Prophylaxis of Venous ThromboembolismPhase 1NCT02438098
Rivaroxaban in Bariatric Surgery
A Phase 1 study testing Rivaroxaban 10 mg in people with Prophylaxis of Venous Thromboembolism, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
Until now there ist no systematic investigation of the pharmacokinetic parameters of Rivaroxaban in obese patient undergoing bariatric surgery. The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban in obese patients before and after bariatric surgery. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Prophylaxis of Venous Thromboembolism
- What is being tested?
- Rivaroxaban 10 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteSwitzerland
- Study dates
- Jun 2015to Nov 2015
- Phase
- Phase 1
- 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
Who may be able to join
- Patient with scheduled elective bariatric surgery : laparoscopic Roux-en-Y gastric bypass surgery or sleeve resection
- Patient aged 18 years and older
- BMI 35kg/m^2 and higher
- Women of child bearing age: willingness of using a double barrier contraception method during the study
- Informed Consent as documented by signature
Who cannot join
- Intake of oral anticoagulants (phenprocoumon, acenocoumarol, dabigatran, etexilate, apixaban etc.) 4 weeks prior to inclusion in the study
- Application of parenteral anticoagulants (unfractionated heparin, low molecular weight heparins, heparin derivates (fondaparinux etc.) 4 weeks prior to inclusion in the study
- Pharmacologic platelet inhibition 4 weeks prior to inclusion in the study
- Known coagulation disorders (e.g. Willebrand's disease, haemophilia)
- Evidence for deep vein thrombosis or pulmonary embolism in the personal history or in the history of first degree relatives
- Medical condition that is associated with an increased risk for VTE, i.e. active cancer disease, lupus erythematodes chronic inflammatory bowel disease
Show all 20Show fewer
- Active, clinically significant bleeding
- Congenital or acquired bleeding disorder
- Uncontrolled severe hypertension
- Active gastrointestinal disease that can potentially lead to bleeding disorder: oesophagitis, gastritis, gastroesophageal reflux disease, chronic inflammatory bowel disease
- Vascular retinopathy
- Bronchiectasis or history of pulmonary bleeding
- Prior stroke or TIA
- Hereditary galactose intolerance, Lapp lactase deficiency, glucose-lactose malabsorption
- Severe renal impairment with a creatinine clearance (GFR) of <30ml/min
- Positive pregnancy test, pregnancy or nursing women
- High risk of bleeding (e.g. active ulcerative gastrointestinal disease)
- Known intolerance of the study medication rivaroxaban
- Concomitant treatment with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, lopinavir, ritonavir, indinavir)
- Concomitant treatment with an P-glycoprotein inhibitor and weak or moderate CYP3A4 inhibitor (e.g. erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine)
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
Department of Visceral Surgery and Medicine, University Hospital Bern
Bern, 3010
About this study
Official title: Pharmacokinetics and Pharmacodynamics of Single Doses of Rivaroxaban in Obesity Patients Before and After Bariatric Surgery
Until now there ist no systematic investigation of the pharmacokinetic parameters of Rivaroxaban in obese patient undergoing bariatric surgery. The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban in obese patients before and after bariatric surgery.
Patients receive the day before the surgical intervention the first dose of Rivaroxaban (10mg). During the following 24 hours, 9 blood samples are taken.
Read more
The second tablet Rivaroxaban is administered on the third postoperative day, followed again by 9 blood samples during the next 24 hours.
All other blood samples are taken independent from this clinical trial as part of the standard medical treatment during the hospitalization. The hospital stay will not be extended by the study. The outpatient regular follow-up takes place one month after surgery and is combined with the last study visit.
Read the detailed description
Background
The prevalence of obesity and morbid obesity is increasing worldwide and is becoming an increasing medical and socioeconomic burden. Bariatric surgery leads to the most sustained reduction of weight and associated co-morbidities. Obesity is a risk factor for the development of venous thromboembolism and the association between obesity and postoperative VTE is well established. The incidence of symptomatic DVT and PE ranges from 0%-5.4%, respectively 0%-6.4% and remains uncertain. Although the overall incidence seems to be low, VTE represents a significant cause of morbidity and mortality after surgery. Most postdischarge VTE events occur within the first 30 days after surgery and therefore extended chemoprophylaxis after hospital discharge is the standard of care and should be considered especially for patients classified to be at high risk for VTE.
