Clinical trial NCT02164578
Conditions: Type 2 Diabetic Patients
Sponsor: GWT-TUD GmbH
Start date: 2015-04-01; Completion date: 2020-04-30
Enrollment: 179 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: 5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase) arm 2: 100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)
Interventions: intervention 1: Rivaroxaban intervention 2: Aspirin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
TRIAL PROTOCOL 
 
 
MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN 
COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH 
VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION  
 
 
MICROVASC-DIVA 
 
 
 
 
 
Sponsor 
GWT-TUD GmbH 
Blasewitzer Straße 43 
01307 Dresden 
Germany 
Coordinating Principal Investigator 
PD Dr. Frank Pistrosch 
GWT-TUD GmbH, Studienzentrum Prof. 
Hanefeld 
Blasewitzer Str. 43,  
01307 Dresden 
 
 
 
Trial protocol code: MICROVASC-DIVA 
EudraCT number: 2014-001305-41 
 
Final version 6.0 of 07.07.2016 
 
 
The information in this trial protocol is strictly confidential. It is for the use of the sponsor, investigator, trial 
personnel, ethics committee, the authorities, and trial subjects only. This trial protocol may not be passed on to 
third parties without the express consent of the sponsor or the Coordinating Principal Investigator (CPI, “Leiter 
der klinischen Prüfung (LKP)”). 
 




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SIGNATURES OF SPONSOR AND COORDINATING PRINCIPAL INVESTIGATOR 
 
By my signature, I agree to supervise the conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB/EC procedures, the Declaration of Helsinki, 
ICH Good Clinical Practices guidelines, and the applicable legislation governing the conduct of 
clinical studies. 
 
 
Sponsor 
 
 
 
 
 
Claus-Peter Held 
 
place and date 
 
 
 
 
 
Coordinating Principal Investigator 
 
 
 
 
 
PD Dr. Frank Pistrosch 
 
place and date 
 
 
 
 


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SIGNATURES OF INVESTIGATOR 
 
By my signature, I agree to supervise the conduct of this study and to ensure its conduct in 
compliance with the protocol, informed consent, IRB/EC procedures, the Declaration of Helsinki, 
ICH Good Clinical Practices guidelines, and the applicable legislation governing the conduct of 
clinical studies. 
 
Investigators 
 
 
 
 
 
Name of investigator 
 
date and signature 
 
 
 
 
 
 
Name of investigator 
 
date and signature 
 
 
 
 
 
 
Name of investigator 
 
date and signature 
 
 
 
 
 
 
Name of investigator 
 
date and signature 
 
 
 
 
 
 


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SYNOPSIS 
 
Sponsor 
GWT-TUD GmbH 
Blasewitzer Straße 43 
01307 Dresden 
Germany 
Coordinating 
Principal Investigator 
PD Dr. med. Frank Pistrosch 
Title of the clinical 
trial 
Microvascular and antiinflammatory effects of Rivaroxaban compared to low 
dose aspirin in type 2 diabetic patients with very high cardiovascular risk and 
subclinical inflammation  
Indication 
Rivaroxaban 5 mg b.i.d vs. aspirin 100 mg qd in patients with type 2 diabetes 
and very high cardiovascular risk 
Phase 
III b 
Type of trial, trial 
design, methodology 
prospective, comparative active controlled, randomized, 2 parallel arms,   
open study 
Number of subjects 
188 patients in (94 patients each arm) 
Treatment Groups 
Arm A (treatment group):  
 
Rivaroxaban 
5 mg 
b.i.d 
Arm B (control group):   
 
ASS 100 mg qd 
Treatment period 
20 weeks  
+ additional 32 weeks (extension study for 80 patients) 
Time plan 
 
First patient first visit (FPFV): 
April 2015 
Last patient first visit (LPFV): 
July 2017 
Last patient last visit (LPLV): 
August 2018 
Database Lock: 
December 2018 
Final study report: 
April 2019 


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Study objectives 
Primary objectives 
Difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 20 weeks 
treatment between rivaroxoban and aspirin therapy  
Additionally the difference of arterial stiffness after 52 weeks treatment 
(extension study) between rivaroxoban and aspirin therapy will be evaluated. 
 
 
Secondary objectives 
 
change of peripheral skin microcirculatory function (measured by 
laserdopplerfluxmetry; LDF) after 20 and 52 weeks of treatment 
 
LDF baseline 
 
LDF after ischemia (endothelial function) 
 
arterial stiffness measured by Mobilograph (IEM Inc.) after 20 weeks 
of treatment 
 
laboratory markers for endothelial function  
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
Microalbuminuria, eGFR 
 
composite of biomarkers of inflammation  
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8 
 
side effects: major bleeding according to ISTH, symptomatic 
thromboembolic events 
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C 
 
coagulation: von Willebrand-Factor, Fibrinogen, 
Prothrombinfragment 1 + 2, D-Dimer, Protein C, Protein S, TAT, 
Quick, aPTT 
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Additional secondary objective for extension period: 
 
Difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 52 
weeks treatment 
 
Explorative Study Objective(s)  
assessment of platelet activation and measurement of mitogenic potential 


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Study end points 
Primary variable 
 
change of maximal postischemic forearm blood flow during reactive 
hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at 
20 weeks 
 
Additional primary variable for extension period: 
 
pulse wave velocity at EOT after 52 weeks 
Study end points 
Secondary variables 
 
change of the area under the postischemic FBF curve over 10 cycles 
of intermittent venous congestion (compared to baseline) after 20 
weeks and EOT Extension 
 
 
 
maximal postischemic skin blood flow (arbitrary units) during 
reactive hyperaemia after 5 min of forearm ischemia at 20 weeks and 
EOT Extension using LDF 
 
change of postischemic skin blood flow (compared to baseline) using 
LDF 
 
Pulse wave velocity at 20 weeks compared to baseline 
 
laboratory parameter (see above) at 20 weeks and EOT Extension 
 
Additional secondary variable for extension period: 
 
change of maximal postischemic forearm blood flow during reactive 
hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at 
EOT after 52 weeks (EOT Extension) 


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Safety Parameter 
Safety Parameter  
 
major bleeding defined as clinically overt and associated with one of 
the following: 
- 
reduction of hemoglobin level of 2 g/L or 
- 
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 Haemostasis (ISTH). 
 
clinically relevant non major 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 
Medical condition 
Medical condition or disease to be investigated: 
Patients with type 2 diabetes and stable cardiovascular disease (CVD) and 
low grade inflammation 


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In-/Exclusion criteria 
Principal 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 statines (if tolerated/clinically indicated) 
 
age 40 – 75 years 


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Principal exclusion criteria: 
 
major 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 ACS with antiplatelet therapy in patients 
with a prior stroke or a transient ischaemic 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.  
 
Measurement of 
results 
Venous occlusion plethysmography for assessment of FBF: 
Endothelium dependent vasodilation of resistance vessels will be assessed in 
both 
arms 
simultaneously using strain-gauge venous occlusion 
plethysmography (Gutmann Medizinelektronik, Eurasburg, Germany or 
Hokanson Pletysmograph EC6). Endothelium dependent dilation of forearm 
resistance vessels will be stimulated in one arm by suprasystolic occlusion for 
5 min and subsequent postischaemic release of endogenous vasodilators. 
The contra lateral arm serves as control. 
Laser Doppler Fluxometry (LDF): 
The 
technique 
of 
micro-lightguide 
spectrophotometry 
and 
laserdopplerfluxmetry will be used to measure microvascular skin blood flow 
and postcapillary tissue oxygenation (sO2) at the lower forearm. LDF skin 
probes will be placed at the lower forearm and on the thenar surface of the 
left hand in between the phalanx of the thumb and the metatarsale of Dig II, 
directly adjacent to the muscle abductor pollicis. Microvascular blood flow 
and post-capillary sO2 will be measured in parallel in a tissue depth of 2 mm 
and 8 mm. Via a cuff on the upper arm a supra-systolic occlusion will be 
induced for 4 minutes, and thereafter, the postischaemic microvascular 
blood flow and sO2 will be recorded as a measure of microvascular 
endothelial function in the skin. 


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Pulse wave velocity and arterial stiffness: 
Measurements will be performed using the Mobil-O-Graph device (IEM Inc., 
Stolberg, Germany). This device allows the non-invasive oscillometric 
analysis of blood pressure and pulse wave over 24 hours. Based on pulse 
wave analysis we calculate the aortic augmentation index as marker of 
arterial stiffness and pulse wave velocity. The Mobil-O-Graph device has 
been validated against gold standard procedures such as applanation 
tonometry (SphygmoCor, AtCor Inc.).  
Measurement of 
results 
Assessment of platelet activation and mitogenic potential 
Platelet activation will be assessed by measuring platelet derived 
microparticles (PMP) by separating platelet poor plasma from platelet rich 
plasma. 
Subsequently, analysis of platelet microparticles and their mitogenic 
potential will be performed after sample thawing. PMP will be measured 
after staining with anti-GP1b antibodies by fluorescence-activated cell 
sorting (FACS). In addition, magnetic beads linked with anti-GP1 b antibodies 
will be used to extract PMP from platelet poor plasma. Extracted PMP will 
then be added to human vascular endothelial cells (HUVECS) and migration 
(Boyden chamber) as well as proliferation (BrdU) of HUVECs will be assessed 
with and without PMP with samples from patients undergoing platelet 
inhibition or rivaroxaban treatment.  
Platelet rich plasma will be used to measure platelet activation by cGMP 
dependent phosphorylation of vasodilator-stimulated phosphoprotein 
(VASP) at Ser-157 which will be detected by flow cytometry. 
Statistical methods 
Efficacy:  
The statistical analysis will be done in the intention to treat and per protocol 
set. The primary parameter will be the maximum FBF at 20 weeks (assessed 
with venous occlusion plethysmography after forearm ischemia) controlling 
for baseline FBF and the Pulse Wave Velocity (PWV) at EOT (extended 
treatment period after 52 weeks) assessed with a sphygmograph 
(Mobilograph®, IEM) using an analysis of covariance (ANCOVA). Independent 
t-test will be used to test the parameters between the groups at the time 
point as well as the change between baseline and 20 weeks of treatment.  
Additionally, measurements will also be compared to an extended treatment 
up to 52 weeks (EOT Extension). 
 
Safety:  
Analysis of bleeding events and safety parameters is required. 


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Statistical methods 
Sample Size Estimation: 
The first primary variable is change of forearm blood blow with venous 
occlusion plethysmography (ΔFBF) after forearm ischemia after 20 weeks 
treatment. The sample size calculation is based on the following 
assumptions: 
H0: ΔFBFRiva ≤ ΔFBFASS 
H1: ΔFBFRiva> ΔFBFASS 
 
Type I error: α = 0.05, one-tailed t-test for independent samples 
 
Power: 1-ß = 0.90 
 
Estimated dropout rate : 25 % 
 
Minimum of expected clinical relevant difference between the 
groups in changes of maximal forearm blood flow (ΔFBF) = 1.2 
ml/100ml with an estimated standard deviation (SD) of σ = 2.4 
ml/100ml [Pistrosch, F. et al. Diabetes Care 27: 484-490, 2004] 
 
Sample size should be N = 188 Patients (N1/2 = 94 patients per arm) for a valid 
number of 141 patients for per protocol analysis. This sample size may also 
provide enough power for further analyses. 
 
Additionally, the second primary variable is the difference of PWV between 
treatment groups at EOT Extension (after 52 week of treatment). The sample 
size calculation is based on the following assumptions:  
H0: PWVRiva=PWVASS 
H1: PWVRiva≠PWVASS 
 
Type I error: α = 0.05, t-test for independent samples  
 
Power: 1-ß = 0.80  
 
Estimated dropout rate : 20 %  
 
Minimum of expected clinical relevant difference between the 
groups in PWV = 0.7 m/s with an estimated standard deviation (SD) 
of σ = 1.0 m/s  
 
Sample size should be N=80 patients (40 patients per arm) for a valid number 
of 66 patients for per protocol analysis. 
 
In summary the necessary sample size would be N=188 patients for the study 
up to week 20 including 80 patients for the extension up to week 52. 
GCP conformance 
The present trial will be conducted in accordance with the valid versions of 
the trial protocol and the internationally recognized Good Clinical Practice 
Guidelines (ICH-GCP), including archiving of essential documents. 
Financing 
GWT-TUD GmbH with support of Bayer Vital GmbH 
 
 


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TABLE OF CONTENTS´ 
1 
INTRODUCTION ............................................................................................................................................................. 17 
2 
OBJECTIVES OF THE CLINICAL TRIAL .......................................................................................................................... 18 
2.1 
RATIONALE FOR THE CLINICAL TRIAL........................................................................................................................... 18 
2.2 
PRIMARY OBJECTIVE.................................................................................................................................................. 19 
2.3 
SECONDARY AND OTHER OBJECTIVES ......................................................................................................................... 19 
2.4 
MEASUREMENT OF MITOGENIC POTENTIAL AND ASSESSMENT OF PLATELET ACTIVATION............................................... 20 
2.5 
RISK-BENEFIT-ASSESSMENT...................................................................................................................................... 20 
3 
ORGANIZATIONAL AND ADMINISTRATIVE ASPECTS OF THE TRIAL ..................................................................... 21 
3.1 
SPONSOR ................................................................................................................................................................. 21 
3.2 
COORDINATING PRINCIPAL INVESTIGATOR AND DEPUTY (LEITER DER KLINISCHEN PRÜFUNG ACCORDING TO GERMAN 
DRUG LAW)............................................................................................................................................................................. 21 
3.3 
MONITORING ........................................................................................................................................................... 21 
3.4 
DATAMANAGEMENT ................................................................................................................................................. 21 
3.5 
STATISTICS ............................................................................................................................................................... 21 
3.6 
DATA AND SAFETY MONITORING BOARD (DSMB) .................................................................................................... 21 
3.7 
INVESTIGATORS AND TRIAL SITES................................................................................................................................ 22 
3.7.1 
REQUIREMENTS FOR INVESTIGATORS AND TRIAL SITES ................................................................................................ 22 
3.8 
OTHER STUDY PERSONNEL......................................................................................................................................... 22 
3.9 
FINANCING............................................................................................................................................................... 22 
4 
TRIAL CONDUCT ............................................................................................................................................................ 23 
4.1 
TIME PLAN ............................................................................................................................................................... 23 
4.2 
DESIGN OVERVIEW ................................................................................................................................................... 23 
4.2.1 
TREATMENT GROUPS ................................................................................................................................................ 23 
4.2.2 
VISIT SCHEDULE ........................................................................................................................................................ 24 
4.3 
END OF THE CLINICAL TRIAL ....................................................................................................................................... 24 
4.4 
JUSTIFICATION OF TRIAL DESIGN ................................................................................................................................ 24 
4.5 
SELECTION OF TRIAL POPULATION.............................................................................................................................. 25 
4.6 
JUSTIFICATION OF GENDER DISTRIBUTION................................................................................................................... 25 
4.7 
JUSTIFICATION OF SELECTION CRITERIA....................................................................................................................... 25 
4.8 
WITHDRAWAL OF TRIAL SUBJECTS AFTER TRIAL START................................................................................................. 25 
4.8.1 
WITHDRAWAL .......................................................................................................................................................... 25 
4.8.2 
DROPOUT PATIENTS.................................................................................................................................................. 25 
4.8.3 
SCREENING FAILURES ................................................................................................................................................ 26 
4.8.4 
REPLACEMENT.......................................................................................................................................................... 26 
4.9 
SUBJECT IDENTIFICATION........................................................................................................................................... 26 
4.10 
PREMATURE TERMINATION OF THE CLINICAL TRIAL ..................................................................................................... 26 
4.10.1 
CLOSURE OF A TRIAL SITE ..................................................................................................................................... 27 
4.11 
IN- AND EXCLUSION CRITERIA OF THE TRIAL ................................................................................................................ 27 
4.11.1 
INCLUSION CRITERIA ............................................................................................................................................ 27 
4.11.2 
EXCLUSION CRITERIA............................................................................................................................................ 28 
4.11.3 
OTHER CRITERIA .................................................................................................................................................. 29 
4.12 
TRIAL PROCEDURE OVERVIEW.................................................................................................................................... 30 
4.12.1 
TABULATED OVERVIEW ........................................................................................................................................ 30 
4.12.2 
DESCRIPTION OF VISITS / SCHEDULE ..................................................................................................................... 31 


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4.12.3 
DESCRIPTION OF VISITS / SCHEDULE OF EXTENDED TREATMENT PERIOD (80 OF 188 PATIENTS)............................... 32 
4.13 
DESCRIPTION OF TREATMENT .................................................................................................................................... 33 
4.13.1 
VISIT 0 - SCREENING (DAY -28) ........................................................................................................................... 33 
4.13.2 
VISIT 1 –BASELINE (DAY 0 ± 4 D)......................................................................................................................... 33 
4.13.3 
VISIT 2 AND VISIT 4 - TREATMENT PHASE ............................................................................................................. 34 
4.13.4 
VISIT 3 AND VISIT 5 - TREATMENT PHASE (TELEPHONE VISITS)............................................................................... 34 
4.13.5 
VISIT 6 - END OF TREATMENT VISIT (END OF STUDY VISIT)...................................................................................... 34 
4.14 
DESCRIPTION OF ADDITIONAL EXTENSION TREATMENT PERIOD (80 OF 188 PATIENTS) ................................................. 35 
4.14.1 
VISIT 7, VISIT 9, VISIT 11 AND VISIT 12 – EXTENDED TREATMENT PHASE (TELEPHONE VISITS)................................ 35 
4.14.2 
VISIT 8 AND VISIT 10 – EXTENDED TREATMENT PHASE ON SITE VISIT ..................................................................... 35 
4.14.3 
VISIT EOT OF EXTENDED TREATMENT PERIOD (END OF STUDY VISIT)....................................................................... 35 
4.15 
EVALUATION OF LABORATORY PARAMETERS............................................................................................................... 36 
4.15.1 
LOCAL LABORATORY: ........................................................................................................................................... 37 
4.15.2 
CENTRAL LABORATORY: ....................................................................................................................................... 37 
4.15.3 
ASSESSMENT OF PLATELET ACTIVATION AND MITOGENIC POTENTIAL ...................................................................... 38 
4.16 
DURATION OF THE CLINICAL TRIAL IN THE INDIVIDUAL SUBJECT.................................................................................... 39 
4.17 
ANALYSES AND REPORTING ....................................................................................................................................... 39 
5 
IMP .................................................................................................................................................................................. 40 
5.1 
TREATMENTS TO BE GIVEN ........................................................................................................................................ 40 
5.2 
DESCRIPTION OF THE IMP – RIVAROXABAN (TREATMENT GROUP).............................................................................. 40 
5.2.1 
THERAPEUTIC INDICATION OF 2.5 MG RIVAROXABAN:................................................................................................ 40 
5.2.2 
CONTRAINDICATIONS FOR 2.5 MG RIVAROXABAN: .................................................................................................... 41 
5.3 
DESCRIPTION OF THE IMP – ASPIRIN (ASS 100) (CONTROL GROUP).......................................................................... 41 
5.3.1 
INDICATION:............................................................................................................................................................. 42 
5.3.2 
CONTRAINDICATIONS OF ASS 100 MG: .................................................................................................................... 42 
5.4 
CENTRAL PHARMACY ................................................................................................................................................ 43 
5.5 
LABELING OF THE IMP.............................................................................................................................................. 43 
5.6 
DRUG LOGISTICS AND ACCOUNTABILITY ..................................................................................................................... 43 
5.7 
DISPENSING OF IMP................................................................................................................................................. 44 
5.8 
ASSIGNMENT OF TRIAL SUBJECTS TO TREATMENT GROUPS .......................................................................................... 44 
5.9 
SELECTION OF DOSAGE OF IMP AND FREQUENCY OF TREATMENT ............................................................................... 45 
5.10 
BLINDING ................................................................................................................................................................. 45 
5.11 
PREVIOUS AND CONCOMITANT MEDICATION .............................................................................................................. 45 
5.11.1 
DOSING RECOMMENDATIONS BEFORE AND AFTER INVASIVE PROCEDURES, SURGICAL INTERVENTION AND RESCUE 
THERAPY FOR CLINICAL EMERGENCIES: ...................................................................................................................................... 46 
5.12 
POST-STUDY THERAPY............................................................................................................................................... 46 
6 
EFFICACY AND SAFETY VARIABLES............................................................................................................................. 47 
6.1 
MEASUREMENT TARGET VARIABLES ........................................................................................................................... 47 
6.1.1 
PRIMARY TARGET VARIABLE....................................................................................................................................... 47 
6.1.2 
SECONDARY TARGET VARIABLES................................................................................................................................. 47 
6.1.3 
MEASUREMENT OF SAFETY ANALYSIS ......................................................................................................................... 47 
6.1.4 
RATIONALE FOR ASSESSMENT PROCEDURES................................................................................................................ 48 
6.2 
APPLIED MEASUREMENT PROCEDURES....................................................................................................................... 48 
6.2.1 
VENOUS OCCLUSION PLETHYSMOGRAPHY FOR ASSESSMENT OF FOREARM BLOOD FLOW FBF: ...................................... 48 
6.2.2 
LASER DOPPLER FLUXOMETRY:.................................................................................................................................. 48 
6.2.3 
PULSE WAVE VELOCITY AND ARTERIAL STIFFNESS: ....................................................................................................... 49 


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7 
ADMINISTRATIVE ASPECTS.......................................................................................................................................... 49 
7.1 
DATA DOCUMENTATION ........................................................................................................................................... 49 
7.1.1 
ECRF ....................................................................................................................................................................... 49 
7.1.2 
SOURCE DATA DOCUMENTATION ............................................................................................................................... 49 
7.2 
DATA MANAGEMENT ................................................................................................................................................ 50 
7.3 
DATA QUALITY.......................................................................................................................................................... 51 
7.3.1 
MONITORING ........................................................................................................................................................... 51 
7.3.2 
DATA QUALITY ASSURANCE ....................................................................................................................................... 52 
7.3.3 
AUDITS/INSPECTIONS ............................................................................................................................................... 52 
7.3.4 
ARCHIVING............................................................................................................................................................... 52 
8 
ETHICAL AND REGULATORY ASPECTS ....................................................................................................................... 53 
8.1 
INDEPENDENT ETHICS COMMITTEE............................................................................................................................. 53 
8.2 
NOTIFICATION OF THE AUTHORITIES, APPROVAL AND REGISTRATION ........................................................................... 53 
8.3 
ETHICAL BASIS FOR THE CLINICAL TRIAL ...................................................................................................................... 53 
8.4 
OBTAINING INFORMED CONSENT FROM TRIAL SUBJECTS ............................................................................................. 54 
8.5 
COMPENSATION FOR HEALTH DAMAGE OF SUBJECTS / INSURANCE .............................................................................. 55 
8.6 
CONFIDENTIALITY ..................................................................................................................................................... 55 
9 
STATISTICAL METHODS AND SAMPLE SIZE CALCULATION .................................................................................... 56 
9.1 
GENERAL STATISTICAL CONSIDERATIONS .................................................................................................................... 56 
9.1.1 
DESCRIPTION OF TRIAL SUBJECT GROUPS.................................................................................................................... 56 
9.1.2 
TRIAL POPULATIONS.................................................................................................................................................. 56 
9.1.3 
PRIMARY TARGET VARIABLE....................................................................................................................................... 56 
9.1.4 
SECONDARY VARIABLES ............................................................................................................................................. 56 
9.1.5 
INTERIM ANALYSIS .................................................................................................................................................... 56 
9.1.6 
MISSING VALUES AND OUTLIERS ................................................................................................................................ 57 
9.1.7 
REPORTING CONVENTIONS ........................................................................................................................................ 57 
9.1.8 
SAMPLE SIZE CALCULATION ....................................................................................................................................... 57 
9.2 
STATISTICAL METHODS.............................................................................................................................................. 58 
10 
SAFETY............................................................................................................................................................................. 59 
10.1 
DEFINITIONS OF ADVERSE EVENTS AND ADVERSE DRUG REACTIONS ............................................................................. 59 
10.1.1 
ADVERSE EVENT .................................................................................................................................................. 59 
10.1.2 
ADVERSE DRUG REACTION ................................................................................................................................... 59 
10.1.3 
SERIOUS ADVERSE EVENTS AND SERIOUS ADVERSE REACTIONS ............................................................................... 59 
10.1.1 
UNEXPECTED ADVERSE DRUG REACTION ............................................................................................................... 60 
10.1.2 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS ........................................................................................ 60 
10.2 
DOCUMENTATION AND FOLLOW-UP OF ADVERSE EVENTS ........................................................................................... 60 
10.2.1 
CLASSIFICATIONS FOR ADVERSE EVENT ASSESSMENT.............................................................................................. 61 
10.2.2 
CAUSAL RELATIONSHIP TO PROTOCOL-REQUIRED PROCEDURE(S) ........................................................................... 61 
10.2.3 
ASSESSMENTS AND DOCUMENTATION OF ADVERSE EVENTS ................................................................................... 62 
10.3 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................................................. 62 
10.3.1 
INVESTIGATOR’S NOTIFICATION OF THE SPONSOR .................................................................................................. 62 
10.4 
EXPECTED ADVERSE EVENTS ...................................................................................................................................... 63 
10.4.1 
ADVERSE EVENTS POSSIBLY RELATED TO THE STUDY MEDICATION ........................................................................... 63 
10.5 
SPECIAL SAFETY PRECAUTIONS OF XARELTO® ............................................................................................................. 65 
10.5.1 
OVERDOSE.......................................................................................................................................................... 65 


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10.5.2 
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES ................................................................................................ 65 
10.6 
PREGNANCIES........................................................................................................................................................... 66 
11 
USE OF TRIAL FINDINGS AND PUBLICATION ............................................................................................................ 66 
11.1 
REPORTS .................................................................................................................................................................. 66 
11.1.1 
PERIODIC INFORMATION ...................................................................................................................................... 66 
11.1.2 
ANNUAL SAFETY REPORT OF TRIAL SUBJECTS ......................................................................................................... 66 
11.1.3 
FINAL REPORT ..................................................................................................................................................... 66 
11.2 
PUBLICATION............................................................................................................................................................ 67 
12 
AMENDMENTS TO THE TRIAL PROTOCOL ................................................................................................................ 68 
12.1 
CHANGES TO TRIAL PROTOCOL................................................................................................................................... 68 
12.2 
AMENDMENT 1 ........................................................................................................................................................ 68 
12.2.1 
OVERVIEW OF CHANGES AMENDMENT 1 (VERSION 2.0) ...................................................................................... 68 
12.3 
AMENDMENT 2 ........................................................................................................................................................ 72 
12.3.1 
OVERVIEW OF CHANGES AMENDMENT 2 (VERSION 3.0) ...................................................................................... 72 
12.4 
AMENDMENT 3 ........................................................................................................................................................ 77 
12.4.1 
OVERVIEW OF CHANGES AMENDMENT 3 (VERSION 4.0) ...................................................................................... 77 
12.5 
AMENDMENT 4 ........................................................................................................................................................ 80 
12.5.1 
OVERVIEW OF CHANGES AMENDMENT 4 (VERSION 5.0) ...................................................................................... 80 
12.7 
AMENDMENT 5 ........................................................................................................................................................ 82 
12.7.1 
OVERVIEW OF CHANGES AMENDMENT 5 (VERSION 6.0) ...................................................................................... 82 
VISIT 7, VISIT 9, VISIT 11 AND VISIT 12 – EXTENDED TREATMENT PHASE (TELEPHONE VISITS) .................................................... 91 
VISIT 8 AND VISIT 10 – EXTENDED TREATMENT PHASE ON SITE VISIT .......................................................................................... 91 
VISIT EOT OF EXTENDED TREATMENT PERIOD (END OF STUDY VISIT) ........................................................................................... 92 
 
 
 
LIST OF FIGURES 
Figure 1: Trail overview (including extended Treatment Period) ................................................. 30 
 
 
 


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ABBREVIATIONS 
ACS 
Acute coronary syndrome 
ADR 
Adverse drug reaction 
AE 
Adverse Event 
ALT 
alaninetransferase 
AMG 
Arzneimittelgesetz 
BfArM 
Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel 
und Medizinprodukte) 
b.i.d. 
bis in die (lat.) – twice a day 
CPI 
Coordinating Principal Investigator (Leiter der klinischen Prüfung) 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
eCRF 
electronic Case Report Form 
DSMB 
Data and Safety Monitoring Board  
ECG 
Electrocardiogram 
EOT 
End of treatment 
FAS 
Full analysis set 
FBF 
Forearm bloodflow 
FDA 
Food and Drug Administration 
HbA1c 
Glycosylated hemoglobin  
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
ISF 
Investigator Site File 
ITT 
Intent-to-treat analysis 
LDF 
Laser Doppler Fluxometry 
PMP 
Platelet derived microparticles 
PPS 
Per protocol set 
qd 
quaque die (lat.) - daily 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TMF 
Trial Master File 
UFH 
unfractioned heparine 
ULN 
upper limit of normal 
V1-7 
visit 1 to 7 


