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

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ClinicalTrials.gov Identifier: NCT02103101
Recruitment Status : Completed
First Posted : April 3, 2014
Last Update Posted : July 18, 2018
Sponsor:
Collaborator:
Etablissement Français du Sang
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Besancon

Tracking Information
First Submitted Date  ICMJE March 31, 2014
First Posted Date  ICMJE April 3, 2014
Last Update Posted Date July 18, 2018
Actual Study Start Date  ICMJE November 13, 2014
Actual Primary Completion Date October 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 31, 2014)
  • 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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Influence of ABCB1 Polymorphisms on Plasma Concentrations of New Oral Anticoagulants in Case of Serious Adverse Events
Official Title  ICMJE Influence of ABCB1 Polymorphisms on Plasma Concentrations of New Oral Anticoagulants in Case of Serious Adverse Events
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE
  • Anticoagulants
  • Thromboembolism
  • Hemorrhage
Intervention  ICMJE
  • 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).
Study Arms  ICMJE 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.

Interventions:
  • Other: Measurement of Plasma Concentrations of NOACs
  • Genetic: Identification of ABCB1 polymorphisms coding for P-gp
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 17, 2018)
68
Original Estimated Enrollment  ICMJE
 (submitted: March 31, 2014)
90
Actual Study Completion Date  ICMJE October 31, 2017
Actual Primary Completion Date October 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02103101
Other Study ID Numbers  ICMJE Pgp NOAC
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Centre Hospitalier Universitaire de Besancon
Study Sponsor  ICMJE Centre Hospitalier Universitaire de Besancon
Collaborators  ICMJE Etablissement Français du Sang
Investigators  ICMJE
Principal Investigator: Nicolas F Meneveau, MD, PhD Centre Hospitalier Universitaire de Besancon
PRS Account Centre Hospitalier Universitaire de Besancon
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP