Trial Outcomes & Findings for CES1 Crossover Trial of Clopidogrel and Ticagrelor (NCT NCT03161678)

Last Updated: 2024-05-06

Results Overview

Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of clopidogrel \[75mg/d\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after clopidogrel administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-clopidogrel visits.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

111 participants

Primary outcome timeframe

8 days of exposure to clopidogrel (change from baseline at day 8 reported)

Results posted on

2024-05-06

Participant Flow

In our investigation, participants discontinued all vitamins/supplements at least 7 days before their first clinic visit, which is when drug was randomly assigned. Of the 111 enrolled, 11 (3 controls, 1 G143E, and 7 CES1 rs7498748) withdrew prior to clinic visit 1, thus drug was not assigned to those individuals. As such, the number of individuals shown below do not equal 111 (total enrollment number) but instead show the number of individuals who were randomly assigned to a medication (N=100)

Participant milestones

Participant milestones
Measure	Wild-Type Genotype: Clopidogrel First, Then Ticagrelor Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to receive clopidogrel first followed by ticagrelor Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Wild Type Genotype: Ticagrelor First, Then Clopidogrel Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to received ticagrelor first followed by clopidogrel Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) G143E Mutation: Clopidogrel First, Then Ticagrelor Research subjects who carry a CES1 G143E minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to clopidogrel first followed by ticagrelor. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) G143E Mutation: Ticagrelor First, Then Clopidogrel Research subjects who carry a CES1 G143E minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to ticagrelor first followed by clopidogrel. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) Functional Mutation: Clopidogrel First, Then Ticagrelor Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to clopidogrel first followed by ticagrelor. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) Functional Mutation: Ticagrelor First, Then Clopidogrel Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to ticagrelor first followed by clopidogrel. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Intervention 1 (8 Days) STARTED	17	19	10	12	23	19
Intervention 1 (8 Days) COMPLETED	16	18	10	9	22	19
Intervention 1 (8 Days) NOT COMPLETED	1	1	0	3	1	0
Washout (14 Days) STARTED	16	18	10	9	22	19
Washout (14 Days) COMPLETED	16	18	9	9	20	18
Washout (14 Days) NOT COMPLETED	0	0	1	0	2	1
Intervention 2 (8 Days) STARTED	16	18	9	9	20	18
Intervention 2 (8 Days) COMPLETED	16	18	9	8	20	18
Intervention 2 (8 Days) NOT COMPLETED	0	0	0	1	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Wild-Type Genotype: Clopidogrel First, Then Ticagrelor Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to receive clopidogrel first followed by ticagrelor Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Wild Type Genotype: Ticagrelor First, Then Clopidogrel Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to received ticagrelor first followed by clopidogrel Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) G143E Mutation: Clopidogrel First, Then Ticagrelor Research subjects who carry a CES1 G143E minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to clopidogrel first followed by ticagrelor. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) G143E Mutation: Ticagrelor First, Then Clopidogrel Research subjects who carry a CES1 G143E minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to ticagrelor first followed by clopidogrel. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) Functional Mutation: Clopidogrel First, Then Ticagrelor Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to clopidogrel first followed by ticagrelor. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carboxylesterase 1 (CES1) Functional Mutation: Ticagrelor First, Then Clopidogrel Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. This group was randomized to ticagrelor first followed by clopidogrel. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Intervention 1 (8 Days) Withdrawal by Subject	1	1	0	2	1	0
Intervention 1 (8 Days) Adverse Event	0	0	0	1	0	0
Washout (14 Days) Withdrawal by Subject	0	0	1	0	2	1
Intervention 2 (8 Days) Withdrawal by Subject	0	0	0	1	0	0

Baseline Characteristics

CES1 Crossover Trial of Clopidogrel and Ticagrelor

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants With Wild-Type Genotype n=34 Participants Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	All Participants Who Carried the CES1 G143E Mutation n=17 Participants Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	All Participants Who Carried the CES1 Functional Mutation n=38 Participants Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Total n=89 Participants Total of all reporting groups
Age, Continuous	49.1 years STANDARD_DEVIATION 10.6 • n=5 Participants	44.5 years STANDARD_DEVIATION 14.2 • n=7 Participants	52.1 years STANDARD_DEVIATION 12.9 • n=5 Participants	49.5 years STANDARD_DEVIATION 12.5 • n=4 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	6 Participants n=7 Participants	23 Participants n=5 Participants	45 Participants n=4 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	11 Participants n=7 Participants	15 Participants n=5 Participants	44 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	34 Participants n=5 Participants	17 Participants n=7 Participants	38 Participants n=5 Participants	89 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United States	34 participants n=5 Participants	17 participants n=7 Participants	38 participants n=5 Participants	89 participants n=4 Participants
Body Mass Index	27.4 kg/m^2 STANDARD_DEVIATION 4.4 • n=5 Participants	27.6 kg/m^2 STANDARD_DEVIATION 4.7 • n=7 Participants	29.0 kg/m^2 STANDARD_DEVIATION 4.9 • n=5 Participants	28.1 kg/m^2 STANDARD_DEVIATION 4.7 • n=4 Participants
Systolic Blood Pressure	118.2 mm Hg STANDARD_DEVIATION 12.8 • n=5 Participants	117.2 mm Hg STANDARD_DEVIATION 12.0 • n=7 Participants	120.2 mm Hg STANDARD_DEVIATION 13.9 • n=5 Participants	118.9 mm Hg STANDARD_DEVIATION 13.1 • n=4 Participants
Diastolic Blood Pressure	73.8 mm Hg STANDARD_DEVIATION 8.0 • n=5 Participants	70.7 mm Hg STANDARD_DEVIATION 6.8 • n=7 Participants	74.0 mm Hg STANDARD_DEVIATION 7.7 • n=5 Participants	73.7 mm Hg STANDARD_DEVIATION 7.7 • n=4 Participants
Total Cholesterol	210.7 mg/dL STANDARD_DEVIATION 47.0 • n=5 Participants	207.9 mg/dL STANDARD_DEVIATION 56.2 • n=7 Participants	208.8 mg/dL STANDARD_DEVIATION 43.3 • n=5 Participants	209.3 mg/dL STANDARD_DEVIATION 46.8 • n=4 Participants
Low-Density Lipoprotein Cholesterol	135.0 mg/dL STANDARD_DEVIATION 38.4 • n=5 Participants	138.7 mg/dL STANDARD_DEVIATION 49.6 • n=7 Participants	132.0 mg/dL STANDARD_DEVIATION 39.2 • n=5 Participants	134.4 mg/dL STANDARD_DEVIATION 40.7 • n=4 Participants
High-Density Lipoprotein Cholesterol	60.4 mg/dL STANDARD_DEVIATION 18.0 • n=5 Participants	52.8 mg/dL STANDARD_DEVIATION 14.3 • n=7 Participants	60.5 mg/dL STANDARD_DEVIATION 13.3 • n=5 Participants	59.0 mg/dL STANDARD_DEVIATION 15.6 • n=4 Participants
Triglycerides	61.9 mg/dL STANDARD_DEVIATION 21.1 • n=5 Participants	71.5 mg/dL STANDARD_DEVIATION 45.4 • n=7 Participants	69.4 mg/dL STANDARD_DEVIATION 41.2 • n=5 Participants	66.9 mg/dL STANDARD_DEVIATION 35.7 • n=4 Participants

PRIMARY outcome

Timeframe: 8 days of exposure to clopidogrel (change from baseline at day 8 reported)

Population: All of the outcome measures in this trial were pre-specified to be analyzed by genotype. Therefore, Arm/Groups are shown by genotype group rather than per medication sequence order. This is consistent with how baseline characteristics are displayed as well.

Outcome measures

Outcome measures
Measure	Wild-Type Genotype n=34 Participants Research subjects with wild type CES1 genotypes will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carriers of the CES1 G143E Mutation n=17 Participants Research subjects who carry the CES1 G143E allele (rs71647871) will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.	Carriers of CES1 Functional Mutation n=38 Participants Research subjects who carry a CES1 rs7498748 minor allele will be studied before and after oral ingestion of clopidogrel (75 mg/d for 8 days) and ticagrelor (90 mg twice daily for 8 days) treatment. Clopidogrel: Clopidogrel (75 mg/d for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration. Ticagrelor: Ticagrelor (90 mg twice daily for 8 days) will be administered. Measures of pharmacodynamics will be assessed pre- and post-drug administration.
Change in Maximal Platelet Aggregation in Response to Clopidogrel	32.6 Percent Maximal Platelet Aggregation Standard Error 2.7	50.8 Percent Maximal Platelet Aggregation Standard Error 2.1	35.0 Percent Maximal Platelet Aggregation Standard Error 2.1

PRIMARY outcome

Timeframe: 8 days of independent exposure to ticagrelor (change from baseline at day 8 reported)

Ex vivo platelet aggregometry was performed in platelet rich plasma (PRP) after stimulation with 20 μM adenosine diphosphate (ADP) at 2 time points (at baseline prior to drug administration and on the 8th day of ticagrelor \[90 mg twice daily\]). Maximum platelet aggregation is recorded by the platelet aggregometer as a percentage. Data shown below represent the maximum platelet aggregation value obtained at baseline minus the maximum platelet aggregation value obtained after ticagrelor administration. Thus, values recorded below represent changes from baseline at day 8 and the unit is percent maximum aggregation. Higher reported values represent a greater reduction in platelet aggregation while lower reported values signify a smaller reduction in platelet aggregation when comparing baseline and post-ticagrelor visits.