Heart Valve Diseases
Conditions
Brief summary
To validate the dosing algorithm for dabigatran etexilate in patients receiving a mechanical heart valve.
Interventions
DRUGwarfarin 1mg
comparator warfarin
active treatment (medium)
active treatment (low)
DRUGwarfarin 5mg
comparator warfarin
active treatment (high)
DRUGwarfarin 3mg
comparator warfarin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patients aged 18-75 2. Patients who have received a bileaflet mechanical heart valve
Exclusion criteria
1. Prior valve surgery 2. Uncontrolled hypertension 3. severe renal impairment 4. active liver disease 5. increased risk of bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at End of Trial (EoT) at Week 12 | 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. |
| Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations at Steady State (C Trough,ss) at Week 1 | Week 1 | 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. |
| Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 2 | 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. |
| Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 4 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 1 | 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. |
| Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 2 | 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. |
| Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 4 | 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. |
| Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at End of Trial (EoT) Week 12 | 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. |
Countries
Belgium, Canada, Czechia, Denmark, France, Germany, Netherlands, Norway, Poland, Sweden
Participant flow
Pre-assignment details
76 patients were not entered/randomized
Participants by arm
| Arm | Count |
|---|---|
| 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 | 162 |
| 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 | 81 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Non compliance protocol | 2 | 0 |
| Overall Study | Not treated | 6 | 3 |
| Overall Study | Other reason not defined above | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Dabigatran Etexilate (DE) | Warfarin | Total |
|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 9.2 | 55.8 years STANDARD_DEVIATION 10.2 | 56.2 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 60 Participants | 26 Participants | 86 Participants |
| Sex: Female, Male Male | 102 Participants | 55 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 162 | 38 / 89 |
| serious Total, serious adverse events | 19 / 162 | 11 / 89 |
Outcome results
Primary
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations at Steady State (C Trough,ss) at Week 1
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Observed | 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 |
| Predicted | Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations at Steady State (C Trough,ss) at Week 1 | 99.52 ng/mL | Geometric Coefficient of Variation 43.9 |
Comparison: Null hypothesis: The difference of the population average responses was either ≤ to the lower bound or ≥ to the upper bound of the acceptance range .~Alternative hypothesis: The difference of the population average responses was both \> than the lower bound and \< than the upper bound of the acceptance range \[Note: The acceptance range for the geometric mean is 80-125%\]95% CI: [68.08, 80.91]ANOVA
Primary
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at End of Trial (EoT) at 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.
Time frame: Week 12
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Observed | 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 |
| Predicted | Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at End of Trial (EoT) at Week 12 | 104.80 ng/mL | Geometric Coefficient of Variation 59.8 |
Comparison: Null hypothesis: The difference of the population average responses was either ≤ to the lower bound or ≥ to the upper bound of the acceptance range .~Alternative hypothesis: The difference of the population average responses was both \> than the lower bound and \< than the upper bound of the acceptance range \[Note: The acceptance range for the geometric mean is 80-125%\]95% CI: [86.4, 123.4]ANOVA
Primary
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at 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.
Time frame: Week 2
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Observed | 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 |
| Predicted | Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 2 | 99.55 ng/mL | Geometric Coefficient of Variation 40.2 |
Comparison: Null hypothesis: The difference of the population average responses was either ≤ to the lower bound or ≥ to the upper bound of the acceptance range .~Alternative hypothesis: The difference of the population average responses was both \> than the lower bound and \< than the upper bound of the acceptance range \[Note: The acceptance range for the geometric mean is 80-125%\]95% CI: [70.32, 101.44]ANOVA
Primary
Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at 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.
Time frame: Week 4
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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Observed | 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 |
| Predicted | Comparison of Observed and Predicted Trough Dabigatran Plasma Concentrations (C Trough,ss) at Week 4 | 109.36 ng/mL | Geometric Coefficient of Variation 34.3 |
Comparison: Null hypothesis: The difference of the population average responses was either ≤ to the lower bound or ≥ to the upper bound of the acceptance range .~Alternative hypothesis: The difference of the population average responses was both \> than the lower bound and \< than the upper bound of the acceptance range \[Note: The acceptance range for the geometric mean is 80-125%\]95% CI: [88.69, 102.84]ANOVA
Secondary
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at End of Trial (EoT) 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.
Time frame: Week 12
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observed | Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at End of Trial (EoT) Week 12 | 7.4 percentage of participants |
p-value: 0.65Beta Function
Secondary
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at 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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observed | Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 1 | 26.9 percentage of participants |
p-value: <0.001Beta Function
Secondary
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at 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.
Time frame: Week 2
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observed | Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 2 | 19.2 percentage of participants |
p-value: 0.05Beta Function
Secondary
Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at 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.
Time frame: Week 4
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Observed | Percentage of Patients With Observed Trough Dabigatran Plasma Concentrations < 50 ng/mL at Week 4 | 9.8 percentage of participants |
p-value: 0.46Beta Function