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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02406261
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 82
• Locations: 2
• Arms: 2
• Actual Duration (Months): 4
• Patients Per Site: 41
• Patients Per Site Per Month: 10.1

Study Details

Study Description

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: Midazolam; Drug: Donepezil; Drug: Lanabecestat	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 Design

• Study Type: Interventional
• 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
• Actual Study Start Date: Apr 30, 2015
• Actual Primary Completion Date: Aug 31, 2015
• Actual Study Completion Date: Aug 31, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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)]

2. 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)]

3. 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)]

4. 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 Outcome Measures

1. 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)]

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance Inc	Daytona Beach	Florida	United States	32117
2	Covance Inc	Dallas	Texas	United States	75247

Sponsors and Collaborators

• AstraZeneca
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02406261
• Other Study ID Numbers: 16014; I8D-MC-AZER
• First Posted: Apr 2, 2015
• Last Update Posted: Nov 4, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Midazolam; Donepezil; Simvastatin

Study Results

Participant Flow

Recruitment Details	It was planned that all subjects in Cohort B would be enrolled at Site 002.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	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	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
Period Title: Period 1
STARTED	50	32
Received at Least One Dose of Study Drug	50	32
COMPLETED	47	32
NOT COMPLETED	3	0
Period Title: Period 1
STARTED	0	32
COMPLETED	0	29
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	50	32	82
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	50 100%	32 100%	82 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	16 32%	10 31.3%	26 31.7%
Male	34 68%	22 68.8%	56 68.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 42%	7 21.9%	28 34.1%
Not Hispanic or Latino	29 58%	25 78.1%	54 65.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2%	0 0%	1 1.2%
Asian	0 0%	1 3.1%	1 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	20 40%	14 43.8%	34 41.5%
White	27 54%	16 50%	43 52.4%
More than one race	2 4%	1 3.1%	3 3.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	50 100%	32 100%	82 100%

Outcome Measures

1. Primary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	Cohort A
Arm/Group Description	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
Measure Participants	50
Geometric Mean (Geometric Coefficient of Variation) [Nanogram * hour per milliliter (ng*h/mL)]	3200 (21)

2. Primary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	Cohort A
Arm/Group Description	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
Measure Participants	49
AUC(0-∞) Simvastatin Day 2	15.1 (84)
AUC(0-∞) Simvastatin Day 36	21.2 (59)

3. Primary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	Cohort A
Arm/Group Description	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
Measure Participants	49
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)

4. Primary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	Cohort B
Arm/Group Description	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
Measure Participants	31
Day 1	271 (28)
Day 28	285 (23)

5. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	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	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
Measure Participants	50	32
Count of Participants [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Number of Participants Experiencing Suicidal Ideation or Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)
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)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug.

Arm/Group Title	Cohort A	Cohort B
Arm/Group Description	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	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
Measure Participants	50	32
Suicidal Ideation	0 0%	0 0%
Suicidal Behavior	0 0%	0 0%

Adverse Events

Arm/Group Title	Cohort A		Cohort B
Arm/Group Description	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		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
All Cause Mortality
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/50 (12%)		7/32 (21.9%)
Gastrointestinal disorders
Diarrhoea	1/50 (2%)	1	2/32 (6.3%)	2
Injury, poisoning and procedural complications
Contusion	1/50 (2%)	1	2/32 (6.3%)	2
Musculoskeletal and connective tissue disorders
Back pain	0/50 (0%)	0	2/32 (6.3%)	2
Pain in extremity	0/50 (0%)	0	2/32 (6.3%)	2
Nervous system disorders
Headache	2/50 (4%)	2	2/32 (6.3%)	2
Skin and subcutaneous tissue disorders
Pruritus	3/50 (6%)	3	0/32 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.