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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Eli Lilly and Company
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE March 2, 2015
First Posted Date  ICMJE April 2, 2015
Results First Submitted Date  ICMJE December 13, 2018
Results First Posted Date  ICMJE March 22, 2019
Last Update Posted Date November 4, 2019
Actual Study Start Date  ICMJE April 30, 2015
Actual Primary Completion Date August 31, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE A Drug-Drug Interaction Study of Lanabecestat (LY3314814) in Healthy Participants
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Healthy
Intervention  ICMJE
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 1, 2015)
82
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 31, 2015
Actual Primary Completion Date August 31, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02406261
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Eli Lilly and Company
Investigators  ICMJE
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

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP