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Investigation of Drug-drug Interaction of Dabigatran and Ticagrelor

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ClinicalTrials.gov Identifier: NCT01734772
Recruitment Status : Completed
First Posted : November 28, 2012
Results First Posted : May 5, 2014
Last Update Posted : May 5, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: dabigatran etexilate
Drug: ticagrelor
Enrollment 48
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Part 1 Part 2
Hide Arm/Group Description In part 1, 110 mg dabigatran etexilate were dosed twice daily to steady state and a dabigatran PK profile was taken on day 3 (reference). On the day after the reference treatment, ticagrelor treatment was added starting with the concomitant administration of a 180 mg ticagrelor loading dose followed by 90 mg ticagrelor twice daily. Dabigatran PK profiles were taken on day 1 of the test treatment and day 4 of the test treatment. In part 2, 110 mg dabigatran etexilate were dosed twice daily to steady state and a dabigatran PK profile was taken on day 3 (reference). On the day after the reference treatment, 180 mg ticagrelor were given 2 hours after the morning dose of 110 mg dabigatran etexilate and dabigatran PK profile were taken on this day 1 of the test treatment.
Period Title: Overall Study
Started 24 24
Completed 23 21
Not Completed 1 3
Reason Not Completed
Adverse Event             1             2
Withdrawal by Subject             0             1
Arm/Group Title Part 1 Part 2 Total
Hide Arm/Group Description In part 1, 110 mg dabigatran etexilate were dosed twice daily to steady state and a dabigatran PK profile was taken on day 3 (reference). On the day after the reference treatment, ticagrelor treatment was added starting with the concomitant administration of a 180 mg ticagrelor loading dose followed by 90 mg ticagrelor twice daily. Dabigatran PK profiles were taken on day 1 of the test treatment and day 4 of the test treatment. In part 2, 110 mg dabigatran etexilate were dosed twice daily to steady state and a dabigatran PK profile was taken on day 3 (reference). On the day after the reference treatment, 180 mg ticagrelor were given 2 hours after the morning dose of 110 mg dabigatran etexilate and dabigatran PK profile were taken on this day 1 of the test treatment. Total of all reporting groups
Overall Number of Baseline Participants 24 24 48
Hide Baseline Analysis Population Description
Treated Set which includes all subjects who were documented to have received at least 1 dose of trial medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 24 participants 24 participants 48 participants
28.0  (7.2) 28.6  (7.1) 28.3  (7.15)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 24 participants 24 participants 48 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
24
 100.0%
24
 100.0%
48
 100.0%
1.Primary Outcome
Title Total Dabigatran: Area Under the Concentration-time Curve at Steady State Over the Uniform Dosing Interval τ (AUCτ,ss)
Hide Description Area under the concentration-time curve of dabigatran etexilate in plasma at steady state over the uniform dosing interval τ (AUCτ,ss).
Time Frame 47.55, 48.30,49, 49.30,50,50.30,51,52,54,56, 60 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic set: This subject set included all subjects in the TS who provided at least 1 observation for at least 1 PK endpoint without important protocol violations relevant to the evaluation of bioavailability and who had not vomiting at or before 2 times the median tmax,ss of the trial medications on PK study days of both trial parts.
Arm/Group Title Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Hide Arm/Group Description:
Dabigatran Etexilate 110mg twice daily (bid) for 3 days
Single loading dose of Ticagrelor 180 mg on day 1 together with Dabigatran Etexilate 110mg bid.
Multiple dosing of 90 mg bid on days 2 and 3 and 90mg on day 4 together with Dabigatran Etexilate 110mg bid on days 2 and 3 and 110mg in the morning on day 4.
Dabigatran Etexilate 110mg twice daily (bid) for 3 days
Dabigatran Etexilate 110mg morning dose followed by 180mg Ticagrelor 2 hours later.
Overall Number of Participants Analyzed 24 23 23 23 21
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
551
(59.0%)
817
(43.3%)
689
(55.1%)
660
(39.6%)
844
(43.4%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 1, Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.9456
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter geometric Mean Ratio
Estimated Value 149.38
Confidence Interval 90%
124.388 to 179.383
Parameter Dispersion
Type: Standard Deviation
Value: 37.6
Estimation Comments The dispersion value is actually the intraindividual gCV.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 1, Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.5481
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter geometric Mean Ratio
Estimated Value 126.47
Confidence Interval 90%
107.363 to 148.967
Parameter Dispersion
Type: Standard Deviation
Value: 33.3
Estimation Comments The dispersion value is actually the intraindividual gCV.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 2, Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.5665
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter geometric Mean Ratio
Estimated Value 127.01
Confidence Interval 90%
108.047 to 149.295
Parameter Dispersion
Type: Standard Deviation
Value: 31.6
Estimation Comments The dispersion value is actually the intraindividual gCV.
