Single Dose Study in Healthy Participants to Investigate the Safety and Absorption of LY2584702

Phase 1

Completed

• Conditions: Healthy Participants
• Interventions: Drug: LY2584702 Reference Formulation; Drug: Placebo; Drug: LY2584702 Test Formulation

• Registration Number: NCT01372085
• Lead Sponsor: Eli Lilly and Company

Brief Summary

This is a single-centre, placebo-controlled, two-part study in healthy participants.

Part A will be a single dose, single period, placebo-controlled pilot study to explore the safety, tolerability, absorption and pharmacodynamic \[effect of drug on a biological marker-phospho-S6 (pS6) levels in skin biopsies\] of a single dose of 25 milligrams (mg) LY2584702 Reference formulation (RF). Part B is a single dose, placebo-controlled, 4-period crossover study to primarily evaluate the absorption of the Test Formulation (TF) in comparison with the (RF) of LY2584702.

Detailed Description

Not available

Study Timeline

• Study Start: 2011-06
• Study First Submitted: 2011-06-02
• Study First Submitted QC: 2011-06-10
• Study First Posted: 2011-06-13
• Primary Completion: 2011-09
• Study Completion: 2011-09
• Results First Submitted: 2017-09-27
• Status Verified: 2018-08
• Results First Submitted QC: 2018-08-03
• Last Update Submitted: 2018-08-03
• Results First Posted: 2019-01-22
• Last Update Posted: 2019-01-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

Inclusion Criteria

Male participants:

• Agree to use a reliable method of birth control during the study and for at least 1 month following the last dose of study drug

Female participants:

• Women not of childbearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Women with an intact uterus are deemed postmenopausal if they are greater than or equal to 45 years old, who have not taken hormones or oral contraceptives within the last year, and had cessation of menses for at least 1 year, or who have had 6 to 12 months of amenorrhea with follicle-stimulating hormone (FSH) levels consistent with postmenopausal state.

All participants:

• have a screening body mass index (BMI) of 18.5 to 32.0 kilograms per square meter (kg/m^2), inclusive
• have clinical laboratory test results within the normal range for the population or investigator site, or with abnormalities deemed clinically insignificant by the investigator. In particular, participants should have normal or near normal screening liver tests at the discretion of the investigator
• have normal blood pressure and pulse rate (supine) at screening, or with minor deviations judged to be acceptable by the investigator
• have venous access sufficient to allow blood sampling as per the protocol
• 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 ethical review board (ERB) governing the site

Exclusion Criteria

All participants:

• are currently enrolled in, have completed or discontinued within the last 30 days from, a clinical trial involving an investigational product other than the investigational product used in this study; or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Participants that participate in Part A of this study may participate in Part B of the study if the first dosing in Part B is >30 days after the dose of LY2584702 or placebo in Part A.
• have known allergies to LY2584702, or related compounds
• have an abnormality in the 12-lead electrocardiogram (ECG) [including but not limited to Bazett's corrected QT (QTcB) interval >450 milliseconds (msec) for men and >470 msec for women]
• have a history within the last 2 years 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
• have a history of drug or alcohol abuse, or regularly use known drugs of abuse
• show evidence of human immunodeficiency virus infection and/or positive human immunodeficiency virus (HIV) antibodies
• show evidence of hepatitis B and/or positive hepatitis B surface antigen
• intend to use over-the-counter or prescription medication within 14 days prior to dosing or during the study
• use of herbal supplements, grapefruit juice, grapefruits, Seville orange juice, Seville oranges, or Starfruit within 7 days prior to study dosing or intended use during the study
• have donated blood of more than 450 milliliters (mL) within the last 3 months
• 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 from prior to dosing until the completion of each study period [ unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits]

Applicable for Part A only:

• have known allergies to lignocaine, adrenaline, tetracycline, or related compounds, which will be used in the skin biopsy procedure

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Part A: 25 mg RF	LY2584702 Reference Formulation	A single 25 mg dose of LY2584702 RF
Part B: Sequence 1	Placebo	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by placebo in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 2	LY2584702 Test Formulation	Placebo during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 3	LY2584702 Reference Formulation	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 3	LY2584702 Test Formulation	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 4	LY2584702 Test Formulation	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by placebo in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 4	Placebo	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by placebo in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 3	Placebo	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part A: Placebo	Placebo	Placebo taken orally
Part B: Sequence 1	LY2584702 Test Formulation	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by placebo in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 2	Placebo	Placebo during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 4	LY2584702 Reference Formulation	A single 10 mg dose of LY2584702 TF during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by placebo in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.
Part B: Sequence 2	LY2584702 Reference Formulation	Placebo during the first intervention period, followed by a single dose of 50 mg RF in the second intervention period, followed by a single dose of 50 mg TF in the third intervention period, followed by either an open-label single dose of 50 mg TF after a high fat breakfast (Period 4a) OR placebo or escalated dose of TF in the fasted state (Period 4b). There will be a washout period of at least 3 days between periods.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax)	Part A: Day 1 and Part B: Periods 1 to 4, Day 1 [Predose, 1 hour (h), 3 h, 4 h, 6 h, 10 h, 24 h, 48 h postdose]	The Cmax following a single oral dose of LY2584702 test formulation \[TF (tablet)\] or reference formulation \[RF (capsule)\] is reported.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics, Area Under the Concentration-Time Curve (AUC)	Part A: Day 1 and Part B: Periods 1 to 4, Day 1 [Predose, 1 hour (h), 3 h, 4 h, 6 h, 10 h, 24 h, 48 h postdose]	AUC from time 0 to the time of the last quantifiable concentration \[AUC(0-tlast)\] and AUC from time 0 to infinity \[AUC(0-inf)\] following a single oral dose of LY2584702 test formulation \[TF (tablet)\] or reference formulation \[RF (capsule)\] is reported.
Part A: QT Interval Corrected by Fridericia's Formula (QTcF) Change From Baseline to Day 1	Part A: Baseline [Day 1 (Predose)] and Day 1 (3 h, 4 h, 6 h, and 24 h postdose)	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and is calculated from electrocardiogram (ECG) data. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between 2 R waves. Using Fridericia's formula: QTcF = QT/RR\^0.33. The QTcF after single oral doses of LY2584702 reference formulation \[RF (capsule)\] were administered in a fasted state are reported at baseline (Day 1, Predose) and 3 hours (h), 4 h, 6 h, and 24 h postdose.
Part B: Baseline-Adjusted Change-From-Predose in the Concentration of Lipids (Total Cholesterol)	Part B: Baseline [Periods 1 and 4a (Day -1)], Periods 3, 4a (Day 1). Lipid concentration measurements were performed at time point 0 and 1 hour (h), 3 h, 4 h, 6 h, 10 h, and 24 h.	Baseline-adjusted change-from-predose in lipid concentrations were measured to assess the LY2584702 effect on lipids under different fed states. The 50-milligram (mg) LY2584702 test formulation \[TF (tablet)\] was the only dose and formulation administered in both the fasted and fed states for comparison. Therefore, changes in total cholesterol after single oral doses of placebo, 10-mg, or 200-mg LY2584702 TF or 25-mg or 50-mg LY2584702 reference formulation \[RF (capsule)\] were not calculated. The baseline-adjusted change-from-predose in total cholesterol levels in the fasted and fed state following a single 50-mg LY2584702 TF dose is reported. Baseline was Day -1 of Period 1 for Period 3 fasted state and baseline was Day -1 of Period 4a for Period 4a fed state. Least squares (LS) means was calculated using mixed model repeating measures (MMRM) and adjusted for treatment, time, treatment by time, and participant.
Part B: Average Time-Matched QT Interval Corrected by Fridericia's Formula (QTcF) Change From Baseline to Day 1	Part B: Baseline [Period 1 (Day -1)] and Periods 1 to 4 (Day 1). Electrocardiograms (ECG) were performed at time point 0 and 3 h, 4 h, 6 h, and 24 h.	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and is calculated from electrocardiogram (ECG) data. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between 2 R waves. Using Fridericia's formula: QTcF = QT/RR\^0.33. The QTcF after single oral doses of LY2584702 test formulation \[TF (tablet)\], LY2584702 reference formulation \[RF (capsule)\], or placebo were administered in a fasted or fed state are reported at baseline (time-matched Day -1 QTcF) and 3 hours (h), 4 h, 6 h, and 24 h postdose. Day 1, Hour 24 was time-matched with Day-1, Hour 0.

Trial Locations

Locations (1)

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.; 🇸🇬 Singapore, Singapore