Trial Outcomes & Findings for A Study of LY2216684 and Warfarin in Healthy Subjects (NCT NCT01263119)
NCT ID: NCT01263119
Last Updated: 2019-01-22
Results Overview
Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
COMPLETED
PHASE1
18 participants
Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3
2019-01-22
Participant Flow
Participant milestones
| Measure |
Warfarin, LY2216684 + Warfarin
Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3.
|
|---|---|
|
Period 1
STARTED
|
18
|
|
Period 1
COMPLETED
|
16
|
|
Period 1
NOT COMPLETED
|
2
|
|
Period 2
STARTED
|
16
|
|
Period 2
COMPLETED
|
14
|
|
Period 2
NOT COMPLETED
|
2
|
Reasons for withdrawal
| Measure |
Warfarin, LY2216684 + Warfarin
Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3.
|
|---|---|
|
Period 1
Protocol Violation
|
2
|
|
Period 2
Adverse Event
|
2
|
Baseline Characteristics
A Study of LY2216684 and Warfarin in Healthy Subjects
Baseline characteristics by cohort
| Measure |
Warfarin, LY2216684 + Warfarin
n=18 Participants
Period 1: Single 10-milligram (mg) warfarin oral dose on Day 1; Washout Period of at least 14 days; Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12, with single 10-mg warfarin oral dose coadministered on Day 3.
|
|---|---|
|
Age, Continuous
|
38.2 years
STANDARD_DEVIATION 6.6 • n=5 Participants
|
|
Sex: Female, Male
Female
|
8 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
6 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Multiple
|
4 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
8 Participants
n=5 Participants
|
|
Region of Enrollment
United States
|
18 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
Least Squares (LS) geometric mean was based on AUC0-∞ of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of S-Warfarin
|
22200 nanogram*hour per milliliter (ng*hr/mL)
Interval 19900.0 to 24700.0
|
20800 nanogram*hour per milliliter (ng*hr/mL)
Interval 18700.0 to 23200.0
|
PRIMARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who received at least 1 dose of warfarin and had evaluable concentration data.
Least Squares (LS) geometric mean was based on Cmax of S-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of S-Warfarin
|
633.00 nanogram per milliliter (ng/mL)
Interval 576.78 to 694.7
|
566.57 nanogram per milliliter (ng/mL)
Interval 516.06 to 622.02
|
PRIMARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and had evaluable concentration data.
This outcome was measured based on Tmax of S-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=15 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Time to Maximum Plasma Concentration (Tmax) of S-Warfarin
|
3.00 hour (h)
Interval 1.0 to 5.0
|
3.00 hour (h)
Interval 1.0 to 4.0
|
SECONDARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
Least Squares (LS) geometric mean was based on AUC0-∞ of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 Hour to Infinity (AUC0-∞) of R-Warfarin
|
43600 ng*h/mL
Interval 39600.0 to 48000.0
|
38000 ng*h/mL
Interval 34500.0 to 41800.0
|
SECONDARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
Least Squares (LS) geometric mean was based on Cmax of R-warfarin; calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of R-Warfarin
|
669.25 ng/mL
Interval 607.1 to 737.76
|
592.38 ng/mL
Interval 537.19 to 653.23
|
SECONDARY outcome
Timeframe: Pre-dose, 1, 2, 3, 4, 5, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
This outcome was measured based on Tmax of R-warfarin on Day 1 of Period 1 when warfarin was administered alone (reference) and on Day 3 of Period 2 when coadministered with LY2216684 (test).
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=15 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacokinetics: Time to Maximum Concentration (Tmax) of R-Warfarin
|
3.02 h
Interval 2.0 to 5.0
|
4.00 h
Interval 2.0 to 8.0
|
SECONDARY outcome
Timeframe: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
The INR is the ratio of a participant's prothrombin time to a normal (control) sample. AUCINR was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacodynamics: Area Under the Curve of the International Normalized Ratio (AUCINR) of Warfarin
|
155 ratio
Interval 152.0 to 157.0
|
149 ratio
Interval 147.0 to 152.0
|
SECONDARY outcome
Timeframe: Predose, 6, 12, 24, 48, 72, 96, 120, 144 hours post-warfarin administration on Days 1 and 3Population: The analysis population included participants who had at least 1 dose of warfarin and evaluable concentration data.
INR is the ratio of a participant's prothrombin time to a normal (control) sample. INRmax was calculated when warfarin was administered alone (reference) on Day 1 of Period 1 and coadministered with LY2216684 (test) on Day 3 of Period 2.
Outcome measures
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 Participants
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=15 Participants
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
|---|---|---|
|
Pharmacodynamics: Maximum Observed International Normalized Ratio (INRmax)
|
1.19 ratio
Interval 1.15 to 1.24
|
1.14 ratio
Interval 1.1 to 1.19
|
Adverse Events
10 mg Warfarin + 18 mg LY2216684 (Test)
10 mg Warfarin Alone (Reference)
18 mg LY2216684 Alone
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
10 mg Warfarin + 18 mg LY2216684 (Test)
n=16 participants at risk
Period 2: Day -1=participant admission; Days 1 to 12=18-mg LY2216684 oral dose, once daily; Day 3=single 10-mg warfarin oral dose; Day 13=discharge.
|
10 mg Warfarin Alone (Reference)
n=18 participants at risk
Period 1: Day -1=participant admission; Day 1=single 10-mg warfarin oral dose; Day 11=discharge. Washout Period: at least 14 days between last dose in Period 1 and first dose in Period 2.
|
18 mg LY2216684 Alone
n=16 participants at risk
Period 2: 18-mg LY2216684 oral dose, once daily on Days 1 to 12.
|
|---|---|---|---|
|
Cardiac disorders
Palpitations
|
18.8%
3/16 • Number of events 3
|
0.00%
0/18
|
0.00%
0/16
|
|
Eye disorders
Vision blurred
|
0.00%
0/16
|
5.6%
1/18 • Number of events 1
|
0.00%
0/16
|
|
Gastrointestinal disorders
Abdominal distension
|
6.2%
1/16 • Number of events 2
|
0.00%
0/18
|
0.00%
0/16
|
|
Gastrointestinal disorders
Abdominal pain
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
6.2%
1/16 • Number of events 1
|
|
Gastrointestinal disorders
Constipation
|
0.00%
0/16
|
5.6%
1/18 • Number of events 1
|
12.5%
2/16 • Number of events 2
|
|
Gastrointestinal disorders
Gastrooesophageal reflux disease
|
0.00%
0/16
|
0.00%
0/18
|
6.2%
1/16 • Number of events 1
|
|
Gastrointestinal disorders
Lip dry
|
0.00%
0/16
|
11.1%
2/18 • Number of events 2
|
0.00%
0/16
|
|
Gastrointestinal disorders
Nausea
|
0.00%
0/16
|
0.00%
0/18
|
25.0%
4/16 • Number of events 4
|
|
Gastrointestinal disorders
Vomiting
|
0.00%
0/16
|
0.00%
0/18
|
18.8%
3/16 • Number of events 3
|
|
General disorders
Asthenia
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
General disorders
Chest discomfort
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
General disorders
Chills
|
0.00%
0/16
|
0.00%
0/18
|
18.8%
3/16 • Number of events 3
|
|
General disorders
Fatigue
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
General disorders
Feeling hot
|
0.00%
0/16
|
0.00%
0/18
|
6.2%
1/16 • Number of events 1
|
|
General disorders
Feeling jittery
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
6.2%
1/16 • Number of events 1
|
|
General disorders
Vessel puncture site pain
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Metabolism and nutrition disorders
Decreased appetite
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Nervous system disorders
Dizziness
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
12.5%
2/16 • Number of events 2
|
|
Nervous system disorders
Headache
|
12.5%
2/16 • Number of events 2
|
0.00%
0/18
|
0.00%
0/16
|
|
Nervous system disorders
Loss of consciousness
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Nervous system disorders
Somnolence
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
25.0%
4/16 • Number of events 4
|
|
Psychiatric disorders
Anxiety
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Psychiatric disorders
Depression
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Renal and urinary disorders
Urinary hesitation
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
0.00%
0/16
|
5.6%
1/18 • Number of events 1
|
0.00%
0/16
|
|
Skin and subcutaneous tissue disorders
Dry skin
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Skin and subcutaneous tissue disorders
Ecchymosis
|
6.2%
1/16 • Number of events 1
|
5.6%
1/18 • Number of events 1
|
0.00%
0/16
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.00%
0/16
|
5.6%
1/18 • Number of events 1
|
0.00%
0/16
|
|
Vascular disorders
Flushing
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
|
Vascular disorders
Peripheral coldness
|
6.2%
1/16 • Number of events 1
|
0.00%
0/18
|
0.00%
0/16
|
Additional Information
Chief Medical Officer
Eli Lilly and Company
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60