Trial Outcomes & Findings for Dabigatran Etexilate in Patients With Mechanical Heart Valves (NCT NCT01452347)

Last Updated: 2014-08-06

Results Overview

Comparisons between dabigatran trough plasma levels as predicted by simulations to those observed in the study are performed to validate the dosing algorithm for Dabigatran Etexilate (DE) . Despite the primary endpoint only being assessed in patients who received dabigatran etexilate, Warfarin was included as a comparator treatment in this study in order to facilitate informal comparisons of outcome events, and to look for efficacy signals in this previously unexplored population.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

328 participants

Primary outcome timeframe

Week 1

Results posted on

2014-08-06

Participant Flow

76 patients were not entered/randomized

Participant milestones

Participant milestones
Measure	Dabigatran Etexilate (DE) Oral administration of 1 capsule of 150 mg (150 mg), 2 capsules of 110 mg (220 mg), or 2 capsules of 150 mg (300 mg) twice daily	Warfarin Oral administration of Warfarin 1mg, 3mg and 5 mg according to target international normalised ratio (INR), as recommended in guidelines, and deemed appropriate by investigator
Overall Study STARTED	168	84
Overall Study COMPLETED	151	77
Overall Study NOT COMPLETED	17	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Dabigatran Etexilate (DE) Oral administration of 1 capsule of 150 mg (150 mg), 2 capsules of 110 mg (220 mg), or 2 capsules of 150 mg (300 mg) twice daily	Warfarin Oral administration of Warfarin 1mg, 3mg and 5 mg according to target international normalised ratio (INR), as recommended in guidelines, and deemed appropriate by investigator
Overall Study Adverse Event	2	1
Overall Study Non compliance protocol	2	0
Overall Study Lost to Follow-up	2	0
Overall Study Withdrawal by Subject	3	3
Overall Study Not treated	6	3
Overall Study Other reason not defined above	2	0

Baseline Characteristics

Dabigatran Etexilate in Patients With Mechanical Heart Valves

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dabigatran Etexilate (DE) n=162 Participants Oral administration of 1 capsule of 150 mg (150 mg), 2 capsules of 110 mg (220 mg), or 2 capsules of 150 mg (300 mg) twice daily	Warfarin n=81 Participants Oral administration of Warfarin 1mg, 3mg and 5 mg according to target international normalised ratio (INR), as recommended in guidelines, and deemed appropriate by investigator	Total n=243 Participants Total of all reporting groups
Age, Continuous	56.3 years STANDARD_DEVIATION 9.2 • n=5 Participants	55.8 years STANDARD_DEVIATION 10.2 • n=7 Participants	56.2 years STANDARD_DEVIATION 9.5 • n=5 Participants
Sex: Female, Male Female	60 Participants n=5 Participants	26 Participants n=7 Participants	86 Participants n=5 Participants
Sex: Female, Male Male	102 Participants n=5 Participants	55 Participants n=7 Participants	157 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 1

Population: Pharmacokinetic set (PKS):Patients were included in the PKS if they were treated with DE, had at least 1 evaluable C trough,ss value and had a non-missing value for gender, age and Creatinine clearance(CrCl) level. Patients who had any important Protocol Violations that may have affected PK data were excluded from the PKS.

Outcome measures

Outcome measures
Measure	Observed n=130 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted n=130 Participants This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations at Steady State (C Trough,ss) at Week 1	73.86 ng/mL Geometric Coefficient of Variation 43.9	99.52 ng/mL Geometric Coefficient of Variation 43.9

PRIMARY outcome

Timeframe: Week 2

Comparisons between dabigatran trough plasma levels as predicted by simulations to those observed in the study are performed to validate the dosing algorithm for Dabigatran Etexilate (DE). Despite the primary endpoint only being assessed in patients who received dabigatran etexilate, Warfarin was included as a comparator treatment in this study in order to facilitate informal comparisons of outcome events, and to look for efficacy signals in this previously unexplored population.

Outcome measures

Outcome measures
Measure	Observed n=26 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted n=26 Participants This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 2	84.08 ng/mL Geometric Coefficient of Variation 40.2	99.55 ng/mL Geometric Coefficient of Variation 40.2

PRIMARY outcome

Timeframe: Week 4

Comparisons between dabigatran trough plasma levels as predicted by simulations to those observed in the study are performed to validate the dosing algorithm for Dabigatran Etexilate (DE). Despite the primary endpoint only being assessed in patients who received dabigatran etexilate, Warfarin was included as a comparator treatment in this study in order to facilitate informal comparisons of outcome events, and to look for efficacy signals in this previously unexplored population.

