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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02568397
• Collaborator: Eli Lilly and Company (Industry)
• Enrollment: 60
• Location: 1
• Arms: 2
• Actual Duration (Months): 3
• Patients Per Site Per Month: 19.9

Study Details

Study Description

Brief Summary

The purpose of this study is to learn about the effect of lanabecestat on how the body absorbs and processes dabigatran etexilate and how dabigatran etexilate affects lanabecestat when they are taken together. This study will last about 28 days and participants will be asked to take an lanabecestat tablet daily for 19 days and a dabigatran etexilate tablet on 3 occasions. Screening is required within 30 days prior to the start of the study.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Lanabecestat; Drug: Dabigatran etexilate	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Effect of LY3314814 on the Pharmacokinetics of Dabigatran in Healthy Subjects
• Actual Study Start Date: Oct 31, 2015
• Actual Primary Completion Date: Jan 31, 2016
• Actual Study Completion Date: Jan 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabigatran Etexilate Single dose of dabigatran etexilate administered orally.	Drug: Dabigatran etexilate; Administered orally
Experimental: Lanabecestat and Dabigatran Etexilate Single dose of lanabecestat administered orally once daily on Days 3 to 21. Single doses of dabigatran etexilate administered orally on Days 16 and 20 during the lanabecestat dosing.	Drug: Lanabecestat; Administered orally; Other Names: LY3314814 AZD3293 ; Drug: Dabigatran etexilate; Administered orally

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetics (PK) : Maximum Concentration (Cmax) of Dabigatran [Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose]

2. Pharmacokinetics: Area Under The Dabigatran Pharmacokinetic (PK) Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity) [Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose]

Secondary Outcome Measures

1. Pharmacokinetics: Maximum Concentration (Cmax) of Lanabecestat [Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose]

2. Pharmacokinetics: Area Under the Lanabecestat Pharmacokinetic (PK) Concentration Versus Time Curve During One Dosing Interval (24 Hours) (AUCtau) [Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose]

3. Pharmacodynamics: Area Under the Effect Versus Time Curve (AUEC) of Thrombin Time [Days 1, 16 and 20: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose]

4. Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) of Thrombin Time [Days 1, 16 and 20: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose]

   Ratio of maximum effect to baseline effect following administration of 150 mg dabigatran etexilate alone on Day 1, 50 mg LY3314814 and 150 mg dabigatran dosed concurrently on Day 16, and 50 mg LY3314814 and 150 mg dabigatran (dosed 4 hours later) on Day 20

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Overtly healthy males and females

Exclusion Criteria:

• Eye abnormalities or disease

• History of vitiligo or any skin color disorder

• Have a history psychiatric or brain disease including seizures

• Have smoked within the last 3 months

• Are unwilling to avoid food and drinks containing grapefruit or Seville oranges for the duration of the study

• Have known allergies to dabigatran etexilate and related compounds

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance	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: NCT02568397
• Other Study ID Numbers: 15997; I8D-MC-AZEE
• First Posted: Oct 5, 2015
• Last Update Posted: Nov 1, 2019
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Dabigatran

Study Results

Participant Flow

Arm/Group Title	Dabigatran Etexilate	LY3314814 + Dabigatran Etexilate
Arm/Group Description	Single dose of dabigatran etexilate administered orally on Day 1.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Single doses of dabigatran etexilate administered orally on Days 16 and 20 during the LY3314814 dosing
Period Title: Period 1
STARTED	60	0
Received at Least 1 Dose of Study Drug	60	0
COMPLETED	60	0
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	0	60
COMPLETED	0	58
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Overall
Arm/Group Description	Overall study population
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.1 (7.9)
Sex: Female, Male (Count of Participants)
Female	8 13.3%
Male	52 86.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 20%
Not Hispanic or Latino	48 80%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	31 51.7%
White	25 41.7%
More than one race	4 6.7%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	60 100%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetics (PK) : Maximum Concentration (Cmax) of Dabigatran
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug and have evaluable pharmacokinetic (PK) data.

Arm/Group Title	Dabigatran Etexilate	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	Single dose of 150mg dabigatran etexilate administered orally on Day 1.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21.Single dose of dabigatran etexilate administered orally 4 hours after LY3314814 administration on Day 20.
Measure Participants	60	56	54
Geometric Mean (Geometric Coefficient of Variation) [nanogram per milliliter (ng/mL)]	128 (69)	148 (56)	138 (46)

2. Primary Outcome

Title	Pharmacokinetics: Area Under The Dabigatran Pharmacokinetic (PK) Concentration Versus Time Curve From Zero to Infinity (AUC[0-infinity)
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dabigatran Etexilate	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	Single dose of 150mg dabigatran etexilate administered orally on Day 1.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21.Single dose of dabigatran etexilate administered orally 4 hours after LY3314814 administration on Day 20.
Measure Participants	60	56	54
Geometric Mean (Geometric Coefficient of Variation) [nanogram*hour per milliliter (ng*h/mL)]	1090 (61)	1240 (53)	1110 (44)

3. Secondary Outcome

Title	Pharmacokinetics: Maximum Concentration (Cmax) of Lanabecestat
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose

Outcome Measure Data

Analysis Population Description

All participants who received one dose of study drug and had evaluable PK data.

Arm/Group Title	LY3314814 (AZD3293)	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	50 mg LY3314814 administered orally alone on Day 15.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21.Single dose of dabigatran etexilate administered orally 4 hours after LY3314814 administration on Day 20.
Measure Participants	57	57	56
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	342 (23)	315 (21)	331 (21)

4. Secondary Outcome

Title	Pharmacokinetics: Area Under the Lanabecestat Pharmacokinetic (PK) Concentration Versus Time Curve During One Dosing Interval (24 Hours) (AUCtau)
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose

Outcome Measure Data

Analysis Population Description

All participants who received one dose of study drug and had evaluable PK data.

Arm/Group Title	LY3314814 (AZD3293)	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	50 mg LY3314814 administered orally alone on Day 15	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on Day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 20.
Measure Participants	57	57	56
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	3360 (25)	3300 (26)	3490 (24)

5. Secondary Outcome

Title	Pharmacodynamics: Area Under the Effect Versus Time Curve (AUEC) of Thrombin Time
Time Frame	Days 1, 16 and 20: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug and had evaluable Pharmacodynamic (PD) data.

Arm/Group Title	Dabigatran Extexilate Day 1	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	Single dose of 150 mg dabigatran etexilate administered orally on Day 1	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on Day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21.Single dose of dabigatran etexilate administered orally 4 hours after LY3314814 administration on Day 20.
Measure Participants	57	55	49
Mean (Standard Deviation) [seconds*hour (s*h)]	2080 (517)	2170 (611)	2030 (518)

6. Secondary Outcome

Title	Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) of Thrombin Time
Description	Ratio of maximum effect to baseline effect following administration of 150 mg dabigatran etexilate alone on Day 1, 50 mg LY3314814 and 150 mg dabigatran dosed concurrently on Day 16, and 50 mg LY3314814 and 150 mg dabigatran (dosed 4 hours later) on Day 20
Time Frame	Days 1, 16 and 20: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug and had evaluable Pharmacodynamic (PD) data.

Arm/Group Title	Dabigatran Extexilate Day 1	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	Single dose of 150mg dabigatran etexilate administered orally on Day 1.	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on Day 16.	Single dose of LY3314814 administered orally once daily on Days 3 to 21.Single dose of dabigatran etexilate administered orally 4 hours after LY3314814 administration on Day 20.
Measure Participants	42	42	32
Median (Full Range) [ratio of maximum effect]	7.10	7.09	7.00

Adverse Events

Arm/Group Title	Dabigatran Etexilate		LY3314814 (AZD3293)		LY3314814 and Dabigatran Etexilate Day 16		LY3314814 and Dabigatran Etexilate Day 20
Arm/Group Description	Single dose of 150mg dabigatran etexilate administered orally.		50 mg LY3314814 administered orally alone on Day 15		Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on Day 16.		Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 20.
All Cause Mortality
	Dabigatran Etexilate		LY3314814 (AZD3293)		LY3314814 and Dabigatran Etexilate Day 16		LY3314814 and Dabigatran Etexilate Day 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dabigatran Etexilate		LY3314814 (AZD3293)		LY3314814 and Dabigatran Etexilate Day 16		LY3314814 and Dabigatran Etexilate Day 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/60 (0%)		0/60 (0%)		0/58 (0%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	Dabigatran Etexilate		LY3314814 (AZD3293)		LY3314814 and Dabigatran Etexilate Day 16		LY3314814 and Dabigatran Etexilate Day 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/60 (5%)		8/60 (13.3%)		2/58 (3.4%)		4/58 (6.9%)
Gastrointestinal disorders
Gingival pain	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Nausea	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Vomiting	0/60 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/58 (1.7%)	1
General disorders
Asthenia	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Chest pain	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Fatigue	1/60 (1.7%)	1	0/60 (0%)	0	0/58 (0%)	0	0/58 (0%)	0
Feeling hot	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Vessel puncture site haematoma	1/60 (1.7%)	1	0/60 (0%)	0	0/58 (0%)	0	0/58 (0%)	0
Vessel puncture site swelling	0/60 (0%)	0	0/60 (0%)	0	1/58 (1.7%)	1	0/58 (0%)	0
Infections and infestations
Upper respiratory tract infection	0/60 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/58 (1.7%)	1
Injury, poisoning and procedural complications
Skin abrasion	0/60 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/58 (1.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/60 (1.7%)	1	0/60 (0%)	0	0/58 (0%)	0	0/58 (0%)	0
Nervous system disorders
Dizziness	0/60 (0%)	0	2/60 (3.3%)	2	1/58 (1.7%)	1	0/58 (0%)	0
Headache	0/60 (0%)	0	3/60 (5%)	4	0/58 (0%)	0	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Haemoptysis	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/60 (0%)	0	0/60 (0%)	0	0/58 (0%)	0	1/58 (1.7%)	1
Rash	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	1/58 (1.7%)	2
Skin irritation	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (0%)	0
Vascular disorders
Flushing	0/60 (0%)	0	1/60 (1.7%)	1	0/58 (0%)	0	0/58 (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.