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

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ClinicalTrials.gov Identifier: NCT02406261
Recruitment Status : Completed
First Posted : April 2, 2015
Last Update Posted : May 30, 2017
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Eli Lilly and Company

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

Condition or disease Intervention/treatment Phase
Healthy Drug: Lanabecestat Drug: Simvastatin Drug: Midazolam Drug: Donepezil Phase 1

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  (Clinical Trial)
Actual Enrollment : 82 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Study Start Date : April 2015
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

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

Drug: Lanabecestat
50 mg lanabecestat will be administered orally as 1 × 50-mg tablet
Other Names:
  • LY3314814
  • AZD3293




Primary Outcome Measures :
  1. Description of the pharmacokinetic (PK) profile for Lanabecestat 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 Lanabecestat PK as a function of Lanabecestat dosing duration Other noncompartmental parameters, such as the apparent total body clearance of drug calculated after extravascular administration (CL/F) (Lanabecestat only) and apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) (Lanabecestat only), may be reported.

  2. 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 Lanabecestat PK as a function of Lanabecestat dosing duration

  3. Description of the PK profile for AZD3293 and metabolite following multiple-dose administration Cmax, tmax, AUCtau, 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 Lanabecestat PK as a function of Lanabecestat dosing duration

  4. Trough plasma Lanabecestat 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 Lanabecestat PK as a function of Lanabecestat dosing duration

  5. 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 Lanabecestat 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.

  6. 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 Lanabecestat 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.

  7. Description of the PK profile for Lanabecestat and its metabolite in terms of Cmax, tmax, AUCtau, and CL/F (Lanabecestat 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 Lanabecestat on the PK of single-dose donepezil (oral) in healthy subjects

  8. Plasma concentrations of Lanabecestat and its metabolite [ Time Frame: Days 1 and 14 in Period 2, 2 hours postdose of Lanabecestat (Cohort B) ]
    Primary objectives are to evaluate the effect of 50 mg multiple-dose Lanabecestat on the PK of single-dose donepezil (oral) in healthy subjects

  9. 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 Lanabecestat 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.


Secondary Outcome Measures :
  1. Safety and tolerability of Lanabecestat 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 Lanabecestat 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

  2. Safety and tolerability of Lanabecestat by means of Columbia-Suicide Severity Rating Scale (C-SSRS), physical examinations, oxygen saturation monitoring, eye and skin examinations, and adverse event (AE) recording [ Time Frame: From screening period up to the follow-up visit ≥7 days after the last dose. ]
    Safety and tolerability of Lanabecestat 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 AE recording, when coadministered with midazolam (Cohort A), simvastatin (Cohort A), and donepezil (Cohort B) in healthy subjects



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02406261


Locations
United States, Florida
Covance Inc
Daytona Beach, Florida, United States, 32117
United States, Texas
Covance Inc
Dallas, Texas, United States, 75247
Sponsors and Collaborators
Eli Lilly and Company
AstraZeneca
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

Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02406261     History of Changes
Other Study ID Numbers: 16014
I8D-MC-AZER ( Other Identifier: Eli Lilly and Company )
First Posted: April 2, 2015    Key Record Dates
Last Update Posted: May 30, 2017
Last Verified: May 2017

Additional relevant MeSH terms:
Midazolam
Donepezil
Simvastatin
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Cholinesterase Inhibitors
Cholinergic Agents
Nootropic Agents