type 2 diabetic patients with stable peripheral or carotid artery disease MedDRA version: 21.1 Level: LLT Classification code 10067825 Term: Peripheral arterial disease System Organ Class: 100000004866 MedDRA version: 21.0 Level: PT Classification code 10053247 Term: Insulin-requiring type 2 diabetes mellitus System Organ Class: 10027433 - Metabolism and nutrition disorders
Conditions
Interventions
Trade Name: XARELTO - 2,5 MG - COMPRESSE RIVESTITE CON FILM - USO ORALE - BLISTER (PP/ALU) - 56 COMPRESSE
Product Name: Rivaroxaban
Product Code: [bay59-7939]
Pharmaceutical Form: Tablet
INN or Propo
Sponsors
FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria - T2DM under glucose-lowering treatment; - PAD defined as having one of the following;18 i) previous aorto-femoral bypass surgery, limb bypass surgery, percutaneous transluminal angioplasty revascularization of the iliac, or infrainguinal arteries; ii) limb or foot amputation for arterial vascular disease; iii) intermittent claudication and one or more of either an ankle brachial index (ABI) of less than 0.90 or a peripheral artery stenosis (=50%) documented by angiography or duplex ultrasound; iv) carotid revascularization or asymptomatic carotid artery stenosis of at least 50% diagnosed by duplex ultrasound or angiography. Patients with coronary artery disease and ABI =65 years) yes F.1.3.1 Number of subjects for this age range 48
Exclusion criteria
Exclusion criteria: - Type 1 diabetes mellitus - Insulin therapy - Concomitant treatment with antiplatelet drugs other than aspirin - Ongoing cilostazol treatment - Co-administration of strong CYP3A4 and P-gp inducers or inhibitors: voriconazole, ketoconazole, itraconazole, posaconazole, anti-HIV drugs such as ritonavir - Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) - Concomitant treatment with any selective serotonin reuptake inhibitor (SSRI) or Serotonin And Noradrenaline Reuptake Inhibitor (SNRI), immunomodulators (ciclosporine, tacrolimus), anti-gout (probenecid); disease-modifier drugs for rheumatoid arthritis (i.e. methotrexate) - Chronic use of steroids (prednisone >5 mg/die or equivalent) - Chronic need for nonsteroidal anti-inflammatory drugs (NSAIDs), defined as >3 days/week - Stroke within 1 month - Any history of hemorrhagic or lacunar stroke - Prosthetic heart valves - Active cancer or cancer in complete remission from less than one year, except for treated early-stage squamous or basal cell skin carcinomas; - Chronic liver disease - Congenital or acquired bleeding disorders - Uncontrolled severe (Stage 4) arterial hypertension - Gastrointestinal complications (e.g., inflammatory bowel disease, esophagitis, gastritis and gastroesophageal reflux disease) and other disorders without active ulceration that can potentially lead to bleeding - Recent major surgery (<1 month) - Women with childbearing potential
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The choice of the primary end-point of the study is based on its primary mechanistic hypothesis. We hypothesize that reduced thrombin formation, resulting from FXa inhibition, will down-regulate persistently enhanced (aspirin-resistant) platelet activation that has been previously characterized in T2DM patients with macrovascular complications (including PAD)(19). Therefore, in comparing the effects of very low-dose rivaroxaban combined with low-dose aspirin vs low-dose aspirin alone, we shall test the hypothesis that combined treatment significantly reduces the urinary excretion of TXM, a non-invasive biomarker of in vivo platelet activation (20), in T2DM patients with stable PAD. The primary comparison will be made between urinary TXM excretion rates measured at the end of each treatment period, with each patient serving as his/her own control.;Timepoint(s) of evaluation of this end point: Visit 1: Screening (week - 2). Visit 2: Randomization (week 0): blood and urine sampling, randomization, initiation of treatment study medication, daily diary assignement (Appendix 10). Visit 3 (week 2): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement. Visit 4: (week 4): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement. Crossover treatment. Visit 5 (week 6): blood and urine sampling, study medication accountability (pill count), daily diary collection and new diary assignement. Visit 6: (week 8): end of treatment; blood and urine sampling, study medication accountability (pill count), diary collection.;Main Objective: The primary aim of the present study is to compare the degree of in vivo platelet activation, as reflected by the urinary excretion of the major enzymatic metabolite of thromboxane (TX) A2, 11-dehydro-TXB2 (TXM), in patients with T2DM and stable peripheral or carotid artery disease, randomized to one | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): . In vivo endothelial function: - endothelial anti-thrombotic activity will be assessed by measuring in vivo PGI2 biosynthesis, as reflected by the urinary excretion of its major enzymatic metabolite, 2,3-dinor-6-keto-PGF1¿ (PGIM); - the NO biosynthetic pathway as reflected by the analytes involved in its synthesis, i.e Arginine, the substrate of NO synthase and its products, Citrulline and Ornitine and the synthesis inhibitors, MMA, SDMA and ADMA; - vWF antigen and activity levels; 2. The following pro- and anti-inflammatory cytokines will be measured in peripheral venous blood: IL-2, IL-6, IL-9, IL-10, TNF-alpha. 3. Rivaroxaban plasma peak level (2 to 4 hr after dosing), as reflected by the anti-Xa activity, will be measured. 4. The urinary isoprostane, 8-iso-PGF2¿ will be measured as an index of in vivo lipid peroxidation, as previously described (16). 5. Serum TXB2 will be measured as a biomarker of aspirin pharmacodynamics, to assess the adequacy of platelet COX-1 inhibition, as previously described (16). 6. D-dimer level during the run-in period and on the last day of each period of the randomized treatment schedule (see below).;Timepoint(s) of evaluation of this end point: As in Primary endpoints | — |
Countries
Italy
Contacts
Public ContactDirezione Scientifica IRCCS Policli
Direzione Scientifica IRCCS Policlinico A. Gemelli
Outcome results
None listed