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

Study identifier:15997

ClinicalTrials.gov identifier:NCT02568397

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Effect of LY3314814 on the Pharmacokinetics of Dabigatran in Healthy Subjects

Medical condition

Healthy

Phase

Phase 1

Healthy volunteers

Yes

Study drug

Lanabecestat, Dabigatran etexilate

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 50 Years

Date

Study Start Date: 31 Oct 2015

Primary Completion Date: 31 Jan 2016

Study Completion Date: 31 Jan 2016

Study design

Allocation: Non-randomized
Endpoint Classification: -
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science

Verification:

Verified 01 Oct 2019 by AstraZeneca

Collaborators

Eli Lilly and Company

Inclusion and exclusion criteria

Location

Covance

Dallas, TX, United States, 75247

Arms	Assigned Interventions
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 Name: LY3314814 Other Name: AZD3293 Drug: Dabigatran etexilate Administered orally

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

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
Dabigatran Etexilate	Single dose of dabigatran etexilate administered orally on Day 1.
LY3314814 + Dabigatran Etexilate	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

Participant Flow for 2 periods

Period 1: Period 1

	Dabigatran Etexilate	LY3314814 + Dabigatran Etexilate
STARTED	60	0
Received at Least 1 Dose of Study Drug	60	0
COMPLETED	60	0
NOT COMPLETED	0	0

Period 2: Period 2

	Dabigatran Etexilate	LY3314814 + Dabigatran Etexilate
STARTED	0^[1]	60^[2]
COMPLETED	0	58
NOT COMPLETED	0	2
Withdrawal by Subject	0	1
Physician Decision	0	1

[1]	A single oral dose of 150 mg dabigatran etexilate was administered on Day 1 of Period 1.
[2]	Daily doses of 50 mg LY3314814 were administered daily on Days 3 to 21 of Period 2.

Baseline Characteristics

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

Received at least one dose of study drug.

Reporting Groups

	Description
Overall	Overall study population

Baseline Measures

	Overall
Number of Participants [units: Participants]	60
Age Continuous [units: years] Mean ± Standard Deviation	36.1 ± 7.9
Gender, Male/Female [units: ]
Female	8
Male	52
Ethnicity (NIH/OMB) [units: ]
Hispanic or Latino	12
Not Hispanic or Latino	48
Unknown or Not Reported	0
Race (NIH/OMB) [units: ]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	31
White	25
More than one race	4
Unknown or Not Reported	0
Region of Enrollment [units: ] United States	60

Outcome Measures

1. Primary Outcome Measure: 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 ]

Measure Type	Primary
Measure Name	Pharmacokinetics (PK) : Maximum Concentration (Cmax) of Dabigatran
Measure Description
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose
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.
All participants who received at least one dose of study drug and have evaluable pharmacokinetic (PK) data.

Reporting Groups

	Description
Dabigatran Etexilate	Single dose of 150mg dabigatran etexilate administered orally on Day 1.
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	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.

Measured Values

	Dabigatran Etexilate	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	60	56	54
Pharmacokinetics (PK) : Maximum Concentration (Cmax) of Dabigatran [units: nanogram per milliliter (ng/mL)] Geometric Mean (Geometric Coefficient of Variation)	128 (69%)	148 (56%)	138 (46%)

No statistical analysis provided for Pharmacokinetics (PK) : Maximum Concentration (Cmax) of Dabigatran

2. Primary Outcome Measure: 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 ]

Measure Type	Primary
Measure Name	Pharmacokinetics: Area Under The Dabigatran Pharmacokinetic (PK) Concentration Versus Time Curve from Zero to Infinity (AUC[0-infinity)
Measure Description
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose
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.
All participants who received at least one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
Dabigatran Etexilate	Single dose of 150mg dabigatran etexilate administered orally on Day 1.
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	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.

