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

Study Overview
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Brief Summary
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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

Detailed Description
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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).

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Lanabecestat
* Drug: Simvastatin
* Drug: Midazolam
* Drug: Midazolam
* Drug: Donepezil
* Drug: Lanabecestat


Participation Criteria
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Eligibility Criteria
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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

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: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>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<br>* 50 mg lanabecestat will be administered orally as 1 × 50-mg tablet<br>* Other names: AZD3293;Drug: Simvastatin<br>* 20 mg simvastatin will be administered orally as 1 × 20-mg tablet<br>Drug: Midazolam<br>* 500 mcg midazolam will be administered orally as 0.25 mL of 2-mg/mL syrup<br>Drug: Midazolam<br>* 250 mcg midazolam will be administered intravenous (IV) as 0.25 mL of 1-mg/mL injection solution<br>|
| Experimental: Cohort B<br>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: Donepezil<br>* 5 mg donepezil will be administered orally as 1 × 5-mg tablet<br>Drug: Lanabecestat<br>* 50 mg lanabecestat will be administered orally as 1 × 50-mg tablet<br>* Other names: AZD3293;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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) |