Trial Outcomes & Findings for Pharmacokinetics of Dabigatran Etexilate (Pradaxa®) During Haemodialysis (NCT NCT01241539)

NCT ID: NCT01241539

Last Updated: 2014-04-07

Results Overview

Dialysis clearance of dabigatran from blood (CLD,b) and dialysis clearance of dabigatran from plasma (CLD) were calculated and indicate how quickly dabigatran is cleared out from blood or plasma.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 7 participants
• Primary outcome timeframe: 4 hours
• Results posted on: 2014-04-07

Participant Flow

This was an open-label, 2-period, fixed-sequence, multiple dose trial. On Day 1, all patients were treated with Dabigatran 150 mg, on day 2, with 110 mg at 10:00, and on day 3, 75 mg 8 h before dialysis. The target blood flow rate on day 3 of period 1 was 200mL/min, whilst that in period 2 was 400mL/min.

Participant milestones

Measure	Dabigatran Period 1 target blood flow rate during dialysis was 200mL/min. Period 2 target blood flow rate during dialysis was 400mL/min.
Period 1 STARTED	7
Period 1 COMPLETED	7
Period 1 NOT COMPLETED	0
Period 2 STARTED	7
Period 2 COMPLETED	7
Period 2 NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pharmacokinetics of Dabigatran Etexilate (Pradaxa®) During Haemodialysis

Baseline characteristics by cohort

Measure	Dabigatran n=7 Participants Dabigatran treated patients
Age, Continuous	38.3 Years STANDARD_DEVIATION 10.9 • n=93 Participants
Sex: Female, Male Female	0 Participants n=93 Participants
Sex: Female, Male Male	7 Participants n=93 Participants

PRIMARY outcome

Timeframe: 4 hours

Population: Pharmacokinetic set (PKS) includes all evaluable patients of the treated set who received at least one dose of dabigatran etexilate and who provide at least one observation for at least one Pharmacokinetic (PK) endpoint without important protocol violations relevant to the evaluation of PK.

Dialysis clearance of dabigatran from blood (CLD,b) and dialysis clearance of dabigatran from plasma (CLD) were calculated and indicate how quickly dabigatran is cleared out from blood or plasma.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Dialysis Clearance of Dabigatran Total dabigatran clearance (CLD,b) from blood	161 mL/min Geometric Coefficient of Variation 5.01	241 mL/min Geometric Coefficient of Variation 3.08
Dialysis Clearance of Dabigatran Total dabigatran clearance (CLD) from plasma	120 mL/min Geometric Coefficient of Variation 5.09	183 mL/min Geometric Coefficient of Variation 4.30
Dialysis Clearance of Dabigatran Free dabigatran clearance (CLD,b) from blood	167 mL/min Geometric Coefficient of Variation 4.60	251 mL/min Geometric Coefficient of Variation 2.17
Dialysis Clearance of Dabigatran Free dabigatran clearance (CLD) from plasma	124 mL/min Geometric Coefficient of Variation 4.48	190 mL/min Geometric Coefficient of Variation 3.68

PRIMARY outcome

Timeframe: 4 hours

Population: PKS

Extent of dabigatran that is removed from blood during one complete 4-hour cycle of dialysis was computed by the difference of plasma concentration at the start and at the end of dialysis relative to the start concentration and is therefore measured as a percentage.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis Total Dabigatran	48.8 Percentage Geometric Coefficient of Variation 10.9	59.3 Percentage Geometric Coefficient of Variation 6.69
Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis Free Dabigatran	49.7 Percentage Geometric Coefficient of Variation 9.10	59.3 Percentage Geometric Coefficient of Variation 6.13

PRIMARY outcome

Timeframe: 4 hours

Population: PKS

Plasma concentration extraction ratio was measured directly at the dialysis machine and computed as the difference of the predialysis plasma concentration and the postdialysis plasma concentration relative to the predialysis concentration on the percentage scale (minimum: 0 percent of extraction (worst), maximum: 100 percent of extraction).

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Plasma Concentration Extraction Ratio Total Dabigatran	79.9 Percentage Geometric Coefficient of Variation 9.01	61.4 Percentage Geometric Coefficient of Variation 9.54
Plasma Concentration Extraction Ratio Free Dabigatran	82.6 Percentage Geometric Coefficient of Variation 8.21	63.7 Percentage Geometric Coefficient of Variation 8.60

SECONDARY outcome

Timeframe: Days 2 and 3

Population: Pharmacokinetic set (PKS) includes all evaluable patients of the TS who received at least 1 dose of dabigatran etexilate, who provided at least 1 observation for at least 1 Pharmacokinetics (PK) endpoint, and who did not have important protocol violations relevant to the evaluation of PK

Area under the concentration-time curve of total and free dabigatran in plasma over the time interval from 0 to 8 hours after the second and third administration of dabigatran.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) Free Dabigatran on Day 3	839 ng*hr/mL Geometric Coefficient of Variation 41.3	752 ng*hr/mL Geometric Coefficient of Variation 58.0
Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) Total Dabigatran on Day 2	1230 ng*hr/mL Geometric Coefficient of Variation 57.1	1140 ng*hr/mL Geometric Coefficient of Variation 39.4
Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) Total Dabigatran on Day 3	1280 ng*hr/mL Geometric Coefficient of Variation 54.4	1180 ng*hr/mL Geometric Coefficient of Variation 50.2
Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) Free Dabigatran on Day 2	907 ng*hr/mL Geometric Coefficient of Variation 51.6	802 ng*hr/mL Geometric Coefficient of Variation 44.1

SECONDARY outcome

Timeframe: Days 2 and 3

Population: PKS

Maximum measured concentration of total and free dabigatran in plasma after the second and third administration of dabigatran.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Maximum Plasma Concentrations of Dabigatran (Cmax) Free Dabigatran on Day 3	119 ng/mL Geometric Coefficient of Variation 43.7	105 ng/mL Geometric Coefficient of Variation 57.3
Maximum Plasma Concentrations of Dabigatran (Cmax) Total Dabigatran on Day 2	194 ng/mL Geometric Coefficient of Variation 53.1	171 ng/mL Geometric Coefficient of Variation 36.2
Maximum Plasma Concentrations of Dabigatran (Cmax) Total Dabigatran on Day 3	176 ng/mL Geometric Coefficient of Variation 54.1	159 ng/mL Geometric Coefficient of Variation 50.2
Maximum Plasma Concentrations of Dabigatran (Cmax) Free Dabigatran on Day 2	150 ng/mL Geometric Coefficient of Variation 47.3	126 ng/mL Geometric Coefficient of Variation 38.1

SECONDARY outcome

Timeframe: Day 3

Population: PKS

Time to maximum plasma concentration of total and free dabigatran in plasma after the third administration of dabigatran.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Time to Maximum Plasma Concentration (Tmax) Total Dabigatran	1.49 h Geometric Coefficient of Variation 38.4	2.13 h Geometric Coefficient of Variation 74.1
Time to Maximum Plasma Concentration (Tmax) Free Dabigatran	1.35 h Geometric Coefficient of Variation 38.4	1.83 h Geometric Coefficient of Variation 27.3

SECONDARY outcome

Timeframe: Day 3

Population: TS

Assessment of blood coagulation parameters 'activated partial thromboplastin time' (aPTT) and 'factor IIa inhibition' (anti-FIIa) measured with the diluted thrombin time assay. Time to the formation of a fibrin clot (coagulation) is measured in seconds.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 n=7 Participants Period 2 target blood flow rate during dialysis was 400mL/min
Coagulation Parameters Activated partial thromboplastin time (aPTT)	46.91 sec Standard Deviation 12.22	44.26 sec Standard Deviation 10.98
Coagulation Parameters Factor IIa inhibition (anti-FIIa)	43.27 sec Standard Deviation 7.99	43.09 sec Standard Deviation 5.38

SECONDARY outcome

Timeframe: 2 periods of 5 days each

Population: TS

Tolerability refers to the number of non-tolerable patients as assessed through the subjective examination of adverse events (AE). Safety refers to the number of patients with treatment emergent AEs. These numbers are presented on the overall Dabigatran treatment.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 Period 2 target blood flow rate during dialysis was 400mL/min
Safety and Tolerability Treatment emergent adverse events	2 Participants	—
Safety and Tolerability Assessment of tolerability by the investigator	0 Participants	—

SECONDARY outcome

Timeframe: 2 periods of 5 days each

Population: TS

By study design abnormalities could be due to dialysis or Dabigatran.

Outcome measures

Measure	Dabigatran P1 n=7 Participants Period 1 target blood flow rate during dialysis was 200mL/min	Dabigatran P2 Period 2 target blood flow rate during dialysis was 400mL/min
Additional Safety Parameters Electrocardiogram (ECG) abnormalities	0 Participants	—
Additional Safety Parameters Vital sign abnormalities	0 Participants	—
Additional Safety Parameters Physical finding abnormalities	0 Participants	—
Additional Safety Parameters Laboratory abnormalities: Haematology	0 Participants	—
Additional Safety Parameters Laboratory abnormalities: Clinical chemistry	0 Participants	—

Adverse Events

Dabigatran

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Dabigatran n=7 participants at risk Dabigatran treated patients
Nervous system disorders Headache	14.3% 1/7 • 2 periods of 5 days each Before and after dialysis
Respiratory, thoracic and mediastinal disorders Epistaxis	14.3% 1/7 • 2 periods of 5 days each Before and after dialysis

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

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