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Influence of ABCB1 Polymorphisms on Plasma Concentrations of New Oral Anticoagulants in Case of Serious Adverse Events (Pgp NACO)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified August 2015 by Centre Hospitalier Universitaire de Besancon.
Recruitment status was:  Recruiting
Sponsor:
ClinicalTrials.gov Identifier:
NCT02103101
First Posted: April 3, 2014
Last Update Posted: August 6, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Etablissement Français du Sang
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Besancon
  Purpose

Vitamin K antagonists were hampered by several disadvantages, such as the need for frequent monitoring. In this context, new oral anticoagulants (NOACs) have been developed and are now available on the market. These NOACs, like all anticoagulant drugs, continue to be associated with an increased risk of bleeding. In addition, the lack of antidote and the absence of valid data regarding biological monitoring can pose problems in case of overdose or when emergency surgery is required. Studies investigating the pharmacokinetic properties of rivaroxaban and dabigatran, two NOACs now approved for the market, have shown high variability between individuals, with coefficients of variation of up to 60% for some pharmacokinetic parameters in patients treated after orthopaedic surgery. The relation between plasma concentrations of NOAC and bleeding risk has been clearly established in clinical trials.

Dabigtran, rivaroxaban and apixaban are known substrates of P-glycoprotein (Pgp). Pgp activity can be affected by pharmacological inducing or inhibiting agents. This can lead to a significant change in the pharmacokinetics of NOACs, with a decrease or increase (respectively) in the level of intestinal absorption, leading to respectively reduced or increased plasma concentrations of the drug. Furthermore, there exist genetic mutations of Pgp, presenting in particular a lower level of activity than the non-mutated protein. We hypothesized that the polymorphisms (mutations) of the ABCB1 gene that codes for Pgp could influence plasma concentrations of dabigatran, rivaroxaban and apixaban, and consequently, impact on the concentration of NOACs and as a corollary, on the bleeding and thromboembolic risk of patients treated with these molecules.

The main objective of this study is to study the relation between polymorphisms of the ABCB1 gene that codes for Pgp and plasma concentrations of NOACs in patients treated for a hemorrhagic or thromboembolic complication occurring under NOAC therapy.

Secondary objectives are to evaluate the distribution of ABCB1 polymorphisms among the various hemorrhagic risk factors, and to compare the frequency of the polymorphism in patients from the study population vs the general population.


Condition Intervention
Anticoagulants Thromboembolism Hemorrhage Other: Measurement of Plasma Concentrations of NOACs Genetic: Identification of ABCB1 polymorphisms coding for P-gp

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Influence of ABCB1 Polymorphisms on Plasma Concentrations of New Oral Anticoagulants in Case of Serious Adverse Events

Resource links provided by NLM:


Further study details as provided by Centre Hospitalier Universitaire de Besancon:

Primary Outcome Measures:
  • Measurement of plasma concentrations of new oral anticoagulant agents [ Time Frame: 0 days (at inclusion) ]
    Plasma concentrations of dabigatran, rivaroxaban or apixaban will be measured using High Performance Liquid Chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS). Blood samples will be taken in an EDTA tube and rapidly centrifugated. Plasma will be aliquoted and frozen at minus 80 degrees Celsius for later analysis.

  • Identification of polymorphisms of the gene ABCB1 coding for P-gp [ Time Frame: 0 days (at inclusion) ]
    To investigate the existence of a relation between polymorphisms of ABCB1 and plasma concentrations of new oral anticoagulants, the SNaPshot® Multiplex System will be used enabling multiplexing of SNPs (single nucleotide polymorphisms) of the ABCB1 gene (namely rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167).


Estimated Enrollment: 90
Study Start Date: November 2014
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: November 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Study cohort

Measurement of Plasma Concentrations of NOACs Identification of ABCB1 polymorphisms coding for P-gp

All patients aged over 18 and less than 80 years admitted for a serious adverse event (bleeding or thrombo-embolic complication) while under treatment with any of the following oral anticoagulant agents: dabigatran, rivaroxaban or apixaban. Blood samples will be drawn to measure plasma concentrations of the oral anticoagulant agent at the time of the adverse event, and presence of polymorphisms of ABCB1 will be investigated.

Other: Measurement of Plasma Concentrations of NOACs
Plasma concentrations of dabigatran, rivaroxaban or apixaban will be measured using High Performance Liquid Chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS). Blood samples will be taken in an EDTA tube and rapidly centrifugated. Plasma will be aliquoted and frozen at minus 80 degrees Celsius for later analysis.
Genetic: Identification of ABCB1 polymorphisms coding for P-gp
To investigate the existence of a relation between polymorphisms of ABCB1 and plasma concentrations of new oral anticoagulants, the SNaPshot® Multiplex System will be used enabling multiplexing of SNPs (single nucleotide polymorphisms) of the ABCB1 gene (namely rs4148738, rs2235046, rs1128503, rs10276036, rs1202169, rs1202168, rs1202167).

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients aged >18 and <80 years of age
  • Patients admitted to the University Hospital of Besancon for a serious adverse event (major bleeding complication or thrombo-embolic event) occurring under treatment with any one of the three commercially available new oral anticoagulant agents (rivaroxaban, apixaban or dabigatran).
  • Patients must have social security coverage.
  • Patients must provide written informed consent.

Exclusion Criteria:

  • Hemorrhagic complication from causes not related to drug therapy
  • Hemorrhagic complication occurring in patients not treated with oral anticoagulants at the time of the event
  • Thrombo-embolic complication occurring in patients not treated with oral anticoagulants at the time of the event
  • Legal incapacity, patients under judicial protection
  • Patients with no social security coverage
  • Patients unlikely to be compliant or anticipated by the investigator to be non-compliant with the study requirements
  • Patients in a wash-out period further to participation in a previous clinical trial
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02103101


Contacts
Contact: Nicolas F Meneveau, MD, PhD 33381668539 nicolas.meneveau@univ-fcomte.fr
Contact: Siamak Davani, MD, PhD siamak.davani@univ-fcomte.fr

Locations
France
CHU Besancon Recruiting
Besancon, France, 25000
Contact    33381668630      
Sub-Investigator: Francois Schiele, MD, PhD         
Sub-Investigator: Laurent Obert, MD         
Sub-Investigator: Gilles Capellier, MD         
Sub-Investigator: Thibaut Desmettre, MD         
Sub-Investigator: Nadine Magy, MD         
Sub-Investigator: Thierry Moulin, MD         
Sponsors and Collaborators
Centre Hospitalier Universitaire de Besancon
Etablissement Français du Sang
Investigators
Principal Investigator: Nicolas F Meneveau, MD, PhD Centre Hospitalier Universitaire de Besancon
  More Information

Responsible Party: Centre Hospitalier Universitaire de Besancon
ClinicalTrials.gov Identifier: NCT02103101     History of Changes
Other Study ID Numbers: Pgp NOAC
First Submitted: March 31, 2014
First Posted: April 3, 2014
Last Update Posted: August 6, 2015
Last Verified: August 2015

Keywords provided by Centre Hospitalier Universitaire de Besancon:
polymorphism
ABCB1
P-glycoprotein
oral anticoagulant
dabigatran
apixaban
rivaroxaban
hemorrhagic complication
thrombo-embolism
serious adverse event

Additional relevant MeSH terms:
Hemorrhage
Thromboembolism
Pathologic Processes
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Rivaroxaban
Apixaban
Dabigatran
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action