Measured Values

	Dabigatran Etexilate	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	60	56	54
Pharmacokinetics: Area Under The Dabigatran Pharmacokinetic (PK) Concentration Versus Time Curve from Zero to Infinity (AUC[0-infinity) [units: nanogramhour per milliliter (ngh/mL)] Geometric Mean (Geometric Coefficient of Variation)	1090 (61%)	1240 (53%)	1110 (44%)

No statistical analysis provided for Pharmacokinetics: Area Under The Dabigatran Pharmacokinetic (PK) Concentration Versus Time Curve from Zero to Infinity (AUC[0-infinity)

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

Measure Type	Secondary
Measure Name	Pharmacokinetics: Maximum Concentration (Cmax) of Lanabecestat
Measure Description
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdose
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.
All participants who received one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
LY3314814 (AZD3293)	50 mg LY3314814 administered orally alone on Day 15.
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	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.

Measured Values

	LY3314814 (AZD3293)	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	57	57	56
Pharmacokinetics: Maximum Concentration (Cmax) of Lanabecestat [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	342 (23%)	315 (21%)	331 (21%)

No statistical analysis provided for Pharmacokinetics: Maximum Concentration (Cmax) of Lanabecestat

4. Secondary Outcome Measure: 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 ]

Measure Type	Secondary
Measure Name	Pharmacokinetics: Area Under the Lanabecestat Pharmacokinetic (PK) Concentration Versus Time Curve During One Dosing Interval (24 hours) (AUCtau)
Measure Description
Time Frame	Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose
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.
All participants who received one dose of study drug and had evaluable PK data.

Reporting Groups

	Description
LY3314814 (AZD3293)	50 mg LY3314814 administered orally alone on Day 15
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 20.

Measured Values

	LY3314814 (AZD3293)	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	57	57	56
Pharmacokinetics: Area Under the Lanabecestat Pharmacokinetic (PK) Concentration Versus Time Curve During One Dosing Interval (24 hours) (AUCtau) [units: ng*h/mL] Geometric Mean (Geometric Coefficient of Variation)	3360 (25%)	3300 (26%)	3490 (24%)

No statistical analysis provided for Pharmacokinetics: Area Under the Lanabecestat Pharmacokinetic (PK) Concentration Versus Time Curve During One Dosing Interval (24 hours) (AUCtau)

5. Secondary Outcome Measure: 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 ]

Measure Type	Secondary
Measure Name	Pharmacodynamics: Area Under the Effect Versus Time Curve (AUEC) of Thrombin Time
Measure Description
Time Frame	Days 1, 16 and 20: Predose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 36 hours postdose
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.
All participants who received at least one dose of study drug and had evaluable Pharmacodynamic (PD) data.

Reporting Groups

	Description
Dabigatran Extexilate Day 1	Single dose of 150 mg dabigatran etexilate administered orally on Day 1
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	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.

Measured Values

	Dabigatran Extexilate Day 1	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	57	55	49
Pharmacodynamics: Area Under the Effect Versus Time Curve (AUEC) of Thrombin Time [units: secondshour (sh)] Mean (Standard Deviation)	2080 (517)	2170 (611)	2030 (518)

No statistical analysis provided for Pharmacodynamics: Area Under the Effect Versus Time Curve (AUEC) of Thrombin Time

6. Secondary Outcome Measure: Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) 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 ]

Measure Type	Secondary
Measure Name	Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) of Thrombin Time
Measure 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
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.
All participants who received at least one dose of study drug and had evaluable Pharmacodynamic (PD) data.

Reporting Groups

	Description
Dabigatran Extexilate Day 1	Single dose of 150mg dabigatran etexilate administered orally on Day 1.
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	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.

Measured Values

	Dabigatran Extexilate Day 1	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Number of Participants Analyzed [units:participants]	42	42	32
Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) of Thrombin Time [units: ratio of maximum effect] Median (Full Range)	7.10 (3.49 to 7.84)	7.09 (1.06 to 7.84)	7.00 (1.10 to 7.95)

No statistical analysis provided for Pharmacodynamics: Ratio of Maximum Effect to Baseline Effect (ERmax) of Thrombin Time

Serious Adverse Events

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

Reporting Groups

	Description
Dabigatran Etexilate	Single dose of 150mg dabigatran etexilate administered orally.
LY3314814 (AZD3293)	50 mg LY3314814 administered orally alone on Day 15
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 20.

Serious Adverse Events

	Dabigatran Etexilate	LY3314814 (AZD3293)	LY3314814 and Dabigatran Etexilate Day 16	LY3314814 and Dabigatran Etexilate Day 20
Total, serious adverse events
# participants affected / at risk	0/60 (0.00%)	0/60 (0.00%)	0/58 (0.00%)	0/58 (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	0%

Reporting Groups

	Description
Dabigatran Etexilate	Single dose of 150mg dabigatran etexilate administered orally.
LY3314814 (AZD3293)	50 mg LY3314814 administered orally alone on Day 15
LY3314814 and Dabigatran Etexilate 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 16.
LY3314814 and Dabigatran Etexilate Day 20	Single dose of LY3314814 administered orally once daily on Days 3 to 21. Concurrent single dose of dabigatran etexilate administered orally on day 20.

Other Adverse Events

Dabigatran Etexilate

LY3314814 (AZD3293)

LY3314814 and Dabigatran Etexilate Day 16

LY3314814 and Dabigatran Etexilate Day 20

Total, other (not including serious) adverse events

# participants affected / at risk

3/60 (5.00%)

8/60 (13.33%)

2/58 (3.45%)

4/58 (6.90%)

Gastrointestinal disorders

Gingival pain¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

Gastrointestinal disorders

Vomiting¹,^†

# participants affected / at risk

0/60 (0.00%)

0/58 (0.00%)

1/58 (1.72%)

# events

General disorders

Asthenia¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

General disorders

Chest pain¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

General disorders

Fatigue¹,^†

# participants affected / at risk

1/60 (1.67%)

0/60 (0.00%)

0/58 (0.00%)

# events

General disorders

Feeling hot¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

General disorders

Vessel puncture site haematoma¹,^†

# participants affected / at risk

1/60 (1.67%)

0/60 (0.00%)

0/58 (0.00%)

# events

General disorders

Vessel puncture site swelling¹,^†

# participants affected / at risk

0/60 (0.00%)

1/58 (1.72%)

0/58 (0.00%)

# events

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

0/60 (0.00%)

0/58 (0.00%)

1/58 (1.72%)

# events

Injury, poisoning and procedural complications

Skin abrasion¹,^†

# participants affected / at risk

0/60 (0.00%)

0/58 (0.00%)

1/58 (1.72%)

# events

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

1/60 (1.67%)

0/60 (0.00%)

0/58 (0.00%)

# events

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

0/60 (0.00%)

2/60 (3.33%)

1/58 (1.72%)

0/58 (0.00%)

# events

Nervous system disorders

Headache¹,^†

# participants affected / at risk

0/60 (0.00%)

3/60 (5.00%)

0/58 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Dyspnoea¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

Respiratory, thoracic and mediastinal disorders

Haemoptysis¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

Skin and subcutaneous tissue disorders

Dermatitis contact¹,^†

# participants affected / at risk

0/60 (0.00%)

0/58 (0.00%)

1/58 (1.72%)

# events

Skin and subcutaneous tissue disorders

Rash¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

1/58 (1.72%)

# events

Skin and subcutaneous tissue disorders

Skin irritation¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

Vascular disorders

Flushing¹,^†

# participants affected / at risk

0/60 (0.00%)

1/60 (1.67%)

0/58 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 18.0

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	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 less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description:

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Chief Medical Officer
Organization:	Eli Lilly and Company
Phone	800-545-5079

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

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

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Covance

Trial Results Summaries