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A Pharmacokinetic Study on the Effect of LY2216684 on the Active Metabolite of Clopidogrel

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ClinicalTrials.gov Identifier: NCT01263093
Recruitment Status : Completed
First Posted : December 20, 2010
Results First Posted : October 22, 2018
Last Update Posted : October 22, 2018
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Major Depressive Disorder
Interventions Drug: Clopidogrel
Drug: LY2216684
Enrollment 47
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Clopidogrel First, Then LY2216684 + Clopidogrel LY2216684 + Clopidogrel First, Then Clopidogrel
Hide Arm/Group Description

Period 1: a single 300-milligram (mg) dose of clopidogrel administered orally on Day 1 (Treatment 1).

Period 2: an 18-mg dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).

There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2.

Period 1: an 18-milligram (mg) dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).

Period 2: a single 300-mg dose of clopidogrel administered orally on Day 1 (Treatment 1).

There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2.

Period Title: Period 1
Started 24 23
Completed 24 23
Not Completed 0 0
Period Title: Washout
Started 24 23
Completed 23 23
Not Completed 1 0
Reason Not Completed
Physician Decision             1             0
Period Title: Period 2
Started 23 23
Completed 22 23
Not Completed 1 0
Reason Not Completed
Adverse Event             1             0
Arm/Group Title Clopidogrel First, Then LY2216684 + Clopidogrel LY2216684 + Clopidogrel First, Then Clopidogrel Total
Hide Arm/Group Description

Period 1: a single 300-milligram (mg) dose of clopidogrel administered orally on Day 1 (Treatment 1).

Period 2: an 18-mg dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).

There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2.

Period 1: an 18-milligram (mg) dose of LY2216684 administered orally, once daily (QD) on Days 1 through 3, plus a single 300-mg dose of clopidogrel administered orally on Day 3 (Treatment 2).

Period 2: a single 300-mg dose of clopidogrel administered orally on Day 1 (Treatment 1).

There was a washout period of at least 14 days between the last dose of study drug in Period 1 and the first dose in Period 2.

Total of all reporting groups
Overall Number of Baseline Participants 24 23 47
Hide Baseline Analysis Population Description
All enrolled participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 23 participants 47 participants
40.7  (11.2) 44.5  (11.5) 42.5  (11.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 23 participants 47 participants
Female
10
  41.7%
12
  52.2%
22
  46.8%
Male
14
  58.3%
11
  47.8%
25
  53.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 23 participants 47 participants
Hispanic or Latino
16
  66.7%
12
  52.2%
28
  59.6%
Not Hispanic or Latino
8
  33.3%
11
  47.8%
19
  40.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 23 participants 47 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
  16.7%
5
  21.7%
9
  19.1%
White
20
  83.3%
18
  78.3%
38
  80.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 24 participants 23 participants 47 participants
24
 100.0%
23
 100.0%
47
 100.0%
1.Primary Outcome
Title Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞)
Hide Description R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
Time Frame predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C19*1/*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data, including sufficient data in the terminal elimination phase for R-130964.
Arm/Group Title Clopidogrel LY2216684 + Clopidogrel
Hide Arm/Group Description:
Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1 of Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3 of Treatment 2

Clopidogrel: a single 300-mg dose, administered orally on Day 3 of Treatment 2

Overall Number of Participants Analyzed 31 15
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours*nanograms/milliliters (h*ng/mL)
61.8
(50%)
55.3
(44%)
2.Primary Outcome
Title Pharmacokinetics of R-130964, Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC0-tlast)
Hide Description R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed AUC0-tlast was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
Time Frame predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C19*1/*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
Arm/Group Title Clopidogrel LY2216684 + Clopidogrel
Hide Arm/Group Description:
Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1 of Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3 of Treatment 2

Clopidogrel: a single 300-mg dose, administered orally on Day 3 of Treatment 2

Overall Number of Participants Analyzed 38 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hours*nanograms/milliliters (h*ng/mL)
60.5
(45%)
46.9
(41%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clopidogrel, LY2216684 + Clopidogrel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Geometric Least Squares Means
Estimated Value 0.77
Confidence Interval (2-Sided) 90%
0.72 to 0.83
Estimation Comments Statistical inference was made using the test treatment of LY2216684 + clopidogrel and the reference treatment of clopidogrel alone.
3.Primary Outcome
Title Pharmacokinetics of R-130964, Maximum Observed Drug Concentrations (Cmax)
Hide Description R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Log-transformed Cmax was analyzed using a linear mixed effects model with sequence, period, and treatment as fixed effects and participant as a random effect.
Time Frame predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C19*1/*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
Arm/Group Title Clopidogrel LY2216684 + Clopidogrel
Hide Arm/Group Description:
Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1 of Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3 of Treatment 2

Clopidogrel: a single 300-mg dose, administered orally on Day 3 of Treatment 2

Overall Number of Participants Analyzed 38 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanograms/milliliter (ng/mL)
37.6
(56%)
22.7
(53%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clopidogrel, LY2216684 + Clopidogrel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Geometric Least Squares Means
Estimated Value 0.59
Confidence Interval (2-Sided) 90%
0.53 to 0.67
Estimation Comments Statistical inference was made using the test treatment of LY2216684 + clopidogrel and the reference treatment of clopidogrel alone.
4.Primary Outcome
Title Pharmacokinetics of R-130964, Time to Maximum Observed Drug Concentrations (Tmax)
Hide Description R-130964 is the active metabolite of clopidogrel. Blood samples were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684.
Time Frame predose and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C19*1/*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable R-130964 plasma concentration data.
Arm/Group Title Clopidogrel LY2216684 + Clopidogrel
Hide Arm/Group Description:
Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1 of Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3 of Treatment 2

