Healthy
Conditions
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).
Interventions
DRUGLanabecestat
50 mg lanabecestat will be administered orally as 1 × 50-mg tablet
DRUGSimvastatin
20 mg simvastatin will be administered orally as 1 × 20-mg tablet
DRUGMidazolam
500 mcg midazolam will be administered orally as 0.25 mL of 2-mg/mL syrup
DRUGDonepezil
5 mg donepezil will be administered orally as 1 × 5-mg tablet
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
Countries
United States
Participant flow
Recruitment details
It was planned that all subjects in Cohort B would be enrolled at Site 002.
Participants by arm
| Arm | Count |
|---|---|
| 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 LY3314814, single oral dose on Day 4; 50 mg LY3314814, single oral dose, Days 10 to 37 | 50 |
| Cohort B 5 mg donepezil, single oral dose on Day 1 Period 1; 50 mg LY3314814, single oral dose Days 1 to 43, Period 2; 5 mg donepezil, single oral dose on Day 28 Period 2 | 32 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 0 |
| Period 1 | Lost to Follow-up | 2 | 0 |
| Period 2 | Physician Decision | 0 | 1 |
| Period 2 | Protocol Violation | 0 | 1 |
| Period 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort A | Cohort B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 32 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 7 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 25 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 14 Participants | 34 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 16 Participants | 43 Participants |
| Region of Enrollment United States | 50 Participants | 32 Participants | 82 Participants |
| Sex: Female, Male Female | 16 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 34 Participants | 22 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 50 | 7 / 32 |
| serious Total, serious adverse events | 0 / 50 | 0 / 32 |
Outcome results
Primary
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)
Population: Participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort A | Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814 | 3200 Nanogram * hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 21 |
Primary
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)
Population: Participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | PK Profile for Donepezil: AUC(0-∞) | Day 1 | 271 ng*h/mL | Geometric Coefficient of Variation 28 |
| Cohort A | PK Profile for Donepezil: AUC(0-∞) | Day 28 | 285 ng*h/mL | Geometric Coefficient of Variation 23 |
Primary
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)
Population: Participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose | AUC(0-∞) Oral Day 17 | 6.24 ng*h/mL | Geometric Coefficient of Variation 42 |
| Cohort A | PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose | AUC(0-∞) Oral Day 35 | 5.59 ng*h/mL | Geometric Coefficient of Variation 40 |
| Cohort A | PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose | AUC(0-∞) IV Day 3 | 11.4 ng*h/mL | Geometric Coefficient of Variation 22 |
| Cohort A | PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose | AUC(0-∞) IV Day 37 | 11.6 ng*h/mL | Geometric Coefficient of Variation 21 |
| Cohort A | PK Profile for Midazolam: AUC(0-∞) Oral and IV Dose | AUC(0-∞) Oral Day 1 | 6.53 ng*h/mL | Geometric Coefficient of Variation 38 |
Primary
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)
Population: Participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort A | PK Profile for Simvastatin: AUC(0-∞) | AUC(0-∞) Simvastatin Day 2 | 15.1 ng*h/mL | Geometric Coefficient of Variation 84 |
| Cohort A | PK Profile for Simvastatin: AUC(0-∞) | AUC(0-∞) Simvastatin Day 36 | 21.2 ng*h/mL | Geometric Coefficient of Variation 59 |
Secondary
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.
Time frame: Cohort A: Baseline to Study Completion (Up to Day 50); Cohort B: Baseline to Study Completion (Up to Day 70)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation | 0 Participants |
| Cohort A | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior | 0 Participants |
| Cohort B | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Behavior | 0 Participants |
| Cohort B | Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) | Suicidal Ideation | 0 Participants |
Secondary
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)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A | Number of Participants With One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration | 0 Participants |
| Cohort B | Number of Participants With One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration | 0 Participants |