A Study of LY2484595 on Pharmacokinetics in Healthy Participants

Study Overview
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Brief Summary
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This is a 2-part study. Part 1 is to determine the safety and tolerability in healthy participants of increasing daily doses of LY2484595 for 14 days to achieve a blood level of LY2484595 much higher than what is needed for therapy. The amount of study drug that reaches the bloodstream and the time it takes for the body to get rid of it will be determined. The effect of the study drug on factors in the blood related to cholesterol will be measured. Part 2 is to determine how ketoconazole affects how much of the study drug, LY2484595, gets into the bloodstream and how long it takes to get rid of it. Information about any side effects that may occur will also be collected.

Detailed Description
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This study is a 2-part, multiple ascending dose (MAD) and drug drug interaction (DDI) study to evaluate the safety and tolerability and the effect of cytochrome P450 (CYP) 3A inhibition by ketoconazole on the pharmacokinetics of LY2484595 in healthy participants. In the MAD portion (Part 1) of this study, participants in 4 cohorts (Cohorts A through D) will be randomized to receive either LY2484595 (5 ascending dose levels [100 to 1800 mg]) or placebo. Cohorts will have staggered starts ≥7 days from the previous cohort to allow for review of safety and tolerability. The total duration of Part 1 is approximately 13 weeks including screening. Participants in Cohort A will participate in 2 periods separated by a washout period lasting ≥14 days. During Period 1, participants will receive the starting dose of LY2484595 (100 mg) or placebo once daily (QD) for 14 consecutive days. During Period 2, participants will receive the highest dose of LY2484595 (1800 mg) or placebo QD for 14 consecutive days. Participants will complete a follow-up visit ≥14 days after the last dose of study drug. Participants in Cohorts B, C, and D will receive LY2484595 (300, 600, and 1200 mg LY2484595, respectively) or placebo QD for 14 consecutive days followed by a follow-up visit ≥14 days after last dose of study drug. The DDI portion of this study (Part 2) will be open label and consist of 2 periods. The total duration of Part 2 is approximately 10 weeks. LY2484595 (100 mg) will be administered on Day 1 of Period 1 and on Day 5 of Period 2. In Period 2, ketoconazole (400 mg) will be administered QD for 14 consecutive days (13 days alone [Days 1 through 4 and 6 through 14] + 1 day with LY2484595 [Day 5]). There will be a ≥14-day washout period between dosing during Period 1 and Period 2. Participants will return for a follow-up visit ≥14 days after last dose of study drug.

Official Title
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A Phase 1 Study to Evaluate the Safety and Tolerability of LY2484595 SDSD-PG Tablets and the Effect of CYP3A Inhibition by Ketoconazole on the Pharmacokinetics of LY2484595 in Healthy Subjects

Conditions
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Healthy Participants

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


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 Female participants and women not of childbearing potential due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) or menopause. Postmenopausal is defined as women age >45 with an intact uterus who have not taken hormones or oral contraceptives within the last year, and who have had either cessation of menses greater than or equal to 1 year or 6 to 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) >40 milli-international units per milliliter (40 international units per liter [IU/L]). Have a body mass index (BMI) between 18 to 32 kilograms per square meter (kg/m^2), inclusive Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator Have venous access sufficient to allow for blood sampling Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Have given written informed consent approved by Lilly and the institutional review board (IRB) governing the site Exclusion Criteria: Are currently enrolled in, have completed or discontinued within the last 30 days from a clinical trial involving an investigational product, or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have known allergies to LY2484595 or related compounds, contraindications to ketoconazole or related compounds, or allergies to any components of the formulations Are persons who have previously completed or withdrawn from this study or any other study investigating LY2484595 and have previously received the investigational product Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study and/or poses difficulties in the interpretation of eventual changes occurring during the study Have systolic blood pressure of >140 millimeters of mercury (mmHg) or diastolic blood pressure of >90 mmHg Have a history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data Regularly use known drugs of abuse and/or show positive findings on urinary drug screening Show evidence of human immunodeficiency virus infection (HIV) and/or positive human HIV antibodies Show evidence of hepatitis C and/or positive hepatitis C antibody Show evidence of hepatitis B and/or positive hepatitis B surface antigen Are women with a positive pregnancy test or women who are lactating Have used or intend to use over-the-counter or prescription medication within 14 days prior to dosing unless deemed acceptable by the investigator and sponsor's medical monitor Use of any drugs or substances that are known to be an inducer or inhibitor of cytochrome p450 3A4 (CYP3A4) (for example, St. John's wort) within 30 days prior to first dose of study drug Have donated blood of more than 500 milliliters (mL) within 30 days prior to first dose of study drug Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) or are unwilling to stop alcohol consumption for the duration of the study (1 unit equals 12 ounces [oz] or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits) Consume 5 or more cups of coffee (or other beverages of comparable caffeine content) per day, on a habitual basis, or any subjects unwilling to adhere to study caffeine restriction Have a daily use of greater than or equal to 5 tobacco- or nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) and are unwilling to refrain from using any tobacco- or nicotine-containing products within 7 days prior to first dose through the follow-up visit Have consumed grapefruit, grapefruit juice, Seville orange, Seville orange juice, or starfruit or products that contain these fruits within 7 days prior to first dose and during the study Unwilling to refrain from daily consumption of black licorice containing glycyrrhizic acid (that is, real licorice) In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 (Cohort A): 100 mg, 1800 mg LY2484595, Placebo<br>Period 1: Participants will receive either 100 milligrams (mg) LY2484595 tablets or placebo tablets once daily (QD) by mouth on Days 1 through 14 of Period 1. Washout period lasting ≥14 days. Period 2: Participants will receive either 1800 mg LY2484595 tablets or placebo tablets QD by mouth on Days 1 through 14 of Period 2. | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Part 1 (Cohort B): 300 mg LY2484595, Placebo<br>Participants will receive either 300 milligrams (mg) LY2484595 tablets or placebo tablets once daily (QD) by mouth on Days 1 through 14. | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Part 1 (Cohort C): 600 mg LY2484595, Placebo<br>Participants will receive either 600 milligrams (mg) LY2484595 tablets or placebo tablets once daily (QD) by mouth on Days 1 through 14. | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Part 1 (Cohort D): 1200 mg LY2484595, Placebo<br>Participants will receive either 1200 milligrams (mg) LY2484595 tablets or placebo tablets once daily (QD) by mouth on Days 1 through 14. | Drug: LY2484595<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Part 2 (Cohort E): 100 mg LY2484595 ± 400 mg Ketoconazole<br>Period 1: Participants will receive 100 milligrams (mg) LY2484595 tablet by mouth on Day 1 of Period 1. Washout period lasting ≥14 days. Period 2: Participants will receive 400 mg ketoconazole tablets once daily (QD) by mouth on Days 1 through 14 of Period 2. Participants will receive 100 mg LY2484595 tablet by mouth on Day 5 of Period 2. | Drug: LY2484595<br>* Administered orally<br>Drug: Ketoconazole<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With 1 or More Adverse Events (AEs) or Any Serious AEs | The number of participants with 1 or more AEs is summarized cumulatively. In addition, the number of participants with any serious AEs is summarized cumulatively. A serious AE is defined as an event that results in death, initial or prolonged hospitalization, is life-threatening, leads to persistent or significant disability/incapacity, is associated with congenital anomaly/birth defect, or is considered significant by the investigator for any other reason. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module. | Part 1: Baseline through ≥14 days after last dose of study drug (≥Day 28) | 
| Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | The geometric least squares (LS) means for the maximum observed plasma concentration (Cmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone). | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | 
| Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | The median times to maximum observed plasma concentration (Tmax) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | 
| Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | The geometric least squares (LS) means of area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC0-∞) of LY2484595 following administration of LY2484595 alone and with ketoconazole are reported. Least squares means were calculated from an analysis of variance (ANOVA) model with a fixed effect for treatment and a random effect for participant. The LS means for each treatment and the 90% confidence intervals (CI) for the difference in means were back transformed from the log scale to provide estimates of the geometric means and 90% CIs for the ratio of the geometric means (LY2484595 coadministered with ketoconazole and LY2484595 alone). | Part 2, Period 1, Day 1 through Day 8: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168 Hours Post Dose; Period 2, Day 5 through Day 15: Predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 Hours Post Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics: Change From Baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) Activity |  | Day 1 (Baseline) and Day 21 | 
| Pharmacodynamics: Change From Baseline to Day 21 in High-density Lipoprotein Cholesterol (HDL-C), Low-density Lipoprotein Cholesterol (LDL-C), and Triglycerides (TG) |  | Day 1 (Baseline) and Day 21 | 
| Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of LY2484595 | The maximum observed plasma concentrations (Cmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | 
| Pharmacokinetics: Time of Maximum Observed Plasma Concentration (Tmax) of LY2484595 | The times of maximum observed plasma concentrations (tmax) of LY2484595 after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | 
| Pharmacokinetics: Area Under the Concentration-time Curve (AUC) of LY2484595 | Exposure to LY2484595 in terms of the area under the concentration-time curves (AUC) after a single dose and after once daily (QD) dosing for 14 consecutive days are reported. | Part 1, Periods 1 and 2, Day 1: Predose, 1, 2, 3, 4, 6, 8, 12, and 24 Hours Postdose; Day 14 through Day 21: Predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 Hours Post Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low High-density Lipoprotein (HDL), Cholesterol (HDL-C)