Clopidogrel: a single 300-mg dose, administered orally on Day 3 of Treatment 2

Overall Number of Participants Analyzed 36 36
Median (Full Range)
Unit of Measure: hours
1.50
(1.00 to 2.07)
1.50
(0.50 to 4.00)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Clopidogrel, LY2216684 + Clopidogrel
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3303
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Median of Paired Differences
Estimated Value 0.00
Confidence Interval (2-Sided) 90%
0.00 to 0.25
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage Inhibition of Platelet Aggregation
Hide Description Blood samples for the measurement of platelet aggregation using a point-of-care device, Accumetrics VerifyNow™ P2Y12 (VN-P2Y12), were collected prior to and through 24 hours after administration of clopidogrel alone and in combination with LY2216684. Device-reported percent inhibition of VN-P2Y12 (IPRU) is presented.
Time Frame predose and 2, 4, and 24 hours postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with the CYP2C19*1/*1 genotype, who received at least 1 dose of clopidogrel, and had evaluable IPRU data.
Arm/Group Title Clopidogrel LY2216684 + Clopidogrel
Hide Arm/Group Description:
Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1 of Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3 of Treatment 2

Clopidogrel: a single 300-mg dose, administered orally on Day 3 of Treatment 2

Overall Number of Participants Analyzed 38 37
Mean (Standard Deviation)
Unit of Measure: IPRU
Predose 1.7  (3.2) 1.4  (3.2)
2 Hours Postdose 16.0  (20.3) 7.6  (12.3)
4 Hours Postdose 30.4  (21.8) 14.0  (16.6)
24 Hours Postdose 25.1  (21.1) 14.3  (17.5)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Clopidogrel LY2216684 LY2216684 + Clopidogrel
Hide Arm/Group Description

Clopidogrel: a single 300-milligram (mg) dose, administered orally on Day 1

Time Frame: Treatment 1

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3

Time Frame: Treatment 2; prior to clopidogrel dose on Day 3

LY2216684: 18-milligram (mg) dose, administered orally, once daily (QD) on Days 1 through 3

Clopidogrel: a single 300-mg dose, administered orally on Day 3

Time Frame: Treatment 2; after the clopidogrel dose on Day 3

All-Cause Mortality
Clopidogrel LY2216684 LY2216684 + Clopidogrel
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Clopidogrel LY2216684 LY2216684 + Clopidogrel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/47 (0.00%)      0/46 (0.00%)      0/45 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4%
Clopidogrel LY2216684 LY2216684 + Clopidogrel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/47 (25.53%)      19/46 (41.30%)      11/45 (24.44%)    
Gastrointestinal disorders       
Abdominal pain  1  0/47 (0.00%)  0 3/46 (6.52%)  4 0/45 (0.00%)  0
Nausea  1  1/47 (2.13%)  1 7/46 (15.22%)  8 2/45 (4.44%)  2
Vomiting  1  0/47 (0.00%)  0 3/46 (6.52%)  3 0/45 (0.00%)  0
General disorders       
Chills  1  2/47 (4.26%)  2 1/46 (2.17%)  1 2/45 (4.44%)  2
Pain  1  2/47 (4.26%)  2 0/46 (0.00%)  0 1/45 (2.22%)  1
Pyrexia  1  1/47 (2.13%)  1 0/46 (0.00%)  0 2/45 (4.44%)  2
Nervous system disorders       
Dizziness  1  0/47 (0.00%)  0 2/46 (4.35%)  2 1/45 (2.22%)  1
Headache  1  6/47 (12.77%)  6 1/46 (2.17%)  2 1/45 (2.22%)  1
Paraesthesia  1  0/47 (0.00%)  0 2/46 (4.35%)  2 1/45 (2.22%)  3
Somnolence  1  0/47 (0.00%)  0 7/46 (15.22%)  7 0/45 (0.00%)  0
Psychiatric disorders       
Insomnia  1  0/47 (0.00%)  0 3/46 (6.52%)  3 3/45 (6.67%)  3
Renal and urinary disorders       
Dysuria  1  0/47 (0.00%)  0 2/46 (4.35%)  2 1/45 (2.22%)  1
Urinary hesitation  1  0/47 (0.00%)  0 4/46 (8.70%)  6 0/45 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Cough  1  3/47 (6.38%)  3 0/46 (0.00%)  0 0/45 (0.00%)  0
Skin and subcutaneous tissue disorders       
Hyperhidrosis  1  0/47 (0.00%)  0 2/46 (4.35%)  3 0/45 (0.00%)  0
Rash  1  0/47 (0.00%)  0 1/46 (2.17%)  2 3/45 (6.67%)  4
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
Phone: 800-545-5979
Layout table for additonal information
Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT01263093     History of Changes
Other Study ID Numbers: 12593
H9P-EW-LNBY ( Other Identifier: Eli Lilly and Company )
First Submitted: December 16, 2010
First Posted: December 20, 2010
Results First Submitted: February 17, 2018
Results First Posted: October 22, 2018
Last Update Posted: October 22, 2018