A Drug-Drug Interaction Study of Lanabecestat (LY3314814) in Healthy Participants

A Study to Characterize LY3314814 Pharmacokinetics as a Function of Dosing Duration and to Determine the Effect of LY3314814 on the Pharmacokinetics of CYP3A Substrates in Healthy Subjects

The purpose of this study is to study the effect of lanabecestat on how the body absorbs and processes 3 other medications, midazolam, simvastatin and donepezil and how these 3 medications affect lanabecestat when they are taken together. This study is in 2 cohorts, Cohort A is approximately 44 days long and Cohort B about 70 days only. The screening visit is required within 30 days prior to the start on the study

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Lanabecestat; Drug: Simvastatin; Drug: Midazolam; Drug: Midazolam; Drug: Donepezil

Detailed Description

Astra Zeneca (AZ) registered this trial as sponsor. In July, 2015, sponsorship changed to Eli Lilly and Company (Lilly). In August, 2015, AZ transferred this trial to Lilly's ClinicalTrials.gov account and Lilly updated the record. This trial is not an applicable trial under the Food and Drug Administration Amendments Act of 2007 (FDAAA).

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Covance Inc
  • Texas
    • Dallas, Texas, United States, 75247
      • Covance Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Overtly healthy and either sterile or, male and prepared to use an approved method of contraception
• Have a body mass index (BMI) at screening of 19.0 to 32.0 kilogram per square meter (kg/m^2)

Exclusion Criteria:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the results, or may limit the subject's ability to participate in the study
• History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
• History of previous or ongoing psychiatric disease/condition

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; 500 microgram (mcg) midazolam, single oral dose on Days 1, 17, and 35; 20 mg simvastatin, single oral dose on Days 2 and 36; 250 microgram (mcg) midazolam, intravenous (IV) on Days 3 and 37; 50 mg lanabecestat, single oral dose on Day 4; 50 mg lanabecestat, single oral dose, Days 10 to 37	Drug: Lanabecestat; 50 mg lanabecestat will be administered orally as 1 × 50-mg tablet; Other Names: LY3314814; AZD3293; Drug: Simvastatin; 20 mg simvastatin will be administered orally as 1 × 20-mg tablet; Drug: Midazolam; 500 mcg midazolam will be administered orally as 0.25 mL of 2-mg/mL syrup; Drug: Midazolam; 250 mcg midazolam will be administered intravenous (IV) as 0.25 mL of 1-mg/mL injection solution
Experimental: Cohort B; 5 mg donepezil, single oral dose on Day 1, Period 1; 50 mg lanabecestat, single oral dose Days 1 to 43, Period 2; 5 mg donepezil, single oral dose on Day 28, Period 2	Drug: Lanabecestat; 50 mg lanabecestat will be administered orally as 1 × 50-mg tablet; Other Names: LY3314814; AZD3293; Drug: Donepezil; 5 mg donepezil will be administered orally as 1 × 5-mg tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814	Day 4: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours (Cohort A)
PK Profile for Simvastatin: AUC(0-∞)	Day 2 and 36: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours (Cohort A)
PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose	Day 1, 3, 17, 35, and 37: Predose, 0.25, 0.5, 1, 2, 3, 5, 8, and 12 hours (Cohort A)
PK Profile for Donepezil: AUC(0-∞)	Day 1 and 28: predose 0.5,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96,120, 216, 288, and 360 hours (Cohort B)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration		Cohort A : Baseline to Study Completion (Up to Day 50); Cohort B: Baseline to Study Completion (Up to Day 70)
Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)	C-SSRS captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal behavior is defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation is defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation.	Cohort A: Baseline to Study Completion (Up to Day 50); Cohort B: Baseline to Study Completion (Up to Day 70)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Eli Lilly and Company

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2015
• Primary Completion (Actual): August 31, 2015
• Study Completion (Actual): August 31, 2015

Study Registration Dates

• First Submitted: March 2, 2015
• First Submitted That Met QC Criteria: April 1, 2015
• First Posted (Estimate): April 2, 2015

Study Record Updates

• Last Update Posted (Actual): November 4, 2019
• Last Update Submitted That Met QC Criteria: October 18, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Cholinergic Agents; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Nootropic Agents; Cholinesterase Inhibitors; Midazolam; Simvastatin; Donepezil
• Other Study ID Numbers: 16014; I8D-MC-AZER (Other Identifier: Eli Lilly and Company)