A drug-Drug interaction study of Lanabecestat (LY3314814) in healthy participants

Study identifier:16014

ClinicalTrials.gov identifier:NCT02406261

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

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

Medical condition

Healthy

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Lanabecestat, Simvastatin, Midazolam, Donepezil

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 65 Years

Date

Study Start Date: 30 Apr 2015

Primary Completion Date: 31 Aug 2015

Study Completion Date: 31 Aug 2015

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Other

Verification:

Verified 01 Oct 2019 by AstraZeneca

Collaborators

Eli Lilly and Company

Inclusion and exclusion criteria

Location

Covance Inc

Daytona Beach, Florida, United States, 32117

Location

Covance Inc

Dallas, TX, United States, 75247

Arms	Assigned Interventions
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 Name: LY3314814 Other Name: 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 Name: LY3314814 Other Name: AZD3293

Arms

Assigned Interventions

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 Name: LY3314814

Other Name: 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 Name: LY3314814

Other Name: AZD3293

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
It was planned that all subjects in Cohort B would be enrolled at Site 002.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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 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
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

Participant Flow for 2 periods

Period 1: Period 1

	Cohort A	Cohort B
STARTED	50	32
Received at least one dose of study drug	50	32
COMPLETED	47	32
NOT COMPLETED	3	0
Lost to Follow-up	2	0
Adverse Event	1	0

Period 2: Period 2

	Cohort A	Cohort B
STARTED	0^[1]	32
COMPLETED	0	29
NOT COMPLETED	0	3
Physician Decision	0	1
Protocol Violation	0	1
Withdrawal by Subject	0	1

[1]	Cohort A participated in Period 1 only

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
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
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

Baseline Measures

	Cohort A	Cohort B	Total
Number of Participants [units: Participants]	50	32	82
Age Categorical [units: ]
<=18 years	0	0	0
Between 18 and 65 years	50	32	82
>=65 years	0	0	0
Gender, Male/Female [units: ]
Female	16	10	26
Male	34	22	56
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	21	7	28
Not Hispanic or Latino	29	25	54
Unknown or Not Reported	0	0	0
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	1	0	1
Asian	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	20	14	34
White	27	16	43
More than one race	2	1	3
Unknown or Not Reported	0	0	0
Region of Enrollment [units: ] United States	50	32	82

Outcome Measures

1. Primary Outcome Measure: 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) ]

Measure Type	Primary
Measure Name	Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814
Measure Description
Time Frame	Day 4: Predose, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours (Cohort A)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
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

Measured Values

	Cohort A
Number of Participants Analyzed [units:participants]	50
Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814 [units: Nanogram * hour per milliliter (ng*h/mL)] Geometric Mean (Geometric Coefficient of Variation)	3200 (21%)

No statistical analysis provided for Pharmacokinetic (PK): Area Under the Curve Zero to Infinity (AUC[0-∞]) for LY3314814

2. Primary Outcome Measure: 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) ]

Measure Type	Primary
Measure Name	PK Profile for Simvastatin: AUC(0-∞)
Measure Description
Time Frame	Day 2 and 36: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours (Cohort A)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
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

Measured Values

	Cohort A
Number of Participants Analyzed [units:participants]	49
PK Profile for Simvastatin: AUC(0-∞) [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AUC(0-∞) Simvastatin Day 2	15.1 (84%)
AUC(0-∞) Simvastatin Day 36	21.2 (59%)

No statistical analysis provided for PK Profile for Simvastatin: AUC(0-∞)

3. Primary Outcome Measure: 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) ]

Measure Type	Primary
Measure Name	PK Profile for Midazolam: AUC(0-∞) oral and IV dose
Measure Description
Time Frame	Day 1, 3, 17, 35, and 37: Predose, 0.25, 0.5, 1, 2, 3, 5, 8, and 12 hours (Cohort A)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
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

Measured Values

	Cohort A
Number of Participants Analyzed [units:participants]	49
PK Profile for Midazolam: AUC(0-∞) oral and IV dose [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)
AUC(0-∞) Oral Day 1	6.53 (38%)
AUC(0-∞) Oral Day 17	6.24 (42%)
AUC(0-∞) Oral Day 35	5.59 (40%)
AUC(0-∞) IV Day 3	11.4 (22%)
AUC(0-∞) IV Day 37	11.6 (21%)

No statistical analysis provided for PK Profile for Midazolam: AUC(0-∞) oral and IV dose

4. Primary Outcome Measure: 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) ]

Measure Type	Primary
Measure Name	PK Profile for Donepezil: AUC(0-∞)
Measure Description
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)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
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

Measured Values

	Cohort B
Number of Participants Analyzed [units:participants]	31
PK Profile for Donepezil: AUC(0-∞) [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)
Day 1	271 (28%)
Day 28	285 (23%)

No statistical analysis provided for PK Profile for Donepezil: AUC(0-∞)

5. Secondary Outcome Measure: 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) ]

Measure Type	Secondary
Measure Name	Number of Participants with One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration
Measure Description
Time Frame	Cohort A : Baseline to Study Completion (Up to Day 50); Cohort B: Baseline to Study Completion (Up to Day 70)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug.

Reporting Groups

	Description
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
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

Measured Values

	Cohort A	Cohort B
Number of Participants Analyzed [units:participants]	50	32
Number of Participants with One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration [units: ]	0	0

No statistical analysis provided for Number of Participants with One or More Serious Adverse Events(s) Considered by the Investigator to be Related to Study Drug Administration

6. Secondary Outcome Measure: 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) ]

Measure Type	Secondary
Measure Name	Number of Participants Experiencing Suicidal Ideation or Suicidal behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)
Measure Description	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)
Safety Issue?

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Participants who received at least one dose of study drug.

Reporting Groups

	Description
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
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

Measured Values

	Cohort A	Cohort B
Number of Participants Analyzed [units:participants]	50	32
Number of Participants Experiencing Suicidal Ideation or Suicidal behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) [units: ]
Suicidal Ideation	0	0
Suicidal Behavior	0	0

No statistical analysis provided for Number of Participants Experiencing Suicidal Ideation or Suicidal behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
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
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

Serious Adverse Events

	Cohort A	Cohort B
Total, serious adverse events
# participants affected / at risk	0/50 (0.00%)	0/32 (0.00%)

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
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
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