Anticoagulants are recommended for the prevention of VTE, but there is no consensus regarding optimal method of prophylaxis. Routine perioperative use of drugs such as low-molecular weight heparins (LMWHs), intermittent pneumatic compression and early mobilization are currently the major accepted forms. However, there is currently no class I evidence to provide guidance regarding the type or dose of antithrombotic prophylaxis after bariatric surgery. For parenteral application there is for example limited evidence to guide dosing of thromboprophylaxis in morbid obesity and higher dosages are necessary, because impaired absorption after subcutaneous application.
The knowledge of the effect of extremely high body weight on pharmacokinetic and pharmacodynamics parameters after bariatric surgery especially for novel orally administered anticoagulants that target specific factors in the coagulation cascade is scarce. One promising therapeutic option is rivaroxaban (BAY 59-7939, Rivaroxaban), an orally administered direct factor Xa inhibitor that is approved for several indications in the field of prevention and treatment of thromboembolic disorders.
In several types of bariatric surgery procedures, such as sleeve gastrectomy, Roux-en-Y gastric bypass and biliopancreatic diversion different parts of gastrointestinal tract are bypassed or removed. This could affect the absorption of medications. Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. In a study looking at administration of the crushed tablet via a tube, a 29% and 56% decrease in AUC and Cmax compared to an oral tablet was reported when rivaroxaban granulate is released in the proximal small intestine. The effect of altered anatomy due to RYGB on oral drug absorption and bioavailability is currently unknown. Previous studies focused on drugs like metformin, sertraline or tacrolimus, but they yielded conflicting results. In a case report by Mahlmann et al. the absorption of rivaroxaban was immediate and not significantly impaired by bariatric surgery of the upper GI tract. However, data from larger patient collectives are not available.
Rivaroxaban is already approved for VTE prophylaxis in orthopaedic patients. Up to now, there is no clinical data available regarding obese patients after bariatric surgery. To fill this gap, this phase 1 clinical trial was designed with a study design that allows for intra-patient comparison of the effect of the bariatric surgery regarding pharmacokinetic and pharmacodynamics analysis.
Rivaroxaban as an oral anticoagulant could be an attractive option for VTE prophylaxis compared to subcutaneous (LMWH) standard treatment after bariatric surgery. Especially high-risk patients (high BMI, a history of DVT, obesity hypoventilation syndrome, pulmonary hypertension, hormonal therapy, venous stasis disease, male gender, expected long operative time or open approach, where an extended duration of thromboprophylaxis after hospital discharge is recommended, an oral therapy would be attractive.
Until now there is no systematic investigation of pharmacokinetic parameters of rivaroxaban in obese patient undergoing bariatric surgery. This phase I clinical trial offers the unique opportunity to investigate PK/PD in morbidly obese patients pre and post bariatric surgery. The results of this trial will help to design larger trials in this particular patient population with the final goal of safe and efficient use of rivaroxaban in morbidly patients.
Objective
The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban in obese patients before and after bariatric surgery.
Methods
Investigation of rivaroxaban AUC in bariatric.
- Conditions
- Prophylaxis of Venous Thromboembolism
- Being tested
- Rivaroxaban 10 mg
- Keywords
- Rivaroxaban, Obesity, Bariatric surgery, Pharmacokinetics, Pharmacodynamics
- Medical subject headings
- Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rivaroxaban 10 mgDrug
Patients receive the day before the surgical intervention the first dose of Rivaroxaban (10 mg) p.o. The second tablet Rivaroxaban is administered on the third postoperative day.
| Study group | Role | What they receive |
|---|---|---|
| Rivaroxaban arm | Other | Pharmacokinetics / Pharmacodynamics Receives: Drug: Rivaroxaban 10 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Geometric mean ratio of rivaroxaban AUC (after surgery / before surgery)
Measured: 1 year
Secondary outcomes (9)
AUC of rivaroxaban
Measured: 1 year
Cmax of rivaroxaban
Measured: 1 year
Tmax of rivaroxaban
Measured: 1 year
Prothrombin time (PT)
Measured: 1 year
Activated partial thromboplastin time (aPTT)
Measured: 1 year
Prothrombin fragment (F1+F2)
Measured: 1 year
Thrombin-antithrombin-complexes (TAT)
Measured: 1 year
D-Dimers
Measured: 1 year
Thrombin generation
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2015 (estimated)
- Study startJun 2015
- Primary completionNov 2015
- Study completionNov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Prophylaxis of Venous ThromboembolismStudies of the same condition, open and under way.
- 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
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Collaborators
- Centre Hospitalier Universitaire Vaudois, Bayer
- Responsible party
- Sponsor
- Investigators
- Dino Kroell, ME, Study chair, University of Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02438098
- Sponsor's protocol ID
- 025/15
- Status last verified
- Jan 2016
- First submitted
- 28 Apr 2015
- Last updated
- 8 Jan 2016
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Jan 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics and Pharmacodynamics of Single Doses of Rivaroxaban in Obesity Patients Before and After Bariatric Surgery
- ClinicalTrials.gov ID
- NCT02438098
- Acronym / sponsor ID
- 025/15
- Conditions
- Prophylaxis of Venous Thromboembolism
- Keywords
- Rivaroxaban, Obesity, Bariatric surgery, Pharmacokinetics, Pharmacodynamics
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Collaborators
- Centre Hospitalier Universitaire Vaudois, Bayer
- Study start
- Jun 2015
- Primary completion
- Nov 2015 (actual)
- Study completion
- Nov 2015 (actual)
- First posted
- 8 May 2015 (estimated)
- 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.
Until now there ist no systematic investigation of the pharmacokinetic parameters of Rivaroxaban in obese patient undergoing bariatric surgery. The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban in obese patients before and after bariatric surgery.
Patients receive the day before the surgical intervention the first dose of Rivaroxaban (10mg). During the following 24 hours, 9 blood samples are taken.
The second tablet Rivaroxaban is administered on the third postoperative day, followed again by 9 blood samples during the next 24 hours.
All other blood samples are taken independent from this clinical trial as part of the standard medical treatment during the hospitalization. The hospital stay will not be extended by the study. The outpatient regular follow-up takes place one month after surgery and is combined with the last study visit.
Detailed description
Background
The prevalence of obesity and morbid obesity is increasing worldwide and is becoming an increasing medical and socioeconomic burden. Bariatric surgery leads to the most sustained reduction of weight and associated co-morbidities. Obesity is a risk factor for the development of venous thromboembolism and the association between obesity and postoperative VTE is well established. The incidence of symptomatic DVT and PE ranges from 0%-5.4%, respectively 0%-6.4% and remains uncertain. Although the overall incidence seems to be low, VTE represents a significant cause of morbidity and mortality after surgery. Most postdischarge VTE events occur within the first 30 days after surgery and therefore extended chemoprophylaxis after hospital discharge is the standard of care and should be considered especially for patients classified to be at high risk for VTE.
Anticoagulants are recommended for the prevention of VTE, but there is no consensus regarding optimal method of prophylaxis. Routine perioperative use of drugs such as low-molecular weight heparins (LMWHs), intermittent pneumatic compression and early mobilization are currently the major accepted forms. However, there is currently no class I evidence to provide guidance regarding the type or dose of antithrombotic prophylaxis after bariatric surgery. For parenteral application there is for example limited evidence to guide dosing of thromboprophylaxis in morbid obesity and higher dosages are necessary, because impaired absorption after subcutaneous application.
The knowledge of the effect of extremely high body weight on pharmacokinetic and pharmacodynamics parameters after bariatric surgery especially for novel orally administered anticoagulants that target specific factors in the coagulation cascade is scarce. One promising therapeutic option is rivaroxaban (BAY 59-7939, Rivaroxaban), an orally administered direct factor Xa inhibitor that is approved for several indications in the field of prevention and treatment of thromboembolic disorders.
In several types of bariatric surgery procedures, such as sleeve gastrectomy, Roux-en-Y gastric bypass and biliopancreatic diversion different parts of gastrointestinal tract are bypassed or removed. This could affect the absorption of medications. Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. In a study looking at administration of the crushed tablet via a tube, a 29% and 56% decrease in AUC and Cmax compared to an oral tablet was reported when rivaroxaban granulate is released in the proximal small intestine. The effect of altered anatomy due to RYGB on oral drug absorption and bioavailability is currently unknown. Previous studies focused on drugs like metformin, sertraline or tacrolimus, but they yielded conflicting results. In a case report by Mahlmann et al. the absorption of rivaroxaban was immediate and not significantly impaired by bariatric surgery of the upper GI tract. However, data from larger patient collectives are not available.
Rivaroxaban is already approved for VTE prophylaxis in orthopaedic patients. Up to now, there is no clinical data available regarding obese patients after bariatric surgery. To fill this gap, this phase 1 clinical trial was designed with a study design that allows for intra-patient comparison of the effect of the bariatric surgery regarding pharmacokinetic and pharmacodynamics analysis.
Rivaroxaban as an oral anticoagulant could be an attractive option for VTE prophylaxis compared to subcutaneous (LMWH) standard treatment after bariatric surgery. Especially high-risk patients (high BMI, a history of DVT, obesity hypoventilation syndrome, pulmonary hypertension, hormonal therapy, venous stasis disease, male gender, expected long operative time or open approach, where an extended duration of thromboprophylaxis after hospital discharge is recommended, an oral therapy would be attractive.
Until now there is no systematic investigation of pharmacokinetic parameters of rivaroxaban in obese patient undergoing bariatric surgery. This phase I clinical trial offers the unique opportunity to investigate PK/PD in morbidly obese patients pre and post bariatric surgery. The results of this trial will help to design larger trials in this particular patient population with the final goal of safe and efficient use of rivaroxaban in morbidly patients.
Objective
The aim of this study is to investigate the pharmacokinetic and pharmacodynamic parameters of rivaroxaban in obese patients before and after bariatric surgery.
Methods
Investigation of rivaroxaban AUC in bariatric.
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Rivaroxaban arm | Other | Drug: Rivaroxaban 10 mgPharmacokinetics / Pharmacodynamics |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Patient with scheduled elective bariatric surgery : laparoscopic Roux-en-Y gastric bypass surgery or sleeve resection
- Patient aged 18 years and older
- BMI 35kg/m^2 and higher
- Women of child bearing age: willingness of using a double barrier contraception method during the study
- Informed Consent as documented by signature
Key exclusion criteria (20 listed)
- Intake of oral anticoagulants (phenprocoumon, acenocoumarol, dabigatran, etexilate, apixaban etc.) 4 weeks prior to inclusion in the study
- Application of parenteral anticoagulants (unfractionated heparin, low molecular weight heparins, heparin derivates (fondaparinux etc.) 4 weeks prior to inclusion in the study
- Pharmacologic platelet inhibition 4 weeks prior to inclusion in the study
- Known coagulation disorders (e.g. Willebrand's disease, haemophilia)
- Evidence for deep vein thrombosis or pulmonary embolism in the personal history or in the history of first degree relatives
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 |
|---|---|---|
| Rivaroxaban 10 mgPatients receive the day before the surgical intervention the first dose of Rivaroxaban (10 mg) p.o. The second tablet Rivaroxaban is administered on the third postoperative day. | Drug | Rivaroxaban arm |
Primary outcome
Geometric mean ratio of rivaroxaban AUC (after surgery / before surgery)
Time frame: 1 year
9 secondary outcomes
AUC of rivaroxaban
Time frame: 1 year
Cmax of rivaroxaban
Time frame: 1 year
Tmax of rivaroxaban
Time frame: 1 year
Prothrombin time (PT)
Time frame: 1 year
Activated partial thromboplastin time (aPTT)
Time frame: 1 year
Prothrombin fragment (F1+F2)
Time frame: 1 year
Thrombin-antithrombin-complexes (TAT)
Time frame: 1 year
D-Dimers
Time frame: 1 year
Thrombin generation
Time frame: 1 year
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 8 Jan 2016.
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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.
Dino Kroell, ME study chair
University of Bern
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rivaroxaban 10 mg in people with Prophylaxis of Venous Thromboembolism, run by Insel Gruppe AG, University Hospital Bern 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 5 inclusion and 20 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 8 Jan 2016. 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
Geometric mean ratio of rivaroxaban AUC (after surgery / before surgery) (time frame: 1 year). 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 8 Jan 2016.