- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01590823
An Evaluation of the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate in Hemodialysis Patients
Phase 1 Study of the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate in Hemodialysis Patients
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The frequency of atrial fibrillation (AF) is 10- to 20- fold higher in patients with end stage renal disease (ESRD) compared to the general population (1-5). Conditions contributing to the risk of stroke in AF are highly prevalent in ESRD patients undergoing dialysis (6). A large number of trials have shown the usefulness of oral anticoagulation with warfarin sodium for primary and secondary prevention of stroke in patients with AF (7). Despite that the majority of these trials excluded patients with ESRD, warfarin sodium is commonly prescribed in dialysis patients with AF for prevention of stroke (8). Managing dialysis patients on wafarin sodium is challenging given the plethora of drug and food interactions, need for frequent coagulation monitoring and dose adjustment and lack of large randomized clinical trails assessing the benefit of stroke prevention versus risk of hemorrhage in this population (8,9). Additionally, recent concern regarding the association between vascular calcification enhanced by warfarin sodium in dialysis patients highlights the need for alternative oral anticoagulant therapy (10,11).
A new oral anticoagulant, dabigatran etexilate, which is a direct thrombin inhibitor, has been approved for prevention of stroke in patients with AF and prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip and knee replacement surgeries(12-15). Other indications under investigation include the treatment of VTE (16) and the treatment of thromboembolic complications following acute coronary syndromes (17).
Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed and converted to its active form, dabigatran. Dabigatran specifically and reversibly inhibits thrombin which is a key enzyme required in the coagulation pathway. Dabigatran etexilate posses beneficial properties including: a fixed oral dosage regimen, predictable pharmacokinetic profile, strong association between plasma drug concentration and anticoagulation response, low potential for drug interactions and lack of need for routine coagulation monitoring (18-24). As such, dabigatran etexilate represents a possible improved alternative to warfarin for anticoagulation in dialysis patients with AF.
Dabigatran etexilate has been developed using a fixed dosage regimen of 150 mg twice daily in AF patients with normal renal function for prevention of stroke (12). Limited information regarding dosing dabigatran etexilate in patients with renal impairment or ESRD exists as these patients were excluded from all phase III trials. Despite this, a recent small study investigated the pharmacokinetics of a single oral dose of dabigatran etexilate 150 mg in healthy patients and in patients with mild to severe renal impairment (creatinine clearance >50 to ≤80 , >30 to ≤50 and <30 mL/min) and dabigatran etexilate 50 mg in patients with ESRD requiring maintenance hemodialysis (25).
Systemic exposure to dabigatran and corresponding coagulation response was increased by renal impairment and correlated with the severity of renal dysfunction suggesting that a reduced dose and or extended dose interval may be necessary in patients with mild to severe renal impairment. In the six patients that were studied, hemodialysis removed on average 62% and 68% of the dabigatran entering the dialyzer indicating that hemodialysis can compensate for the impaired dabigatran renal elimination that occurs in ESRD. Unfortunately, a meaningful correlation between dabigatran plasma concentrations and anticoagulation activity could not be determined as the hemodialysis patients were on unfractionated heparin to prevent clotting in their dialysis circuit. Furthermore, the necessity of a post-dialysis dose to maintain dabigatran levels in the therapeutic range was not investigated.
Herein, we propose a pilot study to examine the single dose pharmacokinetics and pharmacodynamics of dabigatran etexilate in hemodialysis patients who are receiving normal saline flushes for prevention of extracorporeal circuit clotting. The specific objective is to establish baseline correlation between plasma dabigatran concentrations versus anticoagulation activity over time. Our long-term objective is to develop an evidence-based recommendation for dabigatran dosing in hemodialysis patients.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Nova Scotia
-
Halifax, Nova Scotia, Canada, b3h 2y9
- Capital Health District Authority, Department of Medicine, Division of Nephrology
-
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients between 18 and 75 years receiving hemodialysis at the Capital District Health Authority Renal Program who are receiving or who are good candidates for normal saline flushes for prevention of extracorporeal circuit clotting will be eligible for this study.
Exclusion Criteria:
Of those fulfilling the inclusion criterion, the following will be excluding characteristics:
- know bleeding diathesis;
- geographic inaccessibility for follow-up of timed blood sampling;
- use of any anticoagulant drugs that might influence results within 48 hours of the study;
- history of allergy/hypersensitivity (including drug allergy) deemed relevant to the trial by the investigators;
- recent or planned diagnostic or therapeutic procedures with potential for bleeding within 14 days before or after drug administration;
- history of familial bleeding disorder;
- history of relevant orthostatic hypotension, fainting spells or blackouts;
- disease of the central nervous system (such as epilepsy);
- chronic or relevant acute infection; and
- use of medication known to potentially increase or decrease dabigtran exposure.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Dabigatran etexilate 110 mg
Single dose of Dabigatran etexilate 110 mg po
|
All participants will receive a single dosage of dabigatran etexilate 110 mg at the start of their 4 hour dialysis session.
Blood sampling will be conducted during and up to 48 hours after participant's dialysis session.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacokinetics following a single dose of dabigatran etexilate in hemodialysis patients.
Time Frame: 0,0.5,1,2,3,4,12,24, and 48 hours post dose following single dabigatran dose
|
Dabigatran plasma concentration following a single dose of dabigatran etexilate in hemodialysis patients
|
0,0.5,1,2,3,4,12,24, and 48 hours post dose following single dabigatran dose
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Fraction of dabigatran in the blood removed by dialysis.
Time Frame: 0,1,2,3 and 4 hours post dose
|
0,1,2,3 and 4 hours post dose
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: jo-anne wilsoon, PharmD, CDHA Renal Program
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Dabigatran Hemodialysis 2012
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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