Pharmacokinetics of Rivaroxaban After Bariatric Surgery

Study Overview
=================
Brief Summary
-----------------
Data on pharmacokinetics of rivaroxaban after bariatric surgery and in morbid obesity are sparse. The aim of this study is to assess the pharmacokinetic and pharmacodynamic parameters of rivaroxaban, used at a therapeutic anticoagulant dose, in patients with previous bariatric surgery, with sleeve gastrectomy or gastric bypass, and in morbid obese subjects. Four groups of 16 subjects per group are studied: Morbid obese subjects / Subjects who have undergone gastric bypass surgery / Subjects who have undergone sleeve gastrectomy surgery / Non-operated control subjects matched for age and BMI with operated subjects. All patients (obese, surgical patients, and controls) will receive rivaroxaban 20mg once daily during 8 days. Blood samples will be taken predose (Baseline) and 0.5, 1, 2, 3, 6, 9, 12 and 24h post rivaroxaban administration at day1 and day8. PK and PD parameters will be compared between groups in order to explore the impact of bariatric surgery, type of surgery and body mass index on the pharmacological profile of rivaroxaban.

Official Title
-----------------
Pharmacokinetics and Pharmacodynamics of rivAroxaban After Bariatric Surgery and in mORBid Obesity

Conditions
-----------------
Bariatric Surgery, Morbid Obesity

Intervention / Treatment
-----------------
* Drug: rivaroxaban 20 mg once daily 8 days


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Creatinine clearance measured by the Cockroft formula ≥ 60 mL / min Patient meeting the specific criteria of one of the 4 groups: morbidly obese patients with BMI ≥ 40 Patients operated by gastric bypass for over a year and with stable weight Patients operated by sleeve gastrectomy for over a year and with stable weight Control group: non-operated subjects but with an age and a BMI corresponding to those of the patients of the 2 operated groups. Exclusion Criteria: Indication for anticoagulant therapy, antiplatelet therapy or long-term nonsteroidal anti-inflammatory drugs Clinically significant bleeding in progress Taking oral or parenteral anticoagulants, or taking platelet antiaggregants within 4 weeks before inclusion Congenital or acquired hemorrhagic disorders (eg von Willebrand disease, hemophilia) Injury or disease, at significant risk of major bleeding (gastrointestinal ulceration, presence of malignant tumors with a high risk of bleeding, recent brain or spinal cord injury, recent cerebral, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected oesophageal varices , arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities) Severe uncontrolled arterial hypertension Active gastrointestinal disease potentially leading to bleeding disorders (esophagitis, gastritis, gastroesophageal reflux disease, chronic inflammatory bowel disease) Vascular retinopathy Bronchiectasis or history of pulmonary bleeding Hypersensitivity to the active substance or to any of the excipients of rivaroxaban Hepatic involvement associated with coagulopathy and clinically significant bleeding risk, including cirrhotic patients with Child Pugh Grade B or C score Concomitant use of potent inhibitors or inducers of CYP3A4 and / or P-gp (azole antifungal or HIV protease inhibitor) Participation in a paid and / or therapeutic study in the previous 3 months Pregnant or lactating women, Women of childbearing potential not using effective contraception

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: morbidly obese patients with BMI ≥ 40<br>Morbidly obese patients with BMI ≥ 40 | Drug: rivaroxaban 20 mg once daily 8 days<br>* Blood samples for the measurement of rivaroxaban PK parameters<br>|
| Experimental: Patients operated by gastric bypass<br>Patients operated by gastric bypass for over a year and with stable weight | Drug: rivaroxaban 20 mg once daily 8 days<br>* Blood samples for the measurement of rivaroxaban PK parameters<br>|
| Experimental: Patients operated by sleeve gastrectomy<br>Patients operated by sleeve gastrectomy for over a year and with stable weight | Drug: rivaroxaban 20 mg once daily 8 days<br>* Blood samples for the measurement of rivaroxaban PK parameters<br>|
| Experimental: Control group: non-operated subjects<br>Control group: non-operated subjects but with an age and a BMI corresponding to those of the patients of the 2 operated groups. | Drug: rivaroxaban 20 mg once daily 8 days<br>* Blood samples for the measurement of rivaroxaban PK parameters<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC of rivaroxaban | Rivaroxaban plasma concentrations was assessed by the reference method at the different sampling points to determine the area under the curve (AUC) | up to 8 days | 
| Cmax of rivaroxaban | Cmax of rivaroxaban was assessed | up to 8 days | 
| Tmax of rivaroxaban | Tmax of rivaroxaban was assessed | up to 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prothrombin time | Prothrombin time of rivaroxaban was assessed | up to 8 days | 
| Activated partial thromboplatin time (aPTT) | Activated partial thromboplatin time was assessed | up to 8 days | 
| Fibrinogen levels | Fibrinogen levels was was assessed | up to 8 days | 
| Rivaroxaban anti-Xa activity | Rivaroxaban anti-Xa activity was assessed | up to 8 days | 
| Rate of bleedings | Treatment-Related Adverse Events were assessed | up to 15 days | 
| Other adverse events | Number of other adverse events than bleedings was assessed | up to 15 days | 
| Thrombin generation test of rivaroxaban | Thrombogram (thrombin generation test) data for each time analyzed allows measurement of peak height . These data will be used to model the PD of rivaroxaban and to estimate the PD variability. | up to 8 days | 
| Thrombin generation test of rivaroxaban | Thrombogram (thrombin generation test) data for each time analyzed allows measurement of thrombin generation potential (FTE). These data will be used to model the PD of rivaroxaban and to estimate the PD variability. | up to 8 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sleeve gastrectomy, gastric bypass, morbid obesity