Type 2 Diabetic Patients
Conditions
Brief summary
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.
Interventions
DRUGRivaroxaban
DRUGAspirin
Sponsors
GWT-TUD GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Post-ischemic Forearm Blood Flow | Baseline and week 20 | 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. |
| Change in Pulse Wave Velocity | Baseline and week 52 | Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Skin Blood Flow | Baseline to week 20 | Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF) |
| Change in Post-ischemic Forearm Blood Flow | Baseline and week 52 | 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. |
| Clinically Relevant Non-major (CRNM) Bleeding | Week 1 to week 20 | 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 |
| Major Bleeding | Week 1 to week 20 | 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). |
| Change in Pulse Wave Velocity | Baseline to week 20 | Change in pulse wave velocity as a marker for arterial stiffness (measured by IEM Mobil-O-Graph) |
Countries
Germany
Participant flow
Recruitment details
From 14th Apr 2015 through 21st Dec 2017, a total of 239 patients were screened at 4 study sites in Germany. Of them, 60 patients did not meet the eligibility criteria. 188 patients were planned to enrol and 80 patients of them should included in the extension period of the study.
Pre-assignment details
179 patients were randomized to one of the two treatment groups, 89 to receive rivaroxaban and 90 to receive acetylsalicylic acid (ASA). In total, 73 patients were included in the extension period, 37 of them received rivaroxaban and 36 received ASA.
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban 5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase) | 89 |
| Aspirin 100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase) | 90 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Period | Adverse Event | 4 | 0 |
| Extension Period | Expiry of study medication | 1 | 0 |
| Extension Period | Protocol Violation | 0 | 1 |
| Extension Period | Withdrawal by Subject | 2 | 0 |
| Treatment Period | Adverse Event | 13 | 6 |
| Treatment Period | Early termination due to expiry of study medication | 1 | 0 |
| Treatment Period | Protocol Violation | 0 | 2 |
| Treatment Period | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Aspirin | Total | Rivaroxaban |
|---|---|---|---|
| Age, Continuous | 64.7 years | 64.4 years | 64.2 years |
| BMI | 33.4 kg/m^2 | 33.3 kg/m^2 | 33.2 kg/m^2 |
| Duration of diabetes | 9.24 years | 9.22 years | 9.21 years |
| Race/Ethnicity, Customized Caucasian | 90 Participants | 179 Participants | 89 Participants |
| Region of Enrollment Germany | 90 participants | 179 participants | 89 participants |
| Sex: Female, Male Female | 44 Participants | 95 Participants | 51 Participants |
| Sex: Female, Male Male | 46 Participants | 84 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 90 |
| other Total, other adverse events | 0 / 89 | 0 / 90 |
| serious Total, serious adverse events | 4 / 89 | 6 / 90 |
Outcome results
Primary
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.
Time frame: Baseline and week 20
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Post-ischemic Forearm Blood Flow | 3.60 ml/100ml | Standard Deviation 4.69 |
| Aspirin | Change in Post-ischemic Forearm Blood Flow | 1.00 ml/100ml | Standard Deviation 5.27 |
Comparison: The hypothesis H0 is tested against the one-sided alternative hypothesis H1 H0: µ∆FBF,Riva, week 20 ≤ µ∆FBF, ASA, week 20 versus H1: µΔFBF, Riva, week 20 \> µΔFBF, ASA, week 20 by test procedures for continuous data.p-value: 0.004ANCOVA
Primary
Change in Pulse Wave Velocity
Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph)
Time frame: Baseline and week 52
Population: Full Analysis Set of the extension phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Pulse Wave Velocity | 0.24 m/s | Standard Deviation 0.62 |
| Aspirin | Change in Pulse Wave Velocity | 0.51 m/s | Standard Deviation 0.57 |
p-value: 0.07ANCOVA
Secondary
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.
Time frame: Baseline and week 52
Population: Full Analysis Set of the extension phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Post-ischemic Forearm Blood Flow | 6.11 ml/100ml | Standard Deviation 8.83 |
| Aspirin | Change in Post-ischemic Forearm Blood Flow | 1.56 ml/100ml | Standard Deviation 5.34 |
p-value: 0.045ANCOVA
Secondary
Change in Pulse Wave Velocity
Change in pulse wave velocity as a marker for arterial stiffness (measured by IEM Mobil-O-Graph)
Time frame: Baseline to week 20
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Pulse Wave Velocity | 0.02 m/s | Standard Deviation 0.44 |
| Aspirin | Change in Pulse Wave Velocity | 0.14 m/s | Standard Deviation 0.53 |
p-value: 0.125ANCOVA
Secondary
Change in Skin Blood Flow
Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)
Time frame: Baseline to week 20
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Skin Blood Flow | 3.47 arbitrary units | Standard Deviation 44.7 |
| Aspirin | Change in Skin Blood Flow | -6.01 arbitrary units | Standard Deviation 34 |
p-value: 0.217Wilcoxon (Mann-Whitney)
Secondary
Change in Skin Blood Flow
Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)
Time frame: Baseline to week 52
Population: Full Analysis Set of the extension phase
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivaroxaban | Change in Skin Blood Flow | -7.3 arbitrary units | Standard Deviation 45.1 |
| Aspirin | Change in Skin Blood Flow | 5.8 arbitrary units | Standard Deviation 59.5 |
p-value: 0.589Wilcoxon (Mann-Whitney)
Secondary
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
Time frame: Week 1 to week 20
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Clinically Relevant Non-major (CRNM) Bleeding | 11 events |
| Aspirin | Clinically Relevant Non-major (CRNM) Bleeding | 1 events |
Secondary
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
Time frame: Week 1 to week 52
Population: Safety Analysis Set of the extension phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Clinically Relevant Non-major (CRNM) Bleeding | 6 events |
| Aspirin | Clinically Relevant Non-major (CRNM) Bleeding | 1 events |
Secondary
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).
Time frame: Week 1 to week 20
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Major Bleeding | 1 events |
| Aspirin | Major Bleeding | 0 events |
Secondary
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).
Time frame: Week 1 to week 52
Population: Safety Analysis Set of the extension phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivaroxaban | Major Bleeding | 0 events |
| Aspirin | Major Bleeding | 0 events |