Anticoagulants and Bleeding DisordersDAPHNENCT03112525
DAPHNE Study: Direct Anticoagulant PHarmacogeNEtic
An observational study of Anticoagulants and Bleeding Disorders, run by University Hospital, Geneva at 1 site in Switzerland.
Trial summary
New/direct oral anticoagulants (NOAC/DOAC), like apixaban and rivaroxaban, are an interesting alternative to unfractionated or low molecular weight heparin relayed by oral anti-vitamin K anticoagulants (VKA) for the treatment of venous thromboembolism and atrial fibrillation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anticoagulants and Bleeding Disorders
- What is being tested?
- CYP3A4/5 and P-gp phenotyping and CYP3A4/5 and P-gp genotyping
- How many people
- 300 participants
- Where
- 1 siteSwitzerland
- Study dates
- 28 Jun 2017to 7 Jan 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with atrial fibrillation, pulmonary embolism or deep-vein thrombosis, treated or on long-term prophylaxis with rivaroxaban or apixaban in a real-life clinical setting. All patients will be recruited at the Geneva University Hospitals
Who may be able to join
- Understanding of French or English language and provide signed and dated informed consent form.
- Willing to comply with all study procedures and be available for the duration of the study.
- Male or female, aged 18 years or above.
- Diagnosed with atrial fibrillation, deep-vein thrombosis or pulmonary embolism and under rivaroxaban or apixaban drug treatment.
Who cannot join
- Participation in a clinical study that may interfere with participation in this study.
- Under rivaroxaban or apixaban for prophylaxis of deep-vein thrombosis and pulmonary embolism in patients undergoing knee or hip replacement surgery.
- Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study.
- Known allergy to midazolam or to fexofenadine
Trial locations and contacts
1 site in 1 country.
About this study
Official title: DAPHNE Study: Real-Life Observational Study to Evaluate the Impact of the CYP3A4/5/7 and P-gp Pharmacogenetics and Phenotypic Activity on the Pharmacokinetic Profile of the Direct Oral Anticoagulants Rivaroxaban and Apixaban in Hospitalised Patients
New/direct oral anticoagulants (NOAC/DOAC), like apixaban and rivaroxaban, are an interesting alternative to unfractionated or low molecular weight heparin relayed by oral anti-vitamin K anticoagulants (VKA) for the treatment of venous thromboembolism and atrial fibrillation. This new generation of anticoagulants directly inhibit a factor in the blood coagulation pathway and have a wide therapeutic range overcoming several practical issues associated with VKA therapy including the need of routine coagulation monitoring potentially simplifying patient management. However, despite this wide therapeutic range, a large interindividual dose variability related to factors such as age, body surface, smoking, concomitant diseases as well as differences in drug metabolism, could put susceptible patients at risk for uncontrolled bleeding. Both rivaroxaban and apixaban are cleared primarily via cytochrome P450 (CYP) mediated hepatic metabolism, mainly CYP3A, and renal excretion, involving the P-glycoprotein (P-gp). Both CYP3A and P-gp activity show important interindividual variations due to drug interactions and/or genetic polymorphisms in corresponding genes.
The aim of the current study is to evaluate the impact of cytochrome activity and relevant polymorphisms on rivaroxaban/apixaban dosage regimen or treatment efficacy in a hospital setting. The safety issue in this context is particularly relevant, since hospitalisation is linked to a modification of the patient's treatment with often an increase in the number of medications. The resulting changes in metabolism due to modified cytochrome and transporter activities could affect rivaroxaban/apixaban blood concentrations. Our central hypothesis is that genotype and/or phenotype in CYP3A4/5/7 or P-gp may influence the rivaroxaban/apixaban plasma concentration and increase the risk of thrombotic or hemorrhagic events. Thus, investigating how the patient's genotype and/or phenotype for CYP3A4/5/7 and P-gp could potentially alter the bio-disponibility of rivaroxaban and apixaban and therefore the risk to develop adverse events or inefficacy would be of particular interest.