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1 
Introduction 
Type 2 diabetes as part of the metabolic syndrome is associated with dyslipidemia, elevated blood 
pressure, a prothrombotic environment and a proinflammatory state. This cluster of risk factors 
accelerates the development of micro- and macrovascular complications (1). There is increasing 
evidence that patients with type 2 diabetes and high cardiovascular risk have an activated 
coagulation pathway and deteriorated fibrinolysis which resulted in an increased production of 
fibrin which might be involved in the initiation and progression of microvessel disease and 
macrovascular complications(2), (3). 
Rivaroxaban, a factor Xa inhibitor was shown to be as effective as warfarin in the prevention of 
stroke or embolism in patients with non-valvular atrial fibrillation. At the end of 2011, 
Rivaroxaban was approved by the FDA and the EMA for the prevention of thromboembolism in 
patients with non-valvular atrial fibrillation(4).  
The ATLAS trial in patients with acute coronary syndrome was a large international randomized 
study to evaluate efficacy and safety of rivaroxaban vs. placebo on top of background medication 
with low dose aspirin and clopidogrel or ticlopidine. Rivaroxaban significantly reduced the risk of 
cardiovascular (CV) death, myocardial infarction or stroke but had no significant effect on fatal 
bleeding (5). Recently, another large multi-center phase III study has been started in patients with 
stable cardiovascular disease to compare the efficacy of rivaroxaban alone (or in combination 
with aspirin) vs. aspirin alone on prevention of further heart attacks, stroke or cardiovascular 
death (COMPASS trial, www.clinicaltrials.gov, NCT01776424).  
These large mega-trial in high risk patients support our working hypothesis that secondary 
prevention with rivaroxaban low dose therapy is superior for microvascular circulations and – on 
the long run - for CV outcome and mortality in patients with type 2 diabetes and  high 
cardiovascular risk vs. low dose aspirin still used in daily practice. As in the COMPASS study 
rivaroxaban 5.0 mg twice daily will be used for this exploratory study.  
Moreover there is an increasing evidence from mechanistic studies that beyond the anti-
coagulatory action, inhibition of factor Xa might have some additional anti-inflammatory effects 
and that the treatment with factor Xa inhibitors might evolve some beneficial effects in the 
microcirculation (6). Microcirculation is a critical pathway for diabetes related diseases such as 
retinopathy and nephropathy. Even more important diabetic CVD is characterized by multi-vessel 
disease including small vessels. 
Studies with Rivaroxaban or the direct thrombin inhibitor Ximelagatran in comparison to 
antiplatelet therapy demonstrated an increased efficacy regarding cardiovascular end points but 
a small increased risk of bleeding (7). This study will analyze surrogate parameters for CV-outcome 
in a very high risk population with type 2 diabetes. 
The goal of this study is to evaluate microcirculatory and anti-inflammatory effects of Rivaroxaban 
compared to low dose Aspirin in type 2 diabetic patients with high cardiovascular risk according 
to national guidelines and documented subclinical inflammation Thus the results will be of high 


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clinical relevance. Forearm blood flow (FBF) measurement serves as gold standard technique for 
the assessment of endothelial function in resistance vessels and provides sufficient reproducibility 
and validity as documented in the literature (8). Furthermore there was a good correlation 
between impaired FBF and subsequent cardiovascular events (9). Therefore FBF for assessment 
of microvascular function is able to predict macrovascular events. 
Previous studies demonstrated a fast response of forearm blood flow to interventions (10) 
however; forearm blood flow is a marker of endothelial (dys)function and did not measure 
structural changes of large conductive arteries or the microvascular bed. In contrast to forearm 
blood flow changes which occur within a few weeks after an intervention, these structural 
adaptation of the vascular wall usually require a longer time span.  
There are few investigational studies of microvascular skin blood flow in patients with type 2 
diabetes which described significant changes during treatment with glucose lowering drugs after 
36 weeks (11). However; an extrapolation from the capillary bed to structural changes of large 
arteries should be difficult due to the different anatomy of the vascular wall. Pulse wave velocity 
(PWV) as marker of arterial stiffness is an independent predictor of cardiovascular events and 
mortality (12, 13). 
Changes of PWV during medical intervention usually required a longer time span. This had been 
demonstrated in studies with antihypertensive agents (14) as well as in studies with lipid lowering 
medication (15) which required treatment periods of at least 12 months to demonstrate an 
improvement of PWV. We believe that a structural remodeling of the vascular wall in the present 
investigation also needs that period of time. 
 
2 
Objectives of the clinical trial 
Objectives of this clinical trial are the in vivo assessment of microvascular function using different 
non-invasive techniques and the in vitro assessment of biomarkers of endothelial damage, 
inflammation and coagulation/fibrinolysis before and after treatment with either aspirin or 
rivaroxaban in type 2 diabetic patients with high cardiovascular risk and inflammation. 
Furthermore possible functional interactions between mononuclear blood cells and platelets as 
well as expression of mRNA (and protein) within these cells before and after treatment in vitro 
will be assessed. 
2.1 Rationale for the clinical trial 
Type 2 Diabetes is associated with an increased risk of CV events which might be attributable not 
only to macrovascular damage (e.g. atherosclerotic plaques) but also to microvessel disease. 
Previous studies demonstrated a procoagulant state associated with low grade inflammation in 
these patients (3). Furthermore there are disturbances of blood flow due to increased viscosity 
and deteriorations in endothelial function with diminished release of endogenous vasodilators 


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(10). As a result, tissue oxygenation and blood supply to peripheral tissues are reduced. Current 
treatment with aspirin or other antiplatelet drugs have been demonstrated to reduce the risk  of 
macrovascular events due to the prevention of thrombus formation on atherosclerotic plaques in 
the case of secondary prevention. However, antiplatelet therapy has little or no effect on 
microvascular disease (16, 17) (11). The recent introductions of non-vitamin K dependent 
anticoagulant drugs have increased treatment options for prevention of thromboembolic events 
after deep venous thrombosis or in patients with atrial fibrillation. In addition a large prospective 
multicentre study - the ATLAS trial - also demonstrated a risk reduction of CV events in patients 
with ACS in addition to standard of care antiplatelet therapy (18)(5). This might be due to 
improved microvascular function and blood supply to microvascular beds. A measurement of 
microvascular functions in patients receiving non-vitamin K dependent anticoagulant drugs have 
not been evaluated so far. Therefore the present pilot study has to be conducted. 
2.2 Primary objective 
Difference of change of forearm blood flow with venous occlusion plethysmography at baseline and 
after forearm ischemia after 20 weeks treatment between rivaroxoban and aspirin therapy  
Additionally the difference of arterial stiffness after the end of the extension study (week 52) between 
rivaroxoban and aspirin therapy will be evaluated. 
2.3 Secondary and other objectives 
 
change of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF) 
after 20 and 52 weeks of treatment 
 
LDF baseline 
 
LDF after ischemia (endothelial function) 
 
arterial stiffness measured by Mobilograph (IEM Inc.) after 20 weeks of treatment 
 
laboratory markers for endothelial function  
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
Microalbuminuria, eGFR 
 
composite of biomarkers of inflammation  
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8 
 
side effects: major bleeding according to ISTH, symptomatic thromboembolic events 
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C 
 
coagulation: von Willebrand-Factor, Fibrinogen, Prothrombinfragment 1 + 2, D-Dimer, 
Protein C, Protein S, TAT, Quick, aPTT 
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Additional secondary objective for extension period: 
 
Difference of change of forearm blood flow with venous occlusion plethysmography at 
baseline and after forearm ischemia after 52 weeks treatment 


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2.4 Measurement of mitogenic potential and assessment of platelet activation 
The rationale of this study is to clarify whether oral non-vitamin K dependent anticoagulant drugs 
are able to improve microvessel function and hence microcirculation and tissue oxygenation in 
patients with a disturbance of endothelial function. Furthermore we would like to clarify whether 
these drugs act only via inhibition of coagulation or whether there are additional effects on 
inflammation or platelet function. There are no comparable studies in humans so far in the 
literature and the study procedures (non-invasive techniques for assessment of endothelial 
function) bear no additional risk. Venous blood samples will be taken at screening, baseline and 
end of treatment, the whole amount of blood which is required for biochemical tests is about 
150 ml. 
2.5 Risk-Benefit-Assessment 
The major risk of oral anticoagulation is the risk of bleeding. This risk is dose dependent and 
exceeds (in combination with aspirin) the bleeding risk of aspirin 100 mg/d (alone) by a factor of 
2 (ATLAS trial) (13). The bleeding risk is lower than the bleeding risk with Vitamin K dependent 
anticoagulant drugs, especially in the dose of 5 mg b.i.d. (7). Unfortunately there are no direct 
comparisons of the bleeding risk between aspirin 100 mg and rivaroxaban5 mg b.i.d. so far in the 
literature. The results of the COMPASS trial, which is still recruiting will provide further data on 
this issue.  
Since all patients of our planned investigation have a high risk for cardiovascular disease a primary 
prevention of CV events with aspirin 100 mg is recommended by several guidelines (19) however, 
this recommendation is not so strong as the indication for aspirin in the case of secondary 
prevention. In Germany the therapeutic costs for a primary prevention with aspirin 100 mg even 
in high risk patients are not covered by general health insurance, therefore a lot of patients do 
not get a prescription of this medication. The inclusion of these patients with a high CV risk but 
without a major CV event in medical history would offer the possibility to cover high risk patients 
with a recommended treatment for the duration of the study. To minimize the bleeding risk for 
the patients we will conduct four safety visits during the treatment of 20 weeks of study 
medication and will not include patients with an increased risk of bleeding as stated in the 
exclusion criteria.  
In conclusion there is scientific evidence, that patients with a very high cardiovascular risk in a 
state of primary prevention and with a low risk for bleeding should be treated. The standard 
recommended treatment today is low dose aspirin, but in our point of view considering the 
expected advantages of rivaroxaban at a low dose would outweigh the possible increased risk of 
bleeding. 


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3 
Organizational and administrative aspects of the trial 
3.1 Sponsor 
GWT-TUD GmbH 
Blasewitzer Str. 43 
01307 Dresden 
Germany 
 
 
3.2 Coordinating Principal Investigator (Leiter der klinischen Prüfung according 
to German Drug Law) 
 
Coordinating Principal Investigator 
PD Dr. Frank Pistrosch 
GWT, Study centre, Blasewitzer Str. 43, 01307 
Dresden 
Tel.: 
+49 351 4400580 
Fax No: 
+49 351 4400581 
 
 
3.3  
3.3  
3.3  
3.3  
3.3  
3.3  
3.3  
3.3  
3.3  
3 3
3.3 Monitoring 
Monitoring will be conducted in accordance with ICH-GCP E6 (5.18). Monitoring will be performed 
by the sponsor GWT-TUD GmbH. 
3.4 Datamanagement 
Datamanagement will be performed by the sponsor GWT-TUD GmbH. 
3.5 Statistics 
Statistic will be performed by the sponsor GWT-TUD GmbH.  
3.6 Data and Safety Monitoring Board (DSMB) 
A Data Safety Monitoring Board (DSMB) of independent experts will be set up. It will consist of 
two physicians and one statistician who are not involved in the conduct of the trial. The task of 
the DSMB is to oversee the safety of the trial subjects in the clinical trial by periodically assessing 


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the safety and efficacy of the trial therapy and to monitor the integrity and validity of the data 
collected and the conduct of the clinical trial. 
Throughout this process of surveillance, the DSMB will provide the sponsor with 
recommendations with regard to continuing the trial (e.g. termination or modification) based on 
the data collected. The data necessary for the DSMB to fulfill this function will be provided by the 
sponsor as determined by the DSMB charter.  
3.7 Investigators and trial sites 
The multicenter trial is planned to be conducted in up to 7 national trial sites in Germany by 
investigators with special expertise in the field of indication.  
3.7.1 Requirements for investigators and trial sites 
The trial site will be required to have an investigator with at least 2 years experience in conducting 
clinical trials according to GCP as well as a substitute with comparable qualifications. The site must 
have a pool of suitable patients who can be recruited for the study.  
All investigators must be qualified physicians. Each physician must supply his or her curriculum 
vitae (updated), a financial disclosure and certificates of GCP experiences for the TMF. All 
investigators must have skills in the assessment of endothelial function using prespecified 
techniques and should be familiar with anticoagulant treatment.  
Investigators also must 
 
know main features of the law in Germany (“Arzneimittelgesetz”) as well as legal and 
scientific basics of clinical trials 
 
know and sign the study protocol. 
If any of the investigators are not physicians, these must be listed with reasons why they are 
suitable to be involved in the trial. 
All investigators must sign the protocol signature sheet before subject recruitment and treatment 
may start. Likewise, all protocol amendments/integrated protocols must be signed and dated by 
the investigators before coming into effect. 
3.8 Other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the center will be available in the center’s 
investigator site file and the trial master file (TMF) of the sponsor. 
3.9 Financing 
The clinical trial will be financed by the sponsor GWT-TUD GmbH with a support of Bayer Vital 
GmbH. Bayer will also provide the IMP Rivaroxaban (Xarelto® 2.5 mg). 


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4 
Trial conductTime plan 
 
First patient first visit (FPFV): 
April 2015 
Last patient first visit (LPFV): 
July 2017 
Last patient last visit (LPLV): 
August 2018 
Database Lock 
December 2018 
Final study report: 
April 2019 
4.2 Design overview 
This will be a multi center, open-label, controlled study with two treatment arms running in 
parallel. A total of 188 patients of both genders and older than 18 years with type 2 diabetes and 
documented high cardiovascular risk and low grade inflammation will be randomly assigned to 
one of two treatment groups: 
  
4.2.1 Treatment groups 
Arm A:treatment group 
Rivaroxaban  
Patients will receive Rivaroxaban 5 mg b.i.d. for the 
duration of 20 weeks. 
Additionally, 80 patients of the study population will 
continue to receive the Rivaroxaban 5 mg b.i.d. for a 
duration of 52 weeks (extension treatment). 
Arm B: control group  
Aspirin  
Patients will receive treatment with Aspirin 100 mg q.d. for 
the duration of 20 weeks.   
Additionally, 80 patients of the study population will 
continue to receive the Aspirin 100 mg q.d. for a duration 
of 52 weeks (extension treatment). 
TABLE 1: TREATMENT GROUPS 
 
7 study visits will be performed during the study. Subjects are obliged to come to the study center 
for 5 visits. Visits will take place at week –2 (screening – V0), day 0 (randomization/baseline – V1), 
at week 2 (V2), 4 (V3), 8 (V4), 12 (safety/compliance – V5) and week 20 (end of treatment for the 
first study period with vascular function test – V6).). Visit 3 and Visit 5 will be conducted as a 
telephone visit.  
Additionally, 80 patients of the study population will perform 7 additional visits during the 
extension period. These visits will start after week 20. Patients attending the extension period will 
perform overall 14 study visits for 8 of these visits they will come to the study center whereas 
overall 6 visits are performed as telephone visits. The additional visits will take place at week 24 


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(V7), week 28 (V8), week 32 (V9), week 36 (V10), week 40 (V11), week 44 (V12) and week 52 (end 
of treatment extension - V13). Visit 7, 9, 11 and 12 will be conducted as a telephone visit. 
Measurements of FBF, LDF and pletysmography at baseline-visit, visit week 20 (V6) and EOT-visit 
(V13) can be done up to 3 days after the visits in the corresponding study location that provides 
these measurements. Patients will be informed of the procedure by the physician. 
4.2.2 Visit schedule 
4.2.2.1 
Visit schedule for 20 Weeks of treatment 
 
Visit  
specification 
V0 
screening 
V1 
baseline 
V2 
 
V3 
telephone 
V4 
 
V5 
telephone 
V6 
 
week 
day -28 
day 0 
2 
4 
8 
12 
20 
timeframe 
 
+/- 4 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
 
4.2.2.2 
Additional visits for extension period (52 weeks of treatment) 
Visit  
specification 
V7 
telephone 
V8 
 
V9 
telephone 
V10 
 
V11 
telephone 
V12 
telephone 
V13 
EOT 
week 
24 
28 
32 
36 
40 
44 
52 
timeframe 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
 
TABLE 2: VISIT SCHEDULE (TV – TELEPHONE VISIT) 
4.3 End of the clinical trial 
After conclusion of the clinical trial, patient will receive standard medical care as usual for this 
kind of disease. Interim analyses are not planned. 
As for this study the primary objective will be analyzed after LPLV, the end of the study as a whole 
will be the date when the clean database is available. 
4.4 Justification of trial design 
For study objectives, see section 2. For selection of doses, see section 5.9. 


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4.5 Selection of trial population 
Male and female subjects older than 18 years and suffering from type 2 diabetes and CVD are to 
be screened for participation in the present study according to the inclusion and exclusion criteria 
described in section4.11. 
An individual subject may only be included once in the study. 
4.6 Justification of gender distribution 
Male and female subjects will be included in the present study representing the population of 
patients suffering from type 2 diabetes and CVD without any gender prevalence. 
4.7 Justification of selection criteria 
The selection criteria are chosen to ensure that subjects with specific risks for administration of 
the study medication and / or subjects with conditions which may have an impact on the aims of 
the study are excluded. 
4.8 Withdrawal of trial subjects after trial start 
4.8.1 Withdrawal 
Subjects will be withdrawn from the study for the following reasons: 
 
at their own request; at any time during the study and without giving reasons, a subject 
may decline to participate further. The subject will not suffer any disadvantage as a result 
 
if, in the investigator's opinion, continuation of study would bear a potential health risk 
for the patient 
 
at the specific request of the sponsor 
 
in case of violation of in- / exclusion criteria; if the subject develops conditions which 
would have prevented his/her entry into the study according to the in- / exclusion criteria, 
she / he must be withdrawn immediately if safety is concerned; in other cases, the 
investigator will decide whether there is a conflict with the study objectives 
 
non-compliance with the study conditions or instructions from the investigator’s team 
 
in case of suspected or verified pregnancy 
4.8.2 Dropout patients 
A subject who discontinues study participation prematurely for any reason is defined as a 
”dropout” if the subject has already been administered at least one dose of the study medication.  
Any subject removed (dropout) from the study will remain under medical supervision until 
discharge is medically acceptable. In all cases, the reason for withdrawal must be recorded in the 


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eCRF and in the subject’s medical records. The sponsor has to be informed about dropout patients 
by the investigator. 
4.8.3 Screening failures 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the study 
before being administered at least one dose of the study medication is regarded a “screening 
failure”. 
 
Details for the premature termination of the study as a whole or components thereof 
(e.g. centers, treatment arms) are provided in section 4.10. 
4.8.4 Replacement 
Subjects who prematurely discontinue participation after start of treatment – or subjects with 
major protocol violations – may be replaced only if recruitment is not completed and the drop 
out rate exceeds the calculated 25 % drop out patients. A replacement of trial subjects has to be 
released by the PCI. 
4.9 Subject identification 
After informed consent procedure every subject is given a unique subject identification number 
by the site. This screening number is only used during recruitment. All eligible subjects get a 
randomized patient number that will be given by the sponsor during the randomization 
procedure. All patients (subjects) receiving treatment are identifiable by their patient number at 
the site. 
4.10 Premature termination of the clinical trial 
The sponsor has the right to close this study or, if applicable, individual segments thereof 
(e.g. treatment arms; dose steps; centers) at any time, which may be due but not limited to the 
following reasons:  
 
if risk-benefit ratio becomes unacceptable owing to, for example, 
 
safety findings from this study (e.g. SAEs, elevated bleedings, elevated complications in 
the study population) 
 
results of any interim analysis (not planned yet) 
 
results of parallel clinical studies  
 
Results of parallel animal studies (on e.g. toxicity, teratogenicity, carcinogenicity or 
reproduction toxicity) provided by the manufacturer. 
 
if the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame. 


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4.10.1 
Closure of a trial site 
For any of the above closures, the following applies: 
 
closures should occur only after consultation between sponsor and study center(s) 
 
all affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; head of 
study center) must be informed as applicable according to local law 
 
all study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until notification 
given by the sponsor for destruction 
 
in case of a partial study closure, ongoing subjects, including those in post study follow-
up, must be taken care of in an ethical manner 
Details for individual subject's withdrawal can be found in section 4.8 
4.11 In- and exclusion criteria of the trial 
4.11.1 
Inclusion criteria 
Subjects must fulfill all of the following criteria before inclusion in the study: 
 
 
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) 
 
age 40 – 75 years at the first screening visit 
 
stable treatment with statines (if tolerated) 
 
the informed consent form must be signed before any study specific tests or procedures 
are done 
 
ability to understand and follow study-related instructions 


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4.11.2 
Exclusion criteria 
Subjects are to be excluded from the study if they display any of the following criteria before and 
during the trail: 
 
 
major 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, this may 
include 
- 
active internal bleeding 
- 
platelet count < 100.000/µL at the screening visit 
- 
current or recent gastrointestinal ulceration,  
- 
presence of malignant neoplasm at high risk of bleeding,  
- 
recent brain or spinal injury, recent brain, spinal or ophthalmic surgery,  
- 
recent intracranial haemorrhage,  
- 
known or suspected oesophageal varices, arteriovenous malformations, vascular 
aneurysms or major intraspinal or intracerebral vascular abnormalities. 
 
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.) 
except under the circumstances of switching therapy to or from rivaroxaban or when UFH 
is given at doses necessary to maintain an open central venous or arterial catheter  
 
concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or 
a transient ischaemic 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) 
 
as with other antithrombotics, rivaroxaban is not recommended in patients with an 
increased bleeding risk such as: 
- 
congenital or acquired bleeding disorders 
- 
uncontrolled severe arterial hypertension 
- 
active ulcerative gastrointestinal disease 


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- 
vascular retinopathy 
- 
bronchiectasis or history of pulmonary bleeding 
 
known HIV infection at time of screening 
 
known hypersensitivity to the active substance or to any of the excipients 
 
Pregnant or breast-feeding woman and woman without adequate method of 
contraception.  
(The following contraceptive methods are accepted: oral, dermal or vaginal hormonal 
contraception, contraceptive plaster, long-acting injectable contraceptives, implants that 
release progesterone, tubal ligation (female sterilization), intrauterine devices that 
release hormones (hormone spiral), double barrier methods. This means that the 
following are not regarded as safe: condom plus spermicide, simple barrier methods 
(vaginal pessaries, condom, and female condoms), copper spirals, the rhythm method, 
basal temperature method, and the withdrawal method (coitus interruptus)). 
4.11.3 
Other criteria 
 
subject is in custody by order of an authority or a court of law 
 
exclusion periods from other studies or simultaneous participation in other clinical studies 
 
previous assignment to treatment during this study 
 
scheduled (elective) surgery after signing the informed consent form  
 
close affiliation with the investigator (e.g. a close relative) or persons working at the study 
site 
 
subject is an employee of GWT-TUD GmbH or Bayer Vital GmbH 
 
criteria which in the opinion of the investigator preclude participation for scientific 
reasons, for reasons of compliance, or for reasons of the subject’s safety


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4.12 Trial procedure overview 
 
FIGURE 1: TRAIL OVERVIEW (INCLUDING EXTENDED TREATMENT PERIOD) 
 
4.12.1 
Tabulated overview 
Time deviations from the given time points will be documented as protocol deviations, if 
applicable. Respective time windows (if any) are specified in the flow chart mentioned. 


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4.12.2 
Description of visits / schedule 
VISIT 
V0 
V1 
V2 
V3 (TV) 
V4 
V5 (TV) 
V6 
WEEK 
day -28 
 
day 0 
(+/- 4 d) 
2 
(+/- 2 d) 
4 
(+/- 2 d) 
8 
(+/- 2 d) 
12 
(+/- 2 d) 
20 
(+/- 2 d) 
 
SCREEN 
BASELINE 
TREAT 
TREAT 
TREAT 
TREAT 
EOT 
STUDY INFORMED CONSENT 
 
 
 
 
 
 
A 
SCREENING OF INCLUSION AND 
EXCLUSION CRITERIA 
 
 
 
 
 
 
 
VITAL SIGNS (RADIAL PULSE, 
BLOOD PRESSURE) 
 
 
 
 
 
 
 
RANDOMIZATION* 
 
 
 
 
 
 
 
BODY HEIGHT 
 
 
 
 
 
 
 
WAIST/HIP CIRCUMFERENCE 
BODY WEIGHT 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
MEDICAL HISTORY 
 
 
 
 
 
 
 
CONCOMITANT MEDICATION/ 
ACUTE DISEASES 
 
 
 
 
 
 
 
ARTERIAL STIFFNESS 
 
 
 
 
 
 
 
FOREARM BLOOD FLOW 
 
 
 
 
 
 
 
INFLAMMATION LABORATORY(1) 
 
 
 
 
 
 
 
SAFETY LABORATORY(3) 
 
 
 
 
 
 
 
EFFICACY LABORATORY(2) 
 
 
 
 
 
 
 
METABOLIC MARKER(4) 
 
 
 
 
 
 
 
SCREENING LABORATORY(5) 
 
 
 
 
 
 
 
CARDIOVASCULAR MARKER 
 
 
 
 
 
 
 
LDF INVESTIGATIONS 
 
 
 
 
 
 
 
PLATELET ACTIVATION/ 
MITOGENIC POTENTIAL 
 
 
 
 
 
 
 
ADVERSE EVENT REPORTING 
 
 
 
 
 
 
 
DISPENSING/RETURN OF 
MEDICATION/ 
DRUG ACCOUNTABILITY 
 
 
 
 
 
 
 
PREGNANCY TEST 
 
 
 
 
 
 
 
TABLE 3: VISIT-SCHEDULE (1 - 54) PARAMETERS TO BE DETERMINED SEE SECTION 4.14; *RANDOMIZATION CAN BE PERFORMED 
WHEN ALL IN- AND EXCLUSION CRITERIA WERE EXAMINED (RESULTS OF SCREENING LABORATORY MUST BE 
AVAILABLE). RANDOMIZATION CAN BE PERFORMED BETWEEN BASELINE AND RANDOMIZATION.  
 
A: ADDITIONAL INFORMED CONSENT FOR PARTICIPATION TO EXTENDED TREATMENT PERIOD. 


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4.12.3 
Description of visits / schedule of extended treatment period (80 of 188 
patients) 
VISIT 
V7 (TV) 
V8 
V9 (TV) 
V10 
V11 (TV) 
V12 (TV) 
V13 
WEEK 
24 
(+/- 2 d) 
28 
(+/- 2 d) 
32 
(+/- 2 d) 
36 
(+/- 2 d) 
40 
(+/- 2 d) 
44 
(+/- 2 d) 
52 
(+/- 2 d) 
 
TREAT 
TREAT 
TREAT 
TREAT 
TREAT 
TREAT 
EOT 
EXTEN-
SION 
STUDY INFORMED CONSENT 
FOR EXTENSION PERIOD 
 
 
 
 
 
 
 
VITAL SIGNS (RADIAL PULSE, 
BLOOD PRESSURE) 
 
 
 
 
 
 
 
BODY HEIGHT 
 
 
 
 
 
 
 
WAIST/HIP CIRCUMFERENCE 
BODY WEIGHT 
 
 
 
 
 
 
 
CONCOMITANT MEDICATION/ 
ACUTE DISEASES 
 
 
 
 
 
 
 
ARTERIAL STIFFNESS 
 
 
 
 
 
 
 
FOREARM BLOOD FLOW 
 
 
 
 
 
 
 
INFLAMMATION LABORATORY(1) 
 
 
 
 
 
 
 
SAFETY LABORATORY(3) 
 
 
 
 
 
 
 
EFFICACY LABORATORY(2) 
 
 
 
 
 
 
 
METABOLIC MARKER(4) 
 
 
 
 
 
 
 
LDF INVESTIGATIONS 
 
 
 
 
 
 
 
ADVERSE EVENT REPORTING 
 
 
 
 
 
 
 
DISPENSING/RETURN OF 
MEDICATION/ 
DRUG ACCOUNTABILITY 
 
 
 
 
 
 
 
TABLE 4: TABLE 5: VISIT-SCHEDULE OF EXTENDED TREATMENT PERIOD. PARAMETERS TO BE DETERMINED SEE SECTION 4.14;  
 
 


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4.13 Description of treatment 
4.13.1 
Visit 0 - Screening (day -28) 
Due to the fact that not all subjects may fulfill the inclusion/exclusion criteria, a higher number of 
subjects, than needed to be valid for the evaluation of the study, will be asked to participate in 
the screening examination. 
Screening examinations will only be performed after having received the subject’s written 
informed consent. 
within up 28 days prior to the first study drug administration the following measures / actions will 
be performed: 
 
check adherence to inclusion / exclusion criteria 
 
demographic data 
 
body weight, height, BMI 
 
check medical history (in- and exclusion-relevant diseases, metabolic syndromes, risks of 
VTE events and bleedings, etc.) 
 
questioning for special behavior (e.g. participation in previous clinical studies) 
 
check previous medication (medication history); all medication used within the last 
12 weeks 
 
measurement of blood pressure, heart rate (after resting for at least 3 min in supine 
position) 
 
screening laboratory for check of in- and exclusion criteria containing measurement of 
HDL, triglycerides, urinary albumin/creatinin ratio and creatinine 
 
ECG 
 
local safety laboratory parameter(including measurement of hsCRP or PAI1 for 
assessment of in- and exclusion criteria, if not available before screening visit according 
to in- and exclusion criteria) 
 
urine pregnancy test 
 
patients are randomized in one of two treatment groups (Arm A or Arm B). Randomization 
can be performed when all in- and exclusion criteria were examined (Results of screening 
laboratory must be available). Randomization can be performed between baseline and 
randomization 
4.13.2 
Visit 1 –Baseline (day 0 ± 4 d) 
The following actions/measures will be performed: 
 
check adherence to inclusion / exclusion criteria 
 
questioning for adverse events, suspected or verified pregnancy and concomitant 
medication 


