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

• ClinicalTrials.gov Identifier: NCT02406261
• Recruitment Status: Completed
• First Posted: April 2, 2015
• Results First Posted: March 22, 2019
• Last Update Posted: November 4, 2019
• Sponsor: AstraZeneca
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: March 2, 2015
• First Posted Date: April 2, 2015
• Results First Submitted Date: December 13, 2018
• Results First Posted Date: March 22, 2019
• Last Update Posted Date: November 4, 2019
• Actual Study Start Date: April 30, 2015
• Actual Primary Completion Date: August 31, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 13, 2018)

• Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814 [ Time Frame: 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-∞) [ Time Frame: 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 [ Time Frame: 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-∞) [ Time Frame: 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) ]

Original Primary Outcome Measures (submitted: April 1, 2015)

• Description of the pharmacokinetic (PK) profile for AZD3293 and metabolite following single-dose administration in terms of observed maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax) [ Time Frame: Day 4: predose - 120 hours after dose; Days 17, 23, 30: predose- 24 hours postdose (Cohort A) ]
  Primary objectives are to characterize AZD3293 PK as a function of AZD3293 dosing duration Other noncompartmental parameters, such as the apparent total body clearance of drug calculated after extravascular administration (CL/F) (AZD3293 only) and apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) (AZD3293 only), may be reported.
• Description of the PK profile for AZD3293 & metabolite following single-dose administration: area under the curve (AUC(0-∞)), AUC from time zero to time t, where t is the last time point with a measurable concentration (AUC[0-tlast]), half-life (t1/2) [ Time Frame: Day 4: predose - 120 hours after dose; Days 17, 23, 30: predose- 24 hours postdose (Cohort A) ]
  Primary objectives are to characterize AZD3293 PK as a function of AZD3293 dosing duration
• Description of the PK profile for AZD3293 and metabolite following multiple-dose administration Cmax, tmax, AUCτ, accumulation ratio (RA), and apparent total body clearance of drug calculated after extravascular administration (CL/F) (AZD3293 only). [ Time Frame: Days 17, 23, 30: predose-24 hours postdose; Day 37: predose - 120 hours after dose (Cohort A) ]
  Primary objectives are to characterize AZD3293 PK as a function of AZD3293 dosing duration
• Trough plasma AZD3293 and its metabolite concentrations [ Time Frame: One measurement on days 14, 17, 20, 23, 27, 30, 33, and 37 (Cohort A) ]
  Primary objectives are to characterize AZD3293 PK as a function of AZD3293 dosing duration
• Description of the PK profile for simvastatin and metabolite in terms of Cmax, tmax, AUC(0-∞), AUC(0-tlast), and t1/2. [ Time Frame: After each administration of simvastatin (Cohort A) ]
  Primary objectives are • to evaluate the effect of 50 mg multiple-dose AZD3293 on the PK of single-dose simvastatin (oral) in healthy subjects. Other noncompartmental parameters, such as CL/F and Vz/F, may be reported as appropriate.
• Description of the PK profile for midazolam and its metabolite in terms of Cmax, tmax, AUC(0-∞), AUC(0-tlast), and t1/2. [ Time Frame: Following each oral and IV dose administration of midazolam (Cohort A) ]
  Primary objectives are to evaluate the effect of 50 mg multiple-dose AZD3293 on the PK of single-dose midazolam (oral and IV) in healthy subjects Other noncompartmental parameters, such as CL/F and Vz/F, may be reported as appropriate.
• Description of the PK profile for AZD3293 and its metabolite in terms of Cmax, tmax, AUCτ, and CL/F (AZD3293 only) [ Time Frame: Day 28 period 2, predose up to 24 hours postdose (Cohort B) ]
  Primary objectives are to evaluate the effect of 50 mg multiple-dose AZD3293 on the PK of single-dose donepezil (oral) in healthy subjects
• Plasma concentrations of AZD3293 and its metabolite [ Time Frame: Days 1 and 14 in Period 2, 2 hours postdose of AZD3293 (Cohort B) ]
  Primary objectives are to evaluate the effect of 50 mg multiple-dose AZD3293 on the PK of single-dose donepezil (oral) in healthy subjects
• Description of the PK profile for donepezil in terms of Cmax, tmax, AUC(0-∞), AUC(0-tlast), and t1/2. [ Time Frame: From predose and up to 360 hours postdose after each administration of donepezil (Cohort B) ]
  Primary objectives are to evaluate the effect of 50 mg multiple-dose AZD3293 on the PK of single-dose donepezil (oral) in healthy subjects Other noncompartmental parameters, such as CL/F and Vz/F, may be reported as appropriate.

Current Secondary Outcome Measures (submitted: April 22, 2019)

• Number of Participants With One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration [ Time Frame: 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) [ Time Frame: Cohort A: Baseline to Study Completion (Up to Day 50); Cohort B: Baseline to Study Completion (Up to Day 70) ]
  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.

Original Secondary Outcome Measures (submitted: April 1, 2015)

• Safety and tolerability of AZD3293 by means of vital sign measurements, clinical laboratory tests, and electrocardiograms (ECGs). [ Time Frame: From screening period up to the follow-up visit ≥7 days after the last dose. ]
  Safety and tolerability of AZD3293 by means of vital sign measurements, clinical laboratory tests, and ECGs, when coadministered with midazolam (Cohort A), simvastatin (Cohort A), and donepezil (Cohort B) in healthy subjects
• Safety and tolerability of AZD3293 by means of Columbia-Suicide Severity Rating Scale (C-SSRS), physical examinations, oxygen saturation monitoring, eye and skin examinations, and adverse events recording [ Time Frame: From screening period up to the follow-up visit ≥7 days after the last dose. ]
  Safety and tolerability of AZD3293 by means of Columbia-Suicide Severity Rating Scale (C-SSRS), physical examinations (as indicated), oxygen saturation monitoring (Cohort A only), eye and skin examinations, and adverse event recording, when coadministered with midazolam (Cohort A), simvastatin (Cohort A), and donepezil (Cohort B) in healthy subjects

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Drug-Drug Interaction Study of Lanabecestat (LY3314814) in Healthy Participants
• Official Title: 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
• Brief Summary: 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: 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
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Healthy

Intervention

• 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
• Drug: Donepezil
  5 mg donepezil will be administered orally as 1 × 5-mg tablet

Study Arms

• 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

  Interventions:

  • Drug: Lanabecestat
  • Drug: Simvastatin
  • Drug: Midazolam
  • Drug: Midazolam
• 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

  Interventions:

  • Drug: Donepezil
  • Drug: Lanabecestat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 1, 2015): 82
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 31, 2015
• Actual Primary Completion Date: August 31, 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02406261
• Other Study ID Numbers: 16014; I8D-MC-AZER ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: AstraZeneca
• Study Sponsor: AstraZeneca
• 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

• PRS Account: AstraZeneca
• Verification Date: October 2019