Outcome measures

Outcome measures
Measure	Observed n=112 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted n=112 Participants This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 4	104.43 ng/mL Geometric Coefficient of Variation 34.3	109.36 ng/mL Geometric Coefficient of Variation 34.3

PRIMARY outcome

Timeframe: Week 12

Comparisons between dabigatran trough plasma levels as predicted by simulations to those observed in the study are performed to validate the dosing algorithm for Dabigatran Etexilate (DE). (As the trial was stopped prematurely, EOT may not be 12 weeks after randomisation for most of the patients) Despite the primary endpoint only being assessed in patients who received dabigatran etexilate, Warfarin was included as a comparator treatment in this study in order to facilitate informal comparisons of outcome events, and to look for efficacy signals in this previously unexplored population.

Outcome measures

Outcome measures
Measure	Observed n=54 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted n=54 Participants This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at End of Trial (EoT) at Week 12	108.21 ng/mL Geometric Coefficient of Variation 59.8	104.80 ng/mL Geometric Coefficient of Variation 59.8

SECONDARY outcome

Timeframe: Week 1

Percentage of patients with observed Ctrough,ss value \< 50 ng/mL are presented. This outcome measure was only analysed for all patients together and not by dose group.

Outcome measures

Outcome measures
Measure	Observed n=130 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 1	26.9 percentage of participants	—

SECONDARY outcome

Timeframe: Week 2

Percentage of patients with observed Ctrough,ss value \< 50 ng/mL are presented. This outcome measure was only analysed for all patients together and not by dose group.

Outcome measures

Outcome measures
Measure	Observed n=26 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 2	19.2 percentage of participants	—

SECONDARY outcome

Timeframe: Week 4

Percentage of patients with observed Ctrough,ss value \< 50 ng/mL are presented. This outcome measure was only analysed for all patients together and not by dose group.

Outcome measures

Outcome measures
Measure	Observed n=112 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 4	9.8 percentage of participants	—

SECONDARY outcome

Timeframe: Week 12

Percentage of patients with observed Ctrough,ss value \< 50 ng/mL (As the trial was stopped prematurely, EOT may not be 12 weeks after randomisation for most of the patients) This outcome measure was only analysed for all patients together and not by dose group.

Outcome measures

Outcome measures
Measure	Observed n=54 Participants This includes the observed Ctrough,ss value for all patients in the pharmacokinetic set (PKS) who have a corresponding predicted value.	Predicted This includes the predicted Ctrough,ss value for all patients in the PKS who have a corresponding observed value.
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at End of Trial (EoT) Week 12	7.4 percentage of participants	—

Adverse Events

Dabigatran Etexilate

Serious events: 19 serious events

Other events: 64 other events

Deaths: 0 deaths

Warfarin

Serious events: 11 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Dabigatran Etexilate n=162 participants at risk Oral administration of 1 capsule of 150 mg (150 mg), 2 capsules of 110 mg (220 mg), or 2 capsules of 150 mg (300 mg) twice daily	Warfarin n=89 participants at risk Oral administration of Warfarin 1mg, 3mg and 5 mg according to target international normalised ratio (INR), as recommended in guidelines, and deemed appropriate by investigator
Infections and infestations Urinary tract infection	3.1% 5/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	5.6% 5/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Nervous system disorders Dizziness	1.9% 3/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	5.6% 5/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Cardiac disorders Atrial fibrillation	6.8% 11/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	10.1% 9/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Cardiac disorders Pericardial effusion	4.9% 8/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	7.9% 7/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Respiratory, thoracic and mediastinal disorders Pleural effusion	6.8% 11/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	3.4% 3/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Respiratory, thoracic and mediastinal disorders Cough	4.9% 8/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	6.7% 6/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Gastrointestinal disorders Diarrhoea	11.7% 19/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	2.2% 2/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Gastrointestinal disorders Dyspepsia	9.3% 15/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	0.00% 0/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Gastrointestinal disorders Constipation	6.2% 10/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	7.9% 7/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
Gastrointestinal disorders Nausea	3.1% 5/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	5.6% 5/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.
General disorders Oedema peripheral	6.2% 10/162 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.	2.2% 2/89 • From first intake of study drug until last intake of study drug plus 6 days (Up to 101 days). There were 8 patients who switched from dabigatran etexilate to warfarin during the study, and hence these patients are counted in the denominator of both arms. Any AEs which occurred in these patients are only presented under the treatment that the patient was taking at the time of the event.

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER