Microvascular and Antiinflammatory Effects of Rivaroxaban Compared to Aspirin in Type-2 Diabetic Patients With Subclinical Inflammation and High Cardiovascular Risk

Study Overview
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Brief Summary
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Study to investigate microvascular and antiinflammatory effects of Rivaroxaban compared to low dose aspirin in type 2 diabetic patients. Especially patients with cardiovascular disease and subclinical inflammation are in the focus of interest.

Official Title
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Microvascular and Antiinflammatory Effects of Rivaroxaban Compared to Low Dose Aspirin in Type-2 Diabetic Patients With Very High Cardiovascular Risk and Subclinical Inflammation

Conditions
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Type 2 Diabetic Patients

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes duration between 2 and 20 years Two or more components of metabolic syndrome: HDL-cholesterol < 1.0 mmol/L (in males) or < 1.3 mmol/L (in females) Elevated triglycerides (> 1.7 mmol/L) Elevated blood pressure (> 130 mmHg systolic and/or >85 mmHg diastolic or antihypertensive treatment) Elevated waist circumference (> 102 cm in males, > 85 cm in females) Or at least one of the following Carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or Left ventricular hypertrophy or Increased UACR in the absence of other renal diseases than diabetic nephropathy Increased hsCRP (> 2 mg/l but < 10 mg/l) at or within 6 months prior to screening and/or increased PAI 1 (> 15 ng/ml) at or within 6 months prior to screening (the historical hsCRP or PAI 1 value can be used only if the patient was in stable conditions regarding the concomitant diseases and statin therapy since the time point of measurement) Stable treatment with statins (if tolerated/clinically indicated) Age 40 - 75 years Exclusion Criteria: Major cardiovascular (CV) event with need for oral anticoagulation or platelet inhibitor therapy or acute coronary syndrome < 12 month before study entry Sustained uncontrolled hypertension: systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg Hypersensitivity to the active substance or to any of the excipients Active clinically significant bleeding Lesion or condition, if considered to be a significant risk for major bleeding Concomitant treatment of acute coronary syndrome (ACS) with antiplatelet therapy in patients with a prior stroke or a transient ischemic attack (TIA) Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Chronic renal failure with eGFR < 15 ml/min (MDRD formula) Pregnant or breast-feeding woman and woman without adequate method of contraception.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase) | Drug: Rivaroxaban<br> <br> |
| Active Comparator: Aspirin<br>100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase) | Drug: Aspirin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Post-ischemic Forearm Blood Flow | Change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml). Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 20 weeks treatment with rivaroxaban or aspirin. | Baseline and week 20 | 
| Change in Pulse Wave Velocity | Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph) | Baseline and week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Post-ischemic Forearm Blood Flow | Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 52 weeks treatment with rivaroxaban or aspirin. | Baseline and week 52 | 
| Change in Pulse Wave Velocity | Change in pulse wave velocity as a marker for arterial stiffness (measured by IEM Mobil-O-Graph) | Baseline to week 20 | 
| Change in Skin Blood Flow | Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF) | Baseline to week 20 | 
| Change in Skin Blood Flow | Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF) | Baseline to week 52 | 
| Major Bleeding | Major bleeding defined as clinically overt and associated with one of the following: 1) reduction of hemoglobin level of 2 g/L or 2) required transfusion of at least 2 units of red cells or, involved a critical organ or was fatal, in accordance with the recommendation of the International Society on Thrombosis and Hemostasis (ISTH). | Week 1 to week 20 | 
| Major Bleeding | Major bleeding defined as clinically overt and associated with one of the following: 1) reduction of hemoglobin level of 2 g/L or 2) required transfusion of at least 2 units of red cells or, involved a critical organ or was fatal, in accordance with the recommendation of the International Society on Thrombosis and Hemostasis (ISTH). | Week 1 to week 52 | 
| Clinically Relevant Non-major (CRNM) Bleeding | Clinically relevant non-major (CRNM) bleeding defined as at least one of the following: spontaneous skin hematoma of at least 25 cm spontaneous nose bleeding of more than 5 minutes duration macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours spontaneous rectal bleeding (more than spotting on toilet paper) gingival bleeding for more than 5 minutes bleeding leading to hospitalization and/or requiring surgical treatment bleeding leading to a transfusion of less than 2 units of whole blood or red cells any other bleeding event considered clinically relevant by the investigator | Week 1 to week 20 | 
| Clinically Relevant Non-major (CRNM) Bleeding | Clinically relevant non-major (CRNM) bleeding defined as at least one of the following: spontaneous skin hematoma of at least 25 cm spontaneous nose bleeding of more than 5 minutes duration macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours spontaneous rectal bleeding (more than spotting on toilet paper) gingival bleeding for more than 5 minutes bleeding leading to hospitalization and/or requiring surgical treatment bleeding leading to a transfusion of less than 2 units of whole blood or red cells any other bleeding event considered clinically relevant by the investigator | Week 1 to week 52 |