2.Primary Outcome
Title Total Dabigatran: Maximum Measured Concentration at Steady State (Cmax,ss)
Hide Description Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss).
Time Frame 47.55, 48.30,49, 49.30,50,50.30,51,52,54,56, 60 hours
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic set: This subject set included all subjects in the TS who provided at least 1 observation for at least 1 PK endpoint without important protocol violations relevant to the evaluation of bioavailability and who had not vomiting at or before 2 times the median tmax,ss of the trial medications on PK study days of both trial parts.
Arm/Group Title Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Hide Arm/Group Description:
Dabigatran Etexilate 110mg twice daily (bid) for 3 days
Single loading dose of Ticagrelor 180 mg on day 1 together with Dabigatran Etexilate 110mg bid.
Multiple dosing of 90 mg bid on days 2 and 3 and 90mg on day 4 together with Dabigatran Etexilate 110mg bid on days 2 and 3 and 110mg in the morning on day 4.
Dabigatran Etexilate 110mg twice daily (bid) for 3 days
Dabigatran Etexilate 110mg morning dose followed by 180mg Ticagrelor 2 hours later.
Overall Number of Participants Analyzed 24 23 23 23 21
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
83.6
(69.3%)
136
(45.4%)
106
(65.1%)
97.6
(46.5%)
121
(45.2%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 1, Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.9841
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter geometric Mean Ratio
Estimated Value 164.74
Confidence Interval 90%
133.945 to 202.619
Parameter Dispersion
Type: Standard Deviation
Value: 42.9
Estimation Comments The dispersion value is actually the intraindividual gCV.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 1, Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.6003
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter geometric Mean Ratio
Estimated Value 128.61
Confidence Interval 90%
106.370 to 155.495
Parameter Dispersion
Type: Standard Deviation
Value: 39.0
Estimation Comments The dispersion value is actually the intraindividual gCV.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Dabigratan Etexilate 110mg Bid Alone - Part 2, Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments Relative bioavailability
Statistical Test of Hypothesis P-Value 0.4656
Comments p-value for ratio outside interval 80% - 125%
Method ANOVA
Comments Adjustment for effects 'subject' and 'treatment'.
Method of Estimation Estimation Parameter gMean Ratio
Estimated Value 123.82
Confidence Interval 90%
102.695 to 149.288
Parameter Dispersion
Type: Standard Deviation
Value: 36.9
Estimation Comments The dispersion value is actually the intraindividual gCV.
Time Frame 11 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Hide Arm/Group Description Dabigatran Etexilate 110mg twice daily (bid) for 3 days Single loading dose of Ticagrelor 180 mg on day 1 together with Dabigatran Etexilate 110mg bid. Multiple dosing of 90 mg bid on days 2 and 3 and 90mg on day 4 together with Dabigatran Etexilate 110mg bid on days 2 and 3 and 110mg once on day 4. Dabigatran Etexilate 110mg twice daily (bid) for 3 days Dabigatran Etexilate 110mg morning dose followed by 180mg Ticagrelor 2 hours later.
All-Cause Mortality
Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)   0/23 (0.00%)   0/23 (0.00%)   0/24 (0.00%)   0/21 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dabigratan Etexilate 110mg Bid Alone - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 1 Dabigatran Etexilate 110mg Bid + Ticagrelor 90mg Bid - Part 1 Dabigratan Etexilate 110mg Bid Alone - Part 2 Dabigatran Etexilate 110mg Bid + Ticagrelor 180 mg - Part 2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/24 (0.00%)   0/23 (0.00%)   0/23 (0.00%)   2/24 (8.33%)   0/21 (0.00%) 
Nervous system disorders           
Headache  1  0/24 (0.00%)  0/23 (0.00%)  0/23 (0.00%)  2/24 (8.33%)  0/21 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.0
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01734772     History of Changes
Other Study ID Numbers: 1160.142
2012-002656-16 ( EudraCT Number: EudraCT )
First Submitted: November 15, 2012
First Posted: November 28, 2012
Results First Submitted: April 2, 2014
Results First Posted: May 5, 2014
Last Update Posted: May 5, 2014