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 
measurement blood pressure, heart rate (after resting for at least 3 min in supine 
position) 
 
measurement of forearm blood flow 
 
laserdopplerfluxometry (LDF) 
 
measurement of arterial stiffness 
 
efficacy laboratory parameter for endothelial function and coagulation 
 
efficacy laboratory for composite of biomarkers of inflammation 
 
blood samples for assessment of platelet function / mitogenic potential 
 
safety laboratory parameter 
 
assessment of metabolic marker and cardiovascular marker 
 
dispensing of study drug along with intake prescriptions 
4.13.3 
Visit 2 and Visit 4 - Treatment phase 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
assessment of adverse events 
 
questioning for concomitant medication 
 
clinical examination for potential bleeding sides 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
return of study medication and drug accountability 
 
dispense of new study medication 
 
safety laboratory parameter 
4.13.4 
Visit 3 and Visit 5 - Treatment phase (telephone visits)  
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
assessment of adverse events  
 
questioning for concomitant medication  
4.13.5 
Visit 6 - End of treatment visit (end of study visit) 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
questioning for adverse events and concomitant medication 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
measurement of forearm blood flow 
 
laserdopplerfluxometry (LDF) 
 
measurement of arterial stiffness 


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 
efficacy laboratory parameter for endothelial function and coagulation: 
 
efficacy laboratory for composite of biomarkers of inflammation  
 
blood samples for assessment of platelet function / mitogenic potential 
 
safety laboratory parameter 
 
assessment of metabolic marker and cardiovascular marker 
 
return of study drug / drug accountability and drug dispense in the case of additional 
treatment period 
 
advice patient for further treatment after end of study 
4.14 Description of additional extension treatment period (80 of 188 patients) 
4.14.1 
Visit 7, Visit 9, Visit 11 and Visit 12 – Extended treatment phase (telephone 
visits)  
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
assessment of adverse events  
 
questioning for concomitant medication  
4.14.2 
Visit 8 and Visit 10 – Extended treatment phase on site visit 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
assessment of adverse events 
 
questioning for concomitant medication 
 
clinical examination for potential bleeding sides 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
return of study medication and drug accountability 
 
dispense of new study medication 
 
safety laboratory parameter 
4.14.3 
Visit EoT of extended treatment period (end of study visit) 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
questioning for adverse events and concomitant medication 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
measurement of forearm blood flow 
 
laserdopplerfluxometry (LDF) 
 
measurement of arterial stiffness 


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 
efficacy laboratory parameter for endothelial function and coagulation: 
 
efficacy laboratory for composite of biomarkers of inflammation  
 
safety laboratory parameter 
 
assessment of metabolic marker  
 
return of study drug / drug accountability 
 
advice patient for further treatment after end of study 
4.15 Evaluation of laboratory parameters 
Laboratory parameters are centrally or locally determined for the study. During the visits 
following parameters are determined: 
 
screening laboratory 
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR, HDL-C, triglycerides, 
cholesterine, urinary albumin/creatinin ratio, creatinine urine, hsCRP (if not available before 
screening visit according to in- and exclusion criteria), PAI1 (optional), urine pregnancy test 
 
safety laboratory contains:  
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR 
 
inflammation laboratory:  
hsCRP, PAI-1, MCP-1, MPO, IL-6, IL-8, MMP-9, fibrinogen 
 
efficacy laboratory for endothelial function and coagulation: 
VCAM-1, ICAM-1, E-Selectin, P-Selectin, CD40L, von Willebrand factor, ADMA, nitrotyrosin, 
urinary albumin/creatinin ratio, eGFR, UACR, creatinin (serum), fibrinogen (immunolog), 
prothrombin fragment 1 and 2, TAT, D-Dimer, (protein C, protein S), Quick, aPTT 
 
metabolic marker: 
HbA1c, triglycerides, LDL-C, HDL-C, cholesterine 
 
cardiovascular marker:  
NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 


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Platelet function / mitogenic potential: 
see 4.14.3 
4.15.1 
Local laboratory: 
Safety parameters and parameters that are needed for verification of in- and exclusion criteria 
are determined by the local laboratory of each study site. 
4.15.2 
Central laboratory: 
All specimen for central evaluation must be sent to: 
Labor Studienzentrum Professor Hanefeld 
GWT-TUD GmbH 
Fiedlerstr. 43, 
01307 Dresden 
Tel:  +49 (0)351 4400 5970 
Fax: +49 (0)351 4400 581 
 
Inflammation, efficacy and metabolic parameters are determined in different central 
laboratories.  
 
responsible laboratory 
parameters to be determined 
Labor Studienzentrum Professor Hanefeld  
GWT-TUD GmbH 
Fiedlerstr. 34,  
01307 Dresden / Germany 
 
Phone:   
+49 (0)351 4400 5970 
Fax:  
+49 (0)351 4400 581 
HbA1c, hsCRP, PAI-1, MCP-1, MPO, 
IL-6, IL-8, MMP-9, eGFR,  urinary 
albumin/creatinin 
ratio, 
LDL-C, 
HDL-C, trigylceride, cholesterine 
Crea (PAP methode), UACR, VCAM-
1, ICAM-1, E-Selectin, P-Selectin, 
ADMA, Nitrotyrosin, CD40L 
 
Universitätsklinikum Dresden 
Institut für klinische Chemie und Laboratoriumsmedizin 
Fetscherstr. 74 
01307 Dresden / Germany 
Phone:   
+49(0) 351 458 2109  
Fax:  
+49(0) 351 458 4332  
Prothrombin fragment 1 and 2; 
TAT, Protein C, Protein S, D-Dimer, 
Fibrinogen 
immunolog., 
von 
Willebrand factor; Quick, aPTT 
 
Universitäres Herzzentrum Hamburg 
Biomarker Labor (AG Zeller) 
Gebäude O48/4. OG 
Martinistrasse 52 
NT-proBNP, hs-Tnl, GDF-15, MR-ANP 


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20246 Hamburg / Germany 
Phone:   
+49(0) 40 7410 56575 
Fax: 
+49 (0) 40 7410 40194 
 
 
Universitätsklinikum Dresden 
Medizinische Klinik III 
Fetscherstr. 74 
01307 Dresden / Germany 
Phone:   
+49(0) 351 458 4233 
Fax:  
+49(0) 351 458 5333 
Assessment of platelet activation 
and mitogenic potential 
Further details of handling of specimen and shipment will be specified in the laboratory manual. 
4.15.3 
Assessment of platelet activation and mitogenic potential 
Platelet activation will be assessed by measuring platelet derived microparticles (PMP).Therefore 
blood will be carefully drawn into CTAD tubes and platelet poor plasma will be obtained after two 
centrifugations at 2.500 g for 15 minutes. Platelet rich plasma will be prepared by centrifugation 
for 20 minutes at 800 g. After transfer of the platelet fraction HEP buffer and the 
phosphodiesterase inhibitor 3-isobutyl-1- methylxanthine (IMBX) will be added to prevent 
platelet activation and cGMP degradation respectively. Platelet poor and platelet rich plasma will 
be stored at -80°C until further processing. Subsequently, analysis of platelet microparticles and 
their mitogenic potential will be performed after sample thawing. PMP will be measured after 
staining with anti-GP1b antibodies by fluorescence-activated cell sorting (FACS). In addition, 
magnetic beads linked with anti-GP1 b antibodies will be used to extract PMP from platelet poor 
plasma. Therefore, samples will be passed through MACs MS separation columns in order to 
separate platelet-derived microparticles from plasma that contains inhibitors to clotting enzymes. 
Extracted PMP will then be added to human vascular endothelial cells (HUVECS) and migration 
(Boyden chamber) as well as proliferation (BrdU) of HUVECs will be assessed with and without 
PMP with samples from patients undergoing platelet inhibition or rivaroxaban treatment. Platelet 
rich plasma will be used to measure platelet activation. Therefore, cGMP dependent 
phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at Ser-157 will be assessed 
adding a specific AB against VASP-P157 coupled to magnetic beads which will be detected by flow 
cytometry.


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4.16 Duration of the clinical trial in the individual subject 
The total duration of the study will be approximately 20 weeks per subject. Subjects are obliged 
to come to the study center for 5 visits and receive two telephone contacts (visit 3 and visit 5). 
4.17 Analyses and reporting 
Data will be analyzed and reported after the last subject has been followed the EOT visit.  
 
 
 


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5 
IMP 
5.1 Treatments to be given 
Treatment 
Arm 
No. of 
patients 
Type of 
therapy 
Treatment 
Dose / route 
Frequency 
A 
Treatment 
Group 
94 
Rivaroxaban 
active 
5 mg oral 
(2 x 2.5 mg) 
b.i.d. 
B 
Control 
group 
94 
Aspirin 
comparator 
100 mg oral 
q.d. 
TABLE 6: TREATMENT SCHEDULE 
 
5.2 Description of the IMP – Rivaroxaban (treatment group) 
Trade name: 
Xarelto® 
INN (International Nonproprietary Name) 
Rivaroxaban 
Galenical form / formulation 
film coated tablet (light yellow, round 
biconvex tablets marked with BAYER-cross) 
Strength 
2.5 mg (total daily dose of 10 mg) 
Further contents 
Lactose monohydrate 
Type of packaging and content 
aluminium foil blisters in cartons of 56 tablets 
Manufacturer 
Bayer Pharma AG 
Marketing authorization holder 
Bayer Pharma AG 
TABLE 7: IDENTIFICATION OF THE IMP RIVAROXABAN 
 
The indication and contraindications are listed for the strength of 2.5 mg. For dosage 5 mg b.i.d. 
of Rivaroxaban it is necessary to administer the authorized strength of 2.5 mg twice at intervals 
of 12 h. Daily, a total of 4 tablets of 2.5 mg strength are taken. 
5.2.1 Therapeutic indication of 2.5 mg Rivaroxaban: 
Rivaroxaban, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or 
ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an 
acute coronary syndrome (ACS) with elevated cardiac biomarkers.


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5.2.2 Contraindications for 2.5 mg Rivaroxaban: 
 
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, this may 
include 
 
current or recent gastrointestinal ulceration,  
 
presence of malignant neoplasm at high risk of bleeding,  
 
recent brain or spinal injury, recent brain, spinal or ophthalmic surgery,  
 
recent intracranial haemorrhage,  
 
known or suspected oesophageal varices, arteriovenous malformations, vascular 
aneurysms or major intraspinal or intracerebral vascular abnormalities. 
 
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.) 
except under the circumstances of switching therapy to or from rivaroxaban or when UFH 
is given at doses necessary to maintain an open central venous or arterial catheter 
 
concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or 
a transient ischaemic 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) 
 
as with other antithrombotics, rivaroxaban is not recommended in patients with an 
increased bleeding risk such as: 
- 
congenital or acquired bleeding disorders 
- 
uncontrolled severe arterial hypertension 
- 
active ulcerative gastrointestinal disease 
- 
vascular retinopathy 
- 
bronchiectasis or history of pulmonary bleeding 
 
pregnancy and breast feeding 
5.3 Description of the IMP – Aspirin (ASS 100) (control group) 
The IMP ASS 100 TAH of the control group will be preferably used from ratiopharm GmbH. If it 
becomes necessary (from indefinable reasons), instead of ratiopharm, Aspirin® Bayer or 
ASS 100 mg of HEXAL can be used as a control IMP in the same dosage. Both medications have an 
identical authorization profile. 


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Trade name: 
ASS-ratiopharm® 100 mg TAH 
INN (International Nonproprietary Name) 
acetylsalicylic acid 
Galenical form / formulation 
film coated tablet (white, round table with 
one-sided cross) 
Strength 
100 mg 
Further contents 
cellulose 
Type of packaging and content 
cartons of 50 tablets 
Manufacturer 
ratiopharm GmbH 
Marketing authorization holder  
ratiopharm GmbH 
TABLE 8: IDENTIFICATION OF THE IMP ASPIRIN 
For dosage 100 mg of aspirin it is necessary to administer one tablet once a day at intervals of 
24 h. 
5.3.1 Indication: 
Aspirin 100 mg is indicated for 
 
Angina pectoris 
 
acute coronary syndrome 
 
acute myocardial infarction 
 
prophylaxis of reinfarction after vascular surgery or PCI 
 
prophylaxis of stroke or TIA after the occurrence of prior events 
5.3.2 Contraindications of ASS 100 mg: 
Aspirin 100 mg is contraindicated for 
 
hypersensitivity to the active substance or to any of the excipients 
 
prior asthmatic episodes in response to salicylates 
 
gastrointestinal bleeding in medical history, caused by nonsteroidal antiinflammatory 
drugs  
 
current or recent gastrointestinal ulceration, with documented bleeding  
 
increased predisposition to bleeding 
 
liver or kidney failure 
 
severe congestive heart failure  
 
combination with methotrexate ≥ 15 mg per week 
 
during the last trimester of pregnancy 
 


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5.4 Central pharmacy 
The IMP are labelled and shipped to the sites on behalf of the sponsor by the central pharmacy in 
Dresden. The order of the IMP will be in the responsibility of the sponsor. For queries concerning 
the IMP use following contact: 
Klinik-Apotheke 
Universitätsklinikum Carl Gustav Carus / TU Dresden 
Tel. +49 (0)351 458-19331 
Fax +49 (0)351 458-6385 
5.5 Labeling of the IMP 
The IMP will be used in its commercially available form. Special labeling for the present study is 
not necessary according to GCP-V §5 (8) as treatment is unblinded. However, to avoid 
unauthorized usage the package (primary and secondary packaging) will be marked as containing 
study medication according to GCP by central pharmacy.  
A complete record of batch numbers and expiry dates of all study treatment will be maintained 
in the ISF. Batch numbers of administered IMP will be recorded in the drug accountability log for 
each individual patient. All study medication used during the trial will be stored at the study site 
under controlled conditions (protected from light, at room temperature not exceeding 25°C for 
aspirin) and will be inaccessible to unauthorized personnel. In case the IMP is expired or stored 
outside the required temperature limits, the respective batch is not to be used anymore for study 
purposes and has to be put in quarantine until return. 
5.6 Drug logistics and accountability 
All study drugs will be stored at the study site in accordance with GCP requirements and the 
instructions given on the package insert and will be inaccessible to unauthorized personnel. 
Storage conditions and a complete record of batch numbers and expiry dates can be found in the 
TMF; the site-relevant elements of this information will be available in the ISF. The responsible 
site personnel will confirm receipt of study drug in writing and will use the study drug only within 
the framework of this clinical study and in accordance with this protocol. Receipt, distribution, 
return and destruction (if any) of the study drug must be properly documented according to the 
sponsor’s agreed and specified procedures. 
 
 


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5.7 Dispensing of IMP 
All packages should be inspected visually before distribution to the study subjects. The IMP will 
be dispensed to the subjects during the following visits by the site personnel. Each subject will get 
the following amounts of the randomized IMPs. 
 
Visit 
Week 
V0 
day28 
V1 
day 0 ±4d 
V2 
2 ±2d 
V3(TV) 
4 ±2d 
V4 
8 ±2d 
V5(TV) 
12 ±2d 
V6 
20 ±2d 
Dispensed 
medication 
Rivaroxa-
ban 
- 
90 Tabl. 
(3 Packs) 
210 Tabl. 
(7 Packs) 
- 
330 Tabl. 
(11 Packs) 
- 
270 Tabl. 
(9 Packs) 
630 (+270) 
Tabl. = 21 
(+9) Packs 
Aspirin 
- 
50 Tabl. 
(1 Pack) 
50 Tabl. 
(1 Pack) 
- 
50 Tabl. 
(1 Pack) 
- 
100 Tabl. 
(2 Packs) 
150 (+100) 
Tabl. = 3 
(+2) Packs 
TABLE 9: DRUG DISPENSE FOR FIRST TREATMENT PERIOD (1 PACK RIVAROXABAN CONTAINING 30 TABLETS; 1 PACK ASPIRIN 
CONTAINING 50 TABLETS);  
 
OPTIONAL: DISPENSE OF IMP AT V6 FOR PATIENTS PARTICIPATIONS TO EXTENDED TREATMENT PERIOD 
 
Visit 
Week 
V7 (TV) 
24±2d 
V8 
28 ±2d 
V9 (TV) 
32 ±2d 
V10 
36 ±2d 
V11 
(TV) 
40 ±2d 
V12 
(TV) 
44 ±2d 
V13 
52 ±2d 
Dispensed 
medication 
Rivaroxa-
ban 
- 
210 Tabl. 
(7 Packs) 
- 
510 Tabl. 
(17 Packs) 
- 
- 
- 
720 Tabl. = 
24 Packs  
Aspirin 
- 
50 Tabl.  
(1 Pack) 
- 
150 Tabl. 
(3 Packs) 
- 
- 
- 
200 Tabl. = 
4 Packs 
TABLE 10: DRUG DISPENSE FOR EXTENDED TREATMENT PERIOD (80 OF 188 PATIENTS) (1 PACK RIVAROXABAN CONTAINING 
30 TABLETS; 1 PACK ASPIRIN CONTAINING 50 TABLETS) 
 
The dispensing of IMP will be recorded in the drug accountability log in the ISF according to 
provided templates. 
Study subject will receive a medication diary for documentation of intake. 
5.8 Assignment of trial subjects to treatment groups 
All eligible patients will be randomized at baseline visit V1 (after necessary laboratory parameters 
are available) using a central block randomization process based at the sponsor’s site. The study 
site requesting randomization of a patient will send a form containing site ID and screening 
number to the sponsor (Dept. of Medical Consulting; fax +49 351 25933 198, in the time frame 
Monday to Friday 8.00 am to 4.00 pm, not on legal holidays). In return, the site will receive a 
randomization form containing the randomization number and allocation to treatment arm by fax 
or email within 30 min. 


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5.9 Selection of dosage of IMP and frequency of treatment 
Rivaroxaban will be administered at a dose of 5 mg (2 x 2.5 mg) twice daily (each 12 h), aspirin 
will be administered at a dose of 100 mg once daily (each 24 h).  
The first dose of either study drug will be administered to the participants at the day of 
randomisation (visit 1). Further administrations take place at Visit 2 (after 2 weeks) and visit 4 
(after 8 weeks). 
Rivaroxaban will be administered according to the described instructions. Dosage and frequency 
of aspirin treatment applied in this study will follow the general specifications of the given SmPC.  
For patients participating in the extended treatment period, drug dispense will additionally take 
place at visit V6 (after 20 weeks), at visit V8 after 28 weeks and at visit V10 after 36 weeks. 
5.10 Blinding 
Not applicable, open-label study. 
5.11 Previous and concomitant medication 
Rivaroxaban should not be administered concurrently with CYP3A4 and P-gp inhibitors. Co-
administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice 
a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold 
increase in mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects 
which may lead to an increased bleeding risk. Therefore, the use of Rivaroxaban is not 
recommended in patients receiving concomitant systemic treatment with azole-antimycotics 
such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. 
These active substances are strong inhibitors of both CYP3A4 and P-gp.  
 
Patients who will need the above mentioned therapies are excluded from the study participation. 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting 
haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic 
acid (ASA) and platelet aggregation inhibitors since these drugs generally increase bleeding risk. 
Patients who need chronic treatment with NSAID or ASA > 100 mg / day or other platelet 
aggregation inhibitors are excluded from the study participation. 
There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in 
clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated 
quantitative anti-Factor-Xa tests.


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5.11.1 
Dosing recommendations before and after invasive procedures, surgical 
intervention and rescue therapy for clinical emergencies: 
If an invasive procedure or surgical intervention is required, Rivaroxaban should be stopped at 
least 12 hours before the intervention, if possible and based on the clinical judgement of the 
physician. If a patient is to undergo elective surgery and anti-platelet effect is not desired, platelet 
aggregation inhibitors should be discontinued as directed by the manufacturer’s prescribing 
information. 
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
The estimated half life of rivaroxaban is 7 to 11 hours; for aspirin irreversible inhibits platelet 
aggregation. 
Both substances have a wide therapeutic window. Therefore, in case of asymptomatic overdosing 
without overt bleeding complications no specific treatment actions need to be taken and patient 
should be kept under surveillance. For rivaroxaban, gastrointestinal uptake can be reduced by 
activated carbon application within 3 h after intake of rivaroxaban, the same is applicable for 
aspirin. Aspirin might be removed from the circulation by hemodialysis. No specific antidot is 
available for either drug. In case of bleeding complications study treatment should be interrupted 
and symptomatic therapy (fluid resuscitation and blood transfusion as well as mechanical 
measures to control bleeding) should be initiated immediately. In the case of aspirin further 
bleeding can be prevented by platelet transfusion. In the case of rivaroxaban therapy with 
prothrombin complex or recombinant factor VIIa should be considered. 
5.12 Post-study therapy 
After ending of the clinical trial, patients will receive further standard medical care as usual for 
this kind of disease. 


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6 
Efficacy and safety variables 
Specific time points for evaluation of efficacy variables and safety measures are given in 4.13. 
6.1 Measurement target variables 
6.1.1 Primary target variable 
 change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 
min of forearm ischemia (FBF max. ml/100ml) at week 20 
 
Additional primary variable for extension period: 
 pulse wave velocity at EOT after 52 weeks 
6.1.2 Secondary target variables 
 
change of area under the FBF curve over 10 cycles of venous congestion (compared to 
baseline/day 0) at week 20 and EOT Extension 
 
maximal postischemic skin blood flow (arbitrary units) during reactive hyperaemia after 
5 min of forearm ischemia at week 20 and EOT Extension using LDF 
 
change of postischemic skin blood flow using LDF (compared to baseline/day 0) at week 
20 and EOT Extension 
 
pulse wave velocity at 20 weeks and EoT Extension compared to baseline 
 
laboratory parameter (see above) at week 20 and EOT Extension 
 
Additional secondary variable for extension period: 
 
change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 
min of forearm ischemia (FBF max. ml/100ml) at EOT after 52 weeks (EOT Extension) 
6.1.3 Measurement of safety analysis 
 
major bleeding defined as clinically overt and associated with one of the following: 
- 
decrease in hemoglobin level of 2 g/l or 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 Haemostasis (ISTH). 
 
clinically relevant non-major bleeding defined at least one of the following signs:  
- 
spontaneous skin hematoma of at least 25 cm 


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- 
spontaneous nose bleeding of more than 5 min duration  
- 
macroscopic hematuria, either spontaneous or, if associated with an intervention, 
lasting more than 24 h  
- 
spontaneous rectal bleeding (more than spotting on toilet paper)  
- 
gingival bleeding for more than 5 min  
- 
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 
6.1.4 Rationale for assessment procedures 
All parameters evaluated in this study as well as the methods to measure them, are standard 
variables / methods in clinical practice or non-invasive techniques. They are widely used and 
generally recognized as reliable, accurate and relevant. 
6.2 Applied measurement procedures 
6.2.1 Venous occlusion plethysmography for assessment of forearm blood flow FBF: 
Endothelium dependent vasodilation of resistance vessels will be assessed in both arms 
simultaneously 
using 
strain-gauge 
venous 
occlusion 
plethysmography 
(Gutmann 
Medizinelektronik, Eurasburg, Germany or Hokanson Pletysmograph EC6). Patient rest for at least 
20 min in supine position in a temperature controlled room. At both upper arms a cuff for venous 
occlusion will be placed. On the forearm, at the side of its maximal circumference an elastic strain-
gauge is used to assess changes of the forearm circumference after release of the upper arm cuff. 
At start of each assessment of postischemic vasodilation the upper arm cuff will be inflated to 
20 Torr above the arterial blood pressure (but at least 200 Torr) for 5 min to induce forearm 
ischemia. Thereafter the upper arm cuff will be released for free arterial blood inflow into the 
forearm. Every 10 sec the upper arm cuff inflates automatically to 40 Torr to induce venous 
congestion for about 10 sec. These sequences will be repeated 10 times. During venous 
congestion the arterial blood inflow into the forearm causes an increase of its circumference 
which depends on the amount of blood inflow. The latter one is determined by forearm vascular 
resistance due to the arteriolar tense.   
6.2.2 Laser Doppler Fluxometry: 
The technique of micro-lightguide spectrophotometry and laserdopplerfluxometry (LDF) will be 
used to measure microvascular skin blood flow and postcapillary tissue oxygenation (sO2) at the 
lower forearm. LDF skin probes will be placed at the lower forearm and on the thenar surface of 
the left hand in between the phalanx of the thumb and the metatarsale of Dig II, directly adjacent 
to the muscle abductor pollicis. Microvascular blood flow and post-capillary sO2 will be measured 


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in parallel in a tissue depth of 2 mm and 8 mm. Via a cuff on the upper arm a supra-systolic 
occlusion will be induced for 4 minutes, and thereafter, the postischaemic microvascular blood 
flow and sO2 will be recorded as a measure of microvascular endothelial function in the skin. 
Pulse wave velocity and arterial stiffness: 
Measurements will be performed using the Mobil-O-Graph device (IEM Inc., Stolberg, Germany). 
This device allows the non-invasive oscillometric analysis of blood pressure and pulse wave over 
24 hours. Based on pulse wave analysis we calculate the aortic augmentation index as marker of 
arterial stiffness and pulse wave velocity. The Mobil-O-Graph device has been validated against 
gold standard procedures such as applanation tonometry (SphygmoCor, AtCor Inc.) and is used in 
clinical routine. 
6.2.3 Pulse wave velocity and arterial stiffness: 
Measurements will be performed using the Mobil-O-Graph device (IEM Inc., Stolberg, Germany). 
This device allows the non-invasive oscillometric analysis of blood pressure and pulse wave over 
24 hours. Based on pulse wave analysis we calculate the aortic augmentation index as marker of 
arterial stiffness and pulse wave velocity. The Mobil-O-Graph device has been validated against 
gold standard procedures such as applanation tonometry (SphygmoCor, AtCor Inc.). 
 
Each investigator will receive a user manual for the correct application of the techniques. 
7 
Administrative aspects 
7.1 Data documentation 
7.1.1 eCRF 
All data relevant to this trial are to be documented by the responsible investigator in a web-based 
eCRF immediately after measurement has been taken. Entering data may be delegated to 
members of the trial team but the investigator will have to check and sign the eCRF entries. 
Serious Adverse Event Forms have also to be signed and dated by the investigator.  
7.1.2 Source data documentation 
Original records, source data, printouts from medical devices, randomization fax etc. will be 
documented in a separate patient file respectively in a special study file. 
 
All relevant source data should be maintained in this file. The study file should contain: 
 
signed ICF (informed consent form)  
 
source data for medical history and previous medication 


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 
checks of in- and exclusion criteria 
 
randomization form 
 
source data of: 
- 
laboratory data (for safety, efficacy parameter) 
- 
measurements of FBF, LDF, arterial stiffness 
- 
ECG forms 
- 
data of physical examinations 
 
AE /SAE  
 
visit specific information (what was done at each visit) 
 
notifications of drug dispense and return 
 
All source data and data identifiable as source data must be signed by the investigator. All study 
files must contain the patient number (randomization number) for identification and must contain 
information when and by whom the patient was informed. 
If it is necessary to make corrections to any written source data, a single line should be drawn 
through the original entry, the new entry written in, and the form initialed and dated by the 
individual making the correction. 
mistake 
correction 
Birth date:  
09.10.2014 
Birth date: 09.10.201409.10.1958 (corr.: initials/date) 
7.2 Data management 
The IT infrastructure and data management staff will be supplied by GWT. The trial database will 
be developed and validated prior to data entry based on standard operating procedures at GWT. 
The data management system is based on commercial trial software (Macro 4.0) and stores the 
data in a database, storing all changes in an audit trail. The trial software has a user and role 
concept that can be adjusted on a trial-specific basis. The database is integrated into a general IT 
infrastructure and safety concept with a firewall and backup system. A regularly backup of all trial 
data will be performed by InferMed (London). After completion and cleaning of data, the 
database is locked and the data exported for statistical analysis. 
 
Trial sites will enter data online via Internet. Plausibility checks are run during data entry, thereby 
detecting discrepancies immediately. The GWT Data Management will conduct further checks for 
completeness and plausibility and will clarify any questions with the trial sites electronically via 
trial software. Discrepancies and implausible values will be clarified in writing between the data 
manager and the trial site. These electronic queries have to be answered by the trial site without 
unreasonable delay.  
Further details will be specified in the data management manual. 


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7.3 Data quality 
7.3.1 Monitoring 
The trial site will be monitored to ensure the quality of the data collected. The objectives of the 
monitoring procedures are to ensure that the trial subject’s safety and rights as a study participant 
are respected, that accurate, valid and complete data are collected, and that the trial is conducted 
in accordance with the trial protocol, the principles of GCP and local legislation. 
All investigators agree that the monitor will regularly visit each trial site and assure that the 
monitor will receive appropriate support in his activities at the trial site, as agreed in separate 
contracts with each site. The declaration of informed consent includes a statement to the effect 
that the monitor has the right – while observing the provisions of data protection legislation – to 
compare the eCRFs with the trial subject’s medical records (physicians notes, laboratory printouts 
etc.). The investigator will ensure access for the monitor to all necessary documentation for trial-
related monitoring. The purposes of the monitor visits are as follows: 
 
check the informed consent 
 
check inclusion and exclusion criteria 
 
monitor trial subject safety (occurrence and documentation/reporting of AEs and SAEs) 
 
check the completeness and accuracy of entries on the eCRFs 
 
validate the entries on the eCRFs against those in the source documents (source data 
verification) 
 
perform drug accountability checks 
 
evaluate the progress of the trial 
 
evaluate compliance with the trial protocol 
 
assess whether the trial is being performed according to GCP at the trial site 
 
discuss with the investigator aspects of trial conduct and any deficiencies found. 
 
