 in Combination With Atorvastatin | Percent change from baseline = 100*(post-baseline assessment - baseline assessment)/baseline assessment. An increase in the percent change from baseline represented an improvement for HDL-C and a decrease in the percent change from baseline represents an improvement for LDL-C. LS mean was adjusted for baseline value of the variable analyzed. | Baseline, Weeks 2, 4, and 8 | 
| Pharmacokinetics - Area Under the Curve (AUC) of LY2484595 and Atorvastatin |  | Weeks 2, 4, 8, 12 (predose and postdose), and Week 16 | 
| The Number and Severity of Episodes of Rashes at Any Time From Baseline Through Week 12 | All rash cases were adjudicated by a central dermatologist blinded to treatment assignment according to a study-specific Clinical Events Committee (CEC) charter. Rash events were assessed according to clinical relevance (severity). Categories included high risk, low risk, not a relevant dermatosis, or insufficient documentation for determination. High risk rashes included anaphylaxis, toxic epidermal necrolysis, Stevens Johnson Syndrome, Drug Reaction with Eosinophilia and System Symptoms (DRESS), urticaria/angioedema, vasculitis, erythroderma, and lupus-like reaction. All other rashes were considered low risk or not a relevant dermatosis per the Investigator's clinical opinion. A participant could be reported in multiple categories. | Baseline through Week 12 | 
| Change From Baseline to 12 Weeks in Blood Pressure | Blood pressure reported as systolic blood pressure (SBP) and diastolic blood pressure (DBP). LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Change From Baseline to 12 Weeks in Aldosterone | LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Change From Baseline to 12 Weeks in Plasma Renin Activity | LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Change From Baseline to 12 Weeks in Serum Sodium | LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Change From Baseline to 12 Weeks in Serum Bicarbonate | LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Number of Myopathy and Liver Injury Events | Myopathy events were considered muscle-related treatment emergent adverse events (TEAEs) and liver injury events were considered hepatic disorder-related TEAEs reported per Medical Dictionary for Regulatory Activities (MedDRA). An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. TEAEs were newly occurring AEs or AEs worsening after first dose. | Baseline through Week 12 | 
| Change From Baseline to 12 Week Endpoint in Highly-Sensitive C-Reactive Protein (hsCRP) | LS mean was adjusted for baseline value of the variable analyzed. | Baseline and Week 12 | 
| Percent Change From Baseline in Plasma Cholesteryl Ester Transfer Protein (CETP) Activity | Plasma CETP activity assay employed a fluorometric method to determine the CETP transfer activity. Percent change from baseline = 100*(post-baseline assessment - baseline assessment)/baseline assessment. An increase in the percent change from baseline represented an improvement. LS mean was adjusted for baseline value of the variable analyzed. | Baseline, Weeks 4, 8, and 12 | 
| Change From Baseline in Plasma CETP Mass | Plasma CETP mass assay was a solid-phase enzyme-linked immunosorbent assay (ELISA) designated to measure human CETP mass which employed the quantitative enzyme immunoassay principle. An increase in plasma CETP mass represented an improvement. LS mean was adjusted for baseline value of the variable analyzed. | Baseline, Weeks 4, 8, and 12 |