- Conditions
- Anticoagulants and Bleeding Disorders
- Being tested
- CYP3A4/5 and P-gp phenotyping, CYP3A4/5 and P-gp genotyping
- Keywords
- rivaroxaban, apixaban, cytochrome, anticoagulant, transporter, polymorphism, genotyping, phenotyping
- Medical subject headings
- Hemostatic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CYP3A4/5 and P-gp phenotypingDiagnostic test
Phenotyping using a simplified version of the Geneva cocktail
CYP3A4/5 and P-gp genotypingGenetic
Selected CYP3A4, CYP3A5, CYP3A7 and ABCB1 single nucleotide polymorphism (SNP) determination
| Study group | Role | What they receive |
|---|---|---|
| Patient under Rivaroxaban | Not described Receives: Diagnostic Test: CYP3A4/5 and P-gp phenotyping; Genetic: CYP3A4/5 and P-gp genotyping | |
| Patient under Apixaban | Not described Receives: Diagnostic Test: CYP3A4/5 and P-gp phenotyping; Genetic: CYP3A4/5 and P-gp genotyping |
What is being measured
The primary outcome is the main question the study is designed to answer.
Comparison Apixaban Area Under the Curve (AUC) according to patient CYP3A phenotype
Measured: 6 weeks
Comparison Rivaroxaban AUC according to patient P-gp phenotype
Measured: 6 weeks
Comparison Apixaban AUC according to patient CYP3A genotype
Measured: 6 weeks
Comparison Rivaroxaban AUC according to patient P-gp genotype
Measured: 6 weeks
Secondary outcomes (6)
Comparison Apixaban AUC according to patient hepatic function
Measured: 6 weeks
Comparison Rivaroxaban AUC according to patient hepatic function
Measured: 6 weeks
Comparison Apixaban AUC according to patient renal function
Measured: 6 weeks
Comparison Rivaroxaban AUC according to patient renal function
Measured: 6 weeks
Comparison adverse event (bleeding) occurrence according to patient CYP3A phenotype
Measured: 6 weeks
Comparison adverse event (bleeding) occurrence according to patient P-gp phenotype
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2017
- Study start28 Jun 2017
- Primary completion7 Jan 2021
- Study completion7 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Anticoagulants and Bleeding DisordersStudies of the same condition, open and under way.
- More trials run by University Hospital, GenevaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 300 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Geneva
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Victoria Rollason, University Hospital, Geneva
- Investigators
- Jules Desmeules, Pr., Study director, HUGVictoria Rollason, Principal investigator, HUG
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03112525
- Sponsor's protocol ID
- CCER 2016-01490
- Acronym
- DAPHNE
- Status last verified
- Sep 2021
- First submitted
- 7 Apr 2017
- Last updated
- 30 Sep 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- DAPHNE Study: Real-Life Observational Study to Evaluate the Impact of the CYP3A4/5/7 and P-gp Pharmacogenetics and Phenotypic Activity on the Pharmacokinetic Profile of the Direct Oral Anticoagulants Rivaroxaban and Apixaban in Hospitalised Patients
- ClinicalTrials.gov ID
- NCT03112525
- Acronym / sponsor ID
- DAPHNE / CCER 2016-01490
- Conditions
- Anticoagulants and Bleeding Disorders
- Keywords
- rivaroxaban, apixaban, cytochrome, anticoagulant, transporter, polymorphism, genotyping, phenotyping
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 300 participants (actual)
- Lead sponsor
- University Hospital, GenevaUniversity, hospital or other
- Study start
- 28 Jun 2017 (actual)
- Primary completion
- 7 Jan 2021 (actual)
- Study completion
- 7 Jan 2021 (actual)
- First posted
- 13 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
New/direct oral anticoagulants (NOAC/DOAC), like apixaban and rivaroxaban, are an interesting alternative to unfractionated or low molecular weight heparin relayed by oral anti-vitamin K anticoagulants (VKA) for the treatment of venous thromboembolism and atrial fibrillation. This new generation of anticoagulants directly inhibit a factor in the blood coagulation pathway and have a wide therapeutic range overcoming several practical issues associated with VKA therapy including the need of routine coagulation monitoring potentially simplifying patient management. However, despite this wide therapeutic range, a large interindividual dose variability related to factors such as age, body surface, smoking, concomitant diseases as well as differences in drug metabolism, could put susceptible patients at risk for uncontrolled bleeding. Both rivaroxaban and apixaban are cleared primarily via cytochrome P450 (CYP) mediated hepatic metabolism, mainly CYP3A, and renal excretion, involving the P-glycoprotein (P-gp). Both CYP3A and P-gp activity show important interindividual variations due to drug interactions and/or genetic polymorphisms in corresponding genes.
The aim of the current study is to evaluate the impact of cytochrome activity and relevant polymorphisms on rivaroxaban/apixaban dosage regimen or treatment efficacy in a hospital setting. The safety issue in this context is particularly relevant, since hospitalisation is linked to a modification of the patient's treatment with often an increase in the number of medications. The resulting changes in metabolism due to modified cytochrome and transporter activities could affect rivaroxaban/apixaban blood concentrations. Our central hypothesis is that genotype and/or phenotype in CYP3A4/5/7 or P-gp may influence the rivaroxaban/apixaban plasma concentration and increase the risk of thrombotic or hemorrhagic events. Thus, investigating how the patient's genotype and/or phenotype for CYP3A4/5/7 and P-gp could potentially alter the bio-disponibility of rivaroxaban and apixaban and therefore the risk to develop adverse events or inefficacy would be of particular interest.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patient under Rivaroxaban | – | Diagnostic Test: CYP3A4/5 and P-gp phenotyping, Genetic: CYP3A4/5 and P-gp genotyping |
| Patient under Apixaban | – | Diagnostic Test: CYP3A4/5 and P-gp phenotyping, Genetic: CYP3A4/5 and P-gp genotyping |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with atrial fibrillation, pulmonary embolism or deep-vein thrombosis, treated or on long-term prophylaxis with rivaroxaban or apixaban in a real-life clinical setting. All patients will be recruited at the Geneva University Hospitals
Key inclusion criteria (4 listed)
- Understanding of French or English language and provide signed and dated informed consent form.
- Willing to comply with all study procedures and be available for the duration of the study.
- Male or female, aged 18 years or above.
- Diagnosed with atrial fibrillation, deep-vein thrombosis or pulmonary embolism and under rivaroxaban or apixaban drug treatment.
Key exclusion criteria (4 listed)
- Participation in a clinical study that may interfere with participation in this study.
- Under rivaroxaban or apixaban for prophylaxis of deep-vein thrombosis and pulmonary embolism in patients undergoing knee or hip replacement surgery.
- Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study.
- Known allergy to midazolam or to fexofenadine
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CYP3A4/5 and P-gp phenotypingPhenotyping using a simplified version of the Geneva cocktail | Diagnostic test | Patient under Apixaban, Patient under Rivaroxaban |
| CYP3A4/5 and P-gp genotypingSelected CYP3A4, CYP3A5, CYP3A7 and ABCB1 single nucleotide polymorphism (SNP) determination | Genetic | Patient under Apixaban, Patient under Rivaroxaban |
Primary outcome
Comparison Apixaban Area Under the Curve (AUC) according to patient CYP3A phenotype
Time frame: 6 weeks
Comparison Rivaroxaban AUC according to patient P-gp phenotype
Time frame: 6 weeks
Comparison Apixaban AUC according to patient CYP3A genotype
Time frame: 6 weeks
Comparison Rivaroxaban AUC according to patient P-gp genotype
Time frame: 6 weeks
6 secondary outcomes
Comparison Apixaban AUC according to patient hepatic function
Time frame: 6 weeks
Comparison Rivaroxaban AUC according to patient hepatic function
Time frame: 6 weeks
Comparison Apixaban AUC according to patient renal function
Time frame: 6 weeks
Comparison Rivaroxaban AUC according to patient renal function
Time frame: 6 weeks
Comparison adverse event (bleeding) occurrence according to patient CYP3A phenotype
Time frame: 6 weeks
Comparison adverse event (bleeding) occurrence according to patient P-gp phenotype
Time frame: 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jules Desmeules, Pr. study director
HUG
Victoria Rollason principal investigator
HUG
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Anticoagulants and Bleeding Disorders, run by University Hospital, Geneva at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Comparison Apixaban Area Under the Curve (AUC) according to patient CYP3A phenotype (time frame: 6 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2021.