Monitoring at each trial site will be done for 100 % for the ISF, the patient’s informed consent, all 
in- and exclusion criteria, safety parameters and the drug accountability.  
Source data, pre-exisiting disease as well as concomitant medications and disease will be 
monitored for 50 % of the patient data.Monitoring will be adapted to the quality of data recorded 
by the trial site. Monitoring activities will also be adapted to pre-visit checks of the data entered 
to the eCRF or by telephone visits. 
A monitoring visit report will be prepared for each visit describing the progress of the clinical trial 
and any problems (e.g. refusal to give access to documentation). A follow-up letter will be 
prepared for the trial site after each visit. 
 
Further details will be given in the Monitoring Manual. 


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7.3.2 Data quality assurance 
The responsibilities of the German Investigators are set out in the German drug law (AMG), GCP-
Verordnung (GCP-V), the ICH guideline for Good Clinical Practice (ICH-GCP) and in the Directive 
2001/20/EC of the European Union. 
7.3.3 Audits/Inspections 
As part of quality assurance, the sponsor has the right to audit the trial site and any other 
institutions involved in the trial. The aim of an audit is to verify the validity, accuracy and 
completeness of data, to establish the credibility of the clinical trial, and to check whether the 
trial subject’s rights and trial subject safety are being maintained. The sponsor may assign these 
activities to persons otherwise not involved in the trial (auditors). These persons are allowed 
access to all trial documentation (especially the trial protocol, case report forms, trial subjects’ 
medical records, drug accountability documentation, and trial-related correspondence). 
In addition, inspections by regulatory health authority representatives and IEC are possible. The 
investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study. 
All persons conducting audits will keep all trial subject data and other trial data confidential. 
7.3.4 Archiving 
All study relevant data, informed consent forms and other important trial materials will be 
archived for at least 10 years in accordance with §13 Sec. 10 of the national GCP Regulations. 
Essential documents shall be archived safely and securely in such a way that ensures that they are 
readily available upon authorities’ request. 
Patient (hospital) files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice. Where the 
archiving procedures do not meet the minimum timelines required by the sponsor, alternative 
arrangements must be made to ensure the availability of the source documents for the required 
period. 
The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership). 
 
The ISF is not to be destroyed without the sponsor’s approval. The investigator’s contract will 
contain all regulations relevant for the study center.


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8 
Ethical and regulatory aspects 
8.1 Independent ethics committee 
The protocol, ICF and any other supporting study documents will be reviewed by the independent 
ethics committee (IEC) of the State Chamber of Physicians of Saxony (Sächsische 
Landesärztekammer) prior to study initiation as the leading IRB. Each study site may not begin the 
study until the responsible authority/committee for that site has given its written approval, signed 
by the authority chairperson or authorized personnel, and a copy of the approval letter and the 
approved ICF for that site has been provided to the Investigator. 
8.2 Notification of the authorities, approval and registration 
Before the start of the clinical trial, all necessary documentation will be submitted to the 
competent supreme federal authority for approval (Bundesinstitut für Arzneimittel und 
Medizinprdukte, [BfARM]).  
The state authorities in each federal state in which the trial will be conducted will also be notified. 
Prior to start of the study, it will be registered under www.clinicaltrials.gov. 
8.3 Ethical basis for the clinical trial 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by Good Clinical 
Practice (GCP) guidelines and under the guiding principles detailed in the Declaration of Helsinki. 
The study will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers 
before start of the study, according to GCP, local laws, regulations and organizations. When 
necessary, an extension, amendment or renewal of the EC/IRB approval must be obtained. The 
responsible unit (e.g. EC/IRB, head of the study center/medical institution) must supply to the 
sponsor, upon request, a list of the EC/IRB members involved in the vote and a statement to 
confirm that the EC/IRB is organized and operates according to GCP and applicable laws and 
regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation form, or a change of, the protocol to eliminate an immediate hazard to the 
trial subjects without prior IEC/IRB/sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 


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amendment should be submitted to the IEC/IRB/head of medical institution/sponsor.  Any 
deviations from the protocol must be explained and documented by the investigator. 
All investigators and other staff involved in the study will be informed that the competent federal 
authorities and authorized representatives of the sponsor have the right to review trial 
documentation and the trial subjects’ medical records at any time. 
Details on discontinuation of the entire study or parts thereof can be found in Section 4.10. 
8.4 Obtaining informed consent from trial subjects 
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form (ICF) provided by the sponsor. A sample subject information 
and ICF is provided as a document separate to this protocol. 
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject prior to her/his entry into the study (i.e. before any 
examinations and procedures associated with the selection for the study are performed or any 
study-specific data is recorded on study-specific forms). The investigator will also mention that 
written approval of the IRB/IEC has been obtained. 
Each subject will have ample time and opportunity to ask questions and will be informed about 
the right to withdraw from the study at any time without any disadvantage and without having to 
provide reasons for this decision. 
Only if the subject voluntarily agrees to sign the informed consent form and has done so, may 
she/he enter the study. Additionally, the investigator and other information provider (if any) will 
personally sign and date the form. The ICF will be signed in duplicate, one copy remains with the 
subject and the second original is to remain in the ISF or, if locally required, in the patient’s 
note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
 
The ICF and any other written information provided to subjects will be revised whenever 
important new information becomes available that may be relevant to the subject’s consent, or 
there is an amendment to the protocol that necessitates a change to the content of the subject 
information and / or the written informed consent form. 
The investigator will inform the subject of changes in a timely manner and will ask the subject to 
confirm her/his participation in the study by signing each revised informed consent form. Any 
revised written ICF and written information must receive the IEC / IRB`s approval / favorable 
opinion in advance of use. 
Part of the monitoring activities are to check that the most recent ICF was used before the trial 
subject was enrolled and that it was dated and signed by the trial subject himself or herself. 


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8.5 Compensation for health damage of subjects / insurance 
All subjects enrolled in this trial are insured in accordance with § 40 AMG article 1 (8) and article 
3 under the group insurance contract of GMIHO mbH as a subsidiary company of the sponsor 
GWT-TUD GmbH with ALLIANZ Versicherungs-AG covering eventually occurring damage caused 
by the treatment or any actions taken according to the treatment plan. The headquarters, policy 
number and contact information will be provided in the patient information sheet. 
ALLIANZ Versicherungs-AG 
10900 Berlin 
Fax: 0800 - 4400101 
 
Policy Number: AS-9100294133 
8.6 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and / or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor. Only the subject number will be recorded in 
the eCRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of the 
informed consent process, the subjects will be informed in writing that representatives of the 
sponsor, IEC / IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. The 
investigator will maintain a list to enable subjects to be identified in the ISF. 
 
 


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9 
Statistical methods and sample size calculation 
9.1 General statistical considerations 
9.1.1 Description of trial subject groups 
Patients with type 2 diabetes duration between 2 and 20 years in the age range from 40 – 75 years 
showing increased hsCRP (> 2 mg/l but < 10 mg/l) and/or increased PAI 1 (> 15 ng/ml) as well as 
documented atherosclerotic CVD will be included in this prospective, comparative active 
controlled, randomized, 2 parallel arms, open study. No further subgroup analyses were intended. 
9.1.2 Trial populations 
For the analysis, patients not fulfilling the selection criteria of the trial ("non-eligible") will be 
excluded from the statistical analysis. Only casuistic reports will be provided for this group. All 
other patients will primarily be evaluated in an intent-to-treat analysis (ITT) (full analysis set, FAS).  
Analyses of efficacy endpoints will be performed on the per protocol analysis set (PPS) defined as 
the subset of subjects of the FAS who have complete data of primary and secondary target 
variables at the first (V1) and last visit (V6), and who have no major protocol deviations thought 
to impact on the efficacy conclusions of the trial. 
All patients having received at least one application of study medication are generally evaluable 
for safety and will be included in the safety analysis set (SAS). 
9.1.3 Primary target variable 
The primary target variable of this study is the change of maximal postischemic forearm blood 
flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at week 20 
and the difference of PWV between treatment groups at EOT. 
9.1.4 Secondary variables 
The secondary variables are the change of AUC of forearm blood flow compared to baseline, the 
maximal postischemic skin blood flow during reactive hyperaemia after 5 min of forearm 
ischemia, change of postischemic skin blood flow, pulse wave velocity and laboratory parameters. 
9.1.5 Interim analysis 
An interim analysis is not planned due to the explorative character of the trial. 
 
 


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9.1.6 Missing values and outliers 
Missing values will not be imputed. Outliers will be identified by data management and have to 
be checked by the study physician. According to the decision of data management and study 
physician, outliers will be kept in the database or set to “missing” or “not available”. 
9.1.7 Reporting conventions 
P-values ≥ 0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“< 0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be 
reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) 
will be reported to 3 significant digits. 
9.1.8 Sample size calculation 
The primary 
variable is change 
of forearm 
blood blow with venous occlusion 
plethysmography(ΔFBF) after forearm ischemia after 20 weeks treatment. The sample size 
calculation is based on the following assumptions: 
 
H0: Δ FBFRiva ≤ Δ FBFASS 
 
H1: Δ FBFRiva> Δ FBFASS 
 
 
- 
Type I error: α = 0.05, one-tailed t-test for independent samples 
- 
Power: 1-ß = 0.90 
- 
Estimated dropout rate : 25 % 
- 
Minimum of expected clinical relevant difference between the groups in changes of 
maximal forearm blood flow (ΔFBF) = 1.2 ml/100ml with an estimated standard deviation 
(SD) of σ = 2.4 ml/100ml [Pistrosch, F. et al. Diabetes Care 27: 484-490, 2004] 
Sample size should be N = 188 Patients (N1/2 = 94 patients per arm) for a valid number of 141 
patients for per protocol analysis. This sample size may also provide enough power for further 
analyses. 
 
Additionally, the second primary variable is difference of PWV between treatment groups at EOT 
Extension (after 52 week of treatment). The sample size calculation is based on the following 
assumptions:  
H0: PWVRiva=PWVASS 
H1: PWVRiva≠PWVASS 
- 
Type I error: α = 0.05, t-test for independent samples  


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- 
Power: 1-ß = 0.80  
- 
Estimated dropout rate : 20 %  
- 
Minimum of expected clinical relevant difference between the groups in PWV = 0.7 m/s 
with an estimated standard deviation (SD) of σ = 1.0 m/s  
 
Sample size should be N=80 patients (40 patients per arm) for a valid number of 66 patients for 
per protocol analysis. 
 
In summary the necessary sample size would be N=188 patients for the study up to week 20 
including 80 patients for the extension up to week 52. 
 
9.2 Statistical methods 
Descriptive or summary statistics will be displayed for continuous data and for categorical data. 
All continuous variables will be summarised using the following statistics: n (non-missing sample 
size), mean, 95 % confidence interval, standard deviation, median, maximum and minimum. The 
frequency and percentages (based on the non-missing sample size) of observed levels will be 
reported for all categorical measures. In general, all data will be listed, sorted by subject and visit 
number. All summary tables will be annotated with the total population size relevant to that 
table/treatment, including any missing observations. 
Comparisons will be tested at the 2-sided 5% significance level. For the primary study endpoint, a 
one-sided significance level of 5% will be assumed. 
T-tests for independent samples will be used for single comparisons between treatment arms (like 
the primary study endpoint). Analyses of the continuous variables over time will be performed as 
paired t-Test, repeated measures analysis of variance or mixed models. All analyses of categorical 
measures will be performed using Fisher´s exact test, McNemar’s Test or χ² test. Previous 
correlation analyses of outcome variables and possible predictors will provide evidence for 
inclusion in analysis. In this trial, most relevant time points for analyses of longitudinal data for 
secondary study endpoints are at baseline (V1) and after end of treatment (V6). 
Individual listings of treatment-emergent adverse events will be provided. The incidence of 
treatment-emergent adverse events, respectively, will be summarized using WHO SOC terms. 
Analysis of adverse events will be based on the safety analysis set.


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10 
Safety 
10.1 Definitions of adverse events and adverse drug reactions 
10.1.1 
Adverse event 
An adverse event (AE) is any untoward medical occurrence (i.e. any unfavorable and unintended 
sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation subject after randomization /first intake of study medication in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating the 
subject should not be recorded as AE (however, the condition for which the surgery is required 
may be an AE). 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal e.g. physical examination findings, symptoms, diseases, or laboratory or ECG 
test results. 
 
Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are recorded as medical history 
(e.g. seasonal allergy without acute complaints). 
 
Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis). 
 
Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events. 
10.1.2 Adverse drug reaction 
An adverse drug reaction (ADR) is any noxious and unintended response to an IMP related to any 
dose with at least a reasonably possible causal relationship with the IMP. 
10.1.3 Serious adverse events and serious adverse reactions 
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is classified as any 
untoward medical occurrence that, at any dose, meets any of the following criteria (a – f): 
 
results in death 
 
is life-threatening 


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The term ‘life-threatening’ in the definition refers to an event in which the patient was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 
requires inpatient hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
- 
the admission results in a hospital stay of less than 12 hours 
- 
the admission is pre-planned(i.e. elective or scheduled surgery arranged prior to 
the start of the study that is written in the patient / study file) 
- 
the admission is not associated with an AE (e.g. social hospitalization for purposes 
of respite care) 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ‘medically important’ and as such may be reportable as an SAE dependent 
on clinical judgment. In addition, where local regulatory authorities specifically require a 
more stringent definition, the local regulation takes precedence. 
 
results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
 
is a congenital anomaly / birth defect 
 
is another medically important serious event as judged by the investigator 
 
If an AE is classified as an SAE, this is documented on a separate SAE sheet in addition to the standard 
AE documentation.  
10.1.1 
Unexpected adverse drug reaction 
An unexpected ADR is an ADR for which the nature or severity is not consistent with the applicable 
product information available for the IMP. Expected ADRs are listed in the appropriate reference 
document, i.e. in the SmPC. 
10.1.2 
Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event for which the 
nature or severity is not consistent with the product information available for the IMP, is regarded 
as serious, and has at least a possible causal relationship with the IMP. 
10.2 Documentation and follow-up of adverse events 
The sponsor ensures that all persons involved in the treatment of trial subjects are adequately 
informed about the responsibilities and actions required when AEs occur. Trial subjects will be 


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asked at each visit whether they have experienced AEs or SAEs. AEs will be documented in the 
trial subject’s medical records and in the eCRF. 
For the procedure of SAE-reporting see section 10.3. 
10.2.1 
Classifications for adverse event assessment 
All AE/SAE will be assessed and documented by the investigator according to the categories 
detailed below. 
SERIOUSNESS 
For each AE, the seriousness must be determined according to the criteria given in section 10.2.1 
INTENSITY 
The intensity of an AE is classified according to the following categories, taking into account the 
possible range of the intensity of the event: mild, moderate, severe. 
CAUSAL RELATIONSHIP 
The assessment of the causal relationship between an AE and the administration of treatment is 
a clinical decision based on all available information at the time of the completion of the eCRF. 
The assessment is based on the question whether there was a “reasonable causal relationship” 
to the study treatment in question. 
 
For the assessment of the causal relationship to medication following points should be 
considered: 
 
laboratory test abnormalities which cannot be explained by concurrent disease or other 
drugs or chemicals 
 
the response to withdrawal of the drug (dechallenge) and rechallenge information events 
in a reasonable time sequence to administration of the drug rechallenge  
 
Possible answers for an assessment of relationship are “yes” or “no”.  
 
An ADR/SADR is suspected if the causal relationship is assessed as ”yes”. Events assessed as ”no” 
are not suspected ADRs/SADRs. 
10.2.2 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).Possible answers are “yes” or “no” 
ACTION TAKEN WITH STUDY TREATMENT 


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Any action on study treatment to resolve the AE is to be documented using the following 
categories: drug withdrawn, drug interrupted, dose reduced, dose not changed, dose increased, 
not applicable, unknown. 
OTHER SPECIFIC TREATMENT(S) OF ADVERSE EVENTS 
 
None 
 
Remedial drug therapy 
 
Other 
OUTCOME 
The outcome of all events is to be documented as follows: recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, life-threatening, fatal, unknown 
10.2.3 
Assessments and documentation of adverse events 
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the subject will be documented. The observation phase for AEs will 
start with randomization / first intake of study medication and will end in general with the last 
visit. In case of ongoing AEs after the last follow-up visit – especially when related to treatment 
with the study medication – the respective AE will be followed until resolution, if possible. The 
investigator is responsible for the grading of each category mentioned in section 10.2.1. 
For all SAEs the sponsor has to carry out a separate assessment for expectedness, seriousness and 
causal relationship to treatment with the study medication. 
10.3 Reporting of serious adverse events 
10.3.1 
Investigator’s notification of the sponsor 
The definition of SAEs is given in section 10.1. All investigators will be thoroughly instructed and 
trained on all relevant aspects of the investigator’s reporting obligations for SAEs. This 
information, including all relevant contact details, is summarized in the ISF. This information will 
be updated as needed. 
All SAEs occurring during the study ( Screening to EOT) defined in Section 10.1.3 must immediately 
(within 24 hours of the investigator’s awareness) be reported to the sponsor detailed in the 
manual. An SAE form must also be completed within 24 hours of the investigator awareness and 
forwarded to the sponsors safety management. Each SAE must be followed up until resolution or 
stabilization by submission of updated reports to the designated recipient. 
SAEs occurring after the protocol-defined observation period will be processed by the sponsor 
according to all applicable regulations. 


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All SAEs must be sent via Fax or eMail to: 
 
GWT GmbH 
Blasewitzer Str. 43 
Germany - 01307 Dresden 
Fax: 0351 /259 33 199 
eMail: safety@gwtonline.de 
NOTIFICATION OF THE IECS / IRBS 
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, serious 
adverse reactions (SUSARs)) will be performed by the sponsor and / or by the investigator 
according to all applicable regulations if requested by the sponsor. 
NOTIFICATION OF THE AUTHORITIES 
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities will be 
done by the sponsor according to all applicable regulations. 
SPONSOR’S NOTIFICATION OF THE INVESTIGATIONAL SITE 
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations. 
NOTIFICATION OF THE MARKETING AUTHORIZATION HOLDER 
The sponsor will also inform the marketing authorization holder about all SAEs and all SUSARs 
including information reported to the competent supreme authority and ethics committee in 
accordance with contractual agreements. 
10.4 Expected adverse events 
10.4.1 
Adverse events possibly related to the study medication 
For this study, the applicable reference document is the most current version of the SmPC. If 
relevant new safety information is identified, the information will be integrated into an update of 
the SmPC and distributed to all participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable reference 
document and according to all local regulations. 
SUMMARY OF THE SAFETY PROFILE  
The majority of adverse reactions reported for Xarelto® 2.5 mg (Rivaroxaban) (respectively 10 mg 
daily dose) are bleeding complications (gastrointestinal bleeding, etc.).  
Less frequently reported, but more serious, adverse reactions include anemia, allergic reaction, 
dizziness, headache, hematoma, hypotonia which are listed in the table below. The adverse 


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reactions are listed by system organ class and frequency using the following convention: very 
common 
("1/10), 
common 
("1/100 to < 1/10), 
uncommon 
("1/1.000 to < 1/100), 
rare 
("1/10.000 to < 1/1.000), very rare (< 1/10.000), not known (cannot be estimated from the 
available data). Within each frequency grouping, adverse reactions are presented in order of 
decreasing seriousness. 
 
Blood and lymphatic system disorders 
Common 
anemia  
Uncommon 
thrombocythemia  
Immune system disorders 
Uncommon 
allergic reaction, allergic dermatitis 
Nervous system disorders 
Common 
dizziness, headache, syncope 
Uncommon 
cerebral and intracranial haemorrhage 
Eye disorders 
Common 
Eye haemorrhage (including conjunctiva haemorrhage) 
Cardiac disorders 
Common 
tachycardia 
Vascular disorders 
Common 
hypotension, haematoma 
Not known 
Pseudoaneurysm formation following percutaneous intervention 
 
Respiratory, thoracic and mediastinal disorders 
common 
Epistaxis 
uncommon 
Haemoptysis 
Gastrointestinal disorders 
Common 
Gastrointestinal tract haemorrhage (incl. gingival bleeding and rectal 
haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, 
constipation, diarrhoe, vomiting 
Uncommon 
Dry mouth 
Hepatobiliary disorders 
Uncommon  
Hepatic function abnormal 
Rare  
Jaundice 


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Skin and subcutaneous tissue disorders 
Common 
Pruritus (incl. uncommon cases of generalized pruritus), rash, ecchymosis 
Uncommon  
Urticaria, cutaneous and subcutaneous haemorrhage 
Musculoskeletal and connective tissue disorders 
Common 
Pain in extremity 
Uncommon 
Haemarthrosis  
Rare  
Muscle haemorrhage 
Unknown  
Compartment syndrome secondary to a bleeding 
Renal and urinary disorders 
Common  
Urogenital tract haemorrhage (incl. haematuria and menorrhagia) 
Uncommon  
Renal impairment (incl. blood creatinine increased, blood urea increased) 
Unkown  
Renal failure / acute renal failure secondary to a bleeding sufficient to 
cause hypoperfusion 
General disorders and administration site conditions 
Common 
Fever, peripheral oedema, decreased general strength and energy (incl. 
fatigue and asthenia) 
Uncommon 
Feeling unwell (incl. malaise), localized oedema 
Investigations  
Common  
Increase in transaminase 
Uncommon 
Increased bilirubin, increased blood alkaline phosphatase, increased LDH, 
increased lipase, increased amylase, increased GGT 
Rare  
Bilirubin conjugated increased (with or without concomitant increase of 
ALT 
Injury, poisoning and procedural complications 
Common  
Postprocedural 
haemorrhage 
(incl. postoperative anemia, wound 
haemorrhage), contusion, wound secretion 
TABLE 11: TABULATED LIST OF ADVERSE REACTIONS 
10.5 Special safety precautions of Xarelto® 
10.5.1 
Overdose 
Rare cases of overdose up to 600 mg of Xarelto® have been reported without bleeding 
complications or other adverse reactions. In the case of overdose see section 5.11.1.  
10.5.2 
Effects on ability to drive and use machines 


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Xarelto® has a minor influence on the ability to drive and to use machines. Adverse reactions like 
syncope or dizziness have been reported to be common. Patients experiencing these adverse 
reactions should not drive or use machines.  
10.6 Pregnancies 
The investigator must report to the sponsor any pregnancy occurring in a study subject during the 
subject’s participation in this study. The report should be submitted within the same timelines as 
an SAE, although a pregnancy per se is not considered an SAE. In case of a suspected or verified 
pregnancy the subject should be excluded from further study treatment. 
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
abnormal outcome of the mother or the child should be reported. 
11 
Use of trial findings and publication 
11.1 Reports 
11.1.1 
Periodic information 
The investigator of each site will inform the sponsor monthly about the progress of the trial. These 
reports will include the number of recruited patients and screening failures as well as dropouts. 
11.1.2 
Annual safety report of trial subjects 
Once a year or on demand, the sponsor will supply a report on the safety of trial subjects in 
accordance with ENTR/CT 3 with all relevant information during the reference period to the 
competent supreme federal authority and the responsible ethics committee.  
The reference period for the annual report on the safety of trial subjects begins with the date of 
the first approval of the competent supreme federal authority for trials running with same 
investigational medicinal product by the sponsor. This date is the reference date for the start of 
the year of the annual safety report. The sponsor will supply the report within 60 days of one year 
after the reference date (data-lock point). 
11.1.3 
Final report 
The competent authority and ethics committee will be informed within 90 days that the trial has 
officially ended. In case the trial is prematurely terminated the notification period is reduced to 
15 days. Within one year of the completion of the trial, the competent federal authority and the 
ethics committee will be provided with a summary of the final report on the clinical trial 
containing the principle results. 


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11.2 Publication 
It is planned to publish the trial results, in mutual agreement with the CPI, in a scientific journal 
and at German or international congresses. Publication of the results of the trial as a whole is 
intended. The trial will also be registered in a public register (www.clinicaltrials.gov) in accordance 
with the recommendations of the ICMJE. 
Any published data will observe data protection legislation covering the trial subject and 
investigators. Success rates or individual findings at individual trial sites are known only to the 
sponsor. 
Publications or lectures on the findings of the present clinical trial either as a whole or at individual 
investigation sites must be approved by the sponsor in advance, and the sponsor reserves the 
right to review and comment on such documentation before publication. 
By signing the contract to participate in this trial, the investigator declares that he or she agrees 
to submission of the results of this trial to national and international authorities for approval and 
surveillance purposes, and to the Federal Physicians Association, the Association of Statutory 
Health Fund Physicians and to statutory health fund organizations, if required. At the same time, 
the investigator agrees that his or her name, address, qualifications and details of his or her 
involvement in the clinical trial may be made known to these bodies.


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12 
Amendments to the trial protocol 
12.1 Changes to trial protocol 
To ensure that comparable conditions are achieved as far as possible at individual trial sites and 
in the interests of a consistent and valid data analysis, changes to the provisions of this trial 
protocol are not planned. In exceptional cases, however, changes may be made to the trial 
protocol. Such changes can only be made if agreed by the sponsor, sponsor’s representative, the 
CPI and biometrician, and all authors of this trial protocol. Any changes to the trial procedures 
must be made in writing and must be documented with reasons and signed by all authors of the 
original trial protocol. 
Amendments made in accordance with § 10 Secs. 1 and 4 GCP Regulations that require approval 
are submitted to the ethics committee and the supreme federal authority and will not be 
implemented until approved. Exceptions to this are amendments made to avoid immediate 
dangers. 
12.2 Amendment 1 
12.2.1 
Overview of changes Amendment 1 (Version 2.0) 
On request of the national competent authority (BfArM) the procedure for labeling of the IMP 
was requested (section 5.5) and minor corrections regarding the in- and exclusion criteria 
(section 4.11) and the evaluation of laboratory parameters (section 4.14). 
12.2.1.1 
Changes to the protocol text Amendment 1 (Version 2.0) 
In this section, all protocol sections affected by Amendment 1 are detailed and sequence of the 
sections follows the structure of the original protocol (version 1.0 of 10.06.2014).  
The amendment comprises changes to the following sections: sections 4.11and 4.14 and 5.5.  
12.2.1.1.1 
Changes in section 4.11 In- and Exclusion criteria 
Original wording, , page 25 Inclusion criteria (section 4.11.1): 
 
Type 2 diabetes duration between 2 and 20 years 
 
one of the following documented atherosclerotic CVD:  
- 
major cardiovascular event in medical history (myocardial infarction, stroke, 
peripheral artery disease or invasive vascular procedure (balloon angioplasty or 
bypass grafting)) or 
- 
coronary angiography showing a coronary artery stenosis of > 50 % or 
- 
carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or 
- 
left ventricular hypertrophy or 


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- 
macroalbuminuria in the absence of other renal diseases than diabetic nephropathy 
 
increased hsCRP (> 2 mg/l but < 10 mg/l) and/or increased PAI 1 (> 15 ng/ml) 
 
age 40 – 75 years 
 
the informed consent form must be signed before any study specific tests or procedures 
are done 
 
confirmation of the subject’s health insurance coverage prior to the first screening visit 
 
age at least 18 years (inclusive) at the first screening visit 
 
ability to understand and follow study-related instructions 
 
Revised wording, page 25 Inclusion criteria (section 4.11.1): 
 
Type 2 diabetes duration between 2 and 20 years 
 
one of the following documented atherosclerotic CVD:  
- 
major cardiovascular event in medical history (myocardial infarction, stroke, 
peripheral artery disease or invasive vascular procedure (balloon angioplasty or 
bypass grafting)) or 
- 
coronary angiography showing a coronary artery stenosis of > 50 % or 
- 
carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or 
- 
left ventricular hypertrophy or 
- 
macroalbuminuria in the absence of other renal diseases than diabetic nephropathy 
 
increased hsCRP (> 2 mg/l but < 10 mg/l) and/or increased PAI 1 (> 15 ng/ml) 
 
age 40 – 75 years at the first screening visit 
 
stable treatment with statines (if tolerated) 
 
the informed consent form must be signed before any study specific tests or procedures 
are done 
 
confirmation of the subject’s health insurance coverage prior to the first screening visit 
 
ability to understand and follow study-related instructions 
 
Changes were also made in the synopsis. 
 
Original wording, page 25 Exclusion criteria (section 4.11.2): 
 
CV event with need for oral anticoagulation or dual 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 
 
concomitant conditions and therapies 
 
hypersensitivity to the active substance or to any of the excipients  
 
active clinically significant bleeding 
 
[...]  
 


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Revised wording, page 25 Exclusion criteria (section 4.11.2) 
 
CV event with need for oral anticoagulation or dual 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 
 
[...] 
12.2.1.1.2 
Changes in section 4.14 Evaluation of laboratory parameters 
Original wording, page 31 (section 4.14): 
safety laboratory contains:  
hemoglobin, hematocrit, platelets, ALAT, ASAT, creatinine, GFR (calculated), blood cell count, 
total bilirubin, sodium, potassium, hsCRP, PAI1, eGFR 
 
efficacy laboratory for endothelial function and coagulation: 
VCAM-1, ICAM-1, E-Selectin, P-Selectin, CD40L, von Willebrand factor, ADMA, nitrotyrosin, 
microalbuminuria, eGFR, UACR, creatinin (serum), fibrinogen (immunolog), prothrombin 
fragment 1 and 2, PAP, TAT, D-Dimer, (protein C, protein S) 
 
Revised wording, page 31, (section 4.14) 
safety laboratory contains:  
hemