A Study of LY2484595 on Pharmacokinetics in Healthy Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01448824
First received: October 6, 2011
Last updated: February 20, 2012
Last verified: February 2012
  Purpose

This is a 2-part study. Part 1 is to determine the safety and tolerability in healthy subjects 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.


Condition Intervention Phase
Healthy Subjects
Drug: LY2484595
Drug: Placebo
Drug: Ketoconazole
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Eli Lilly and Company:

Primary Outcome Measures:
  • Part 1: Number of subjects with one or more drug related Adverse Events (AEs) or any Serious AEs [ Time Frame: Part 1: Baseline up to Day 28 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: maximum observed plasma concentration (Cmax) of LY2484595 [ Time Frame: Part 2: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: time of maximum observed plasma concentration (tmax) of LY2484595 [ Time Frame: Part 2: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: area under the concentration-time curve(AUC) of LY2484595 [ Time Frame: Part 2: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacodynamics: Change from baseline to Day 21 in Cholesteryl Ester Transfer Protein (CETP) activity [ Time Frame: Part 1: Baseline, up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacodynamics: Change from baseline to Day 21 in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) [ Time Frame: Part 1: Baseline, up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: maximum observed plasma concentration (Cmax) of LY2484595 [ Time Frame: Part 1: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: time of maximum observed plasma concentration (tmax) of LY2484595 [ Time Frame: Part 1: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]
  • Pharmacokinetics: area under the concentration-time curve (AUC) of LY2484595 [ Time Frame: Part 1: Pre-dose up to Day 21 ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: October 2011
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1: LY2484595
100 mg tablets administered to 4 cohorts as multiple ascending doses of ≤ 1800 mg LY2484595 given orally for 14 consecutive days
Drug: LY2484595
Administered orally
Experimental: Part 2: LY2484595
100 mg LY2484595 will be administered orally on 2 separate days as single oral doses (Period 1 Day 1 and Period 2 Day 5)
Drug: LY2484595
Administered orally
Placebo Comparator: Part 1: Placebo
Administered orally once daily for 14 consecutive days
Drug: Placebo
Administered orally
Active Comparator: Part 2: Ketoconazole
400 mg Ketoconazole administered orally once daily for 14 consecutive days in Period 2
Drug: Ketoconazole
Administered orally

Detailed Description:

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 PK of LY2484595 in healthy subjects.

In the MAD portion (Part 1) of this study subjects in 4 cohorts will be randomized to receive either LY2484595 (doses ascending from 100 up to 1800 mg) or placebo. The total duration of Part 1 is approximately 13 weeks including screening.

Subjects in Cohort A will participate in 2 periods of 14 days of consecutive dosing, followed by a follow-up visit ≥14-days after the last dose of study drug. Subjects in Cohorts B, C, and D will receive 14 days of consecutive dosing followed by a follow-up visit ≥14 days after last dose of study drug. Cohorts will have staggered starts ≥7 days from the previous cohort to allow for review of safety and tolerability.

The DDI portion of this study (Part 2) will be open label and consist of two periods. The total duration of Part 2 is approximately 10 weeks. LY2484595 (100 mg) will be administered on Day 1 Period 1 and on Day 5 Period 2. In Period 2, Ketoconazole (400 mg) will be administered QD for a total of 14 days (13 days alone + 1 day with LY2484595). There is at least a 14 day washout period between Period 1 and Period 2, and a follow-up of greater than or equal to 14 days after last dose of study drug.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Are overtly healthy males or females, as determined by medical history and physical examination
  • Female subjects 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 mIU/mL (40 IU/L).
  • Have a body mass index (BMI) between 18 to 32 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 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 CYP3A4 (eg, St. John's wort), within 30 days prior to first dose of study drug
  • Have donated blood of more than 500 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 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
  • 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 (ie, real licorice)
  • In the opinion of the investigator or sponsor, are unsuitable for inclusion in the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01448824

Locations
United States, Florida
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Daytona Beach, Florida, United States, 32117
United States, Texas
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Dallas, Texas, United States, 75247
Sponsors and Collaborators
Eli Lilly and Company
Investigators
Study Director: 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) Eli Lilly and Company
  More Information

No publications provided

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01448824     History of Changes
Other Study ID Numbers: 14460, I1V-MC-EIAL
Study First Received: October 6, 2011
Last Updated: February 20, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Eli Lilly and Company:
Low High-density Lipoprotein (HDL)
Cholesterol (HDL-C)

Additional relevant MeSH terms:
Ketoconazole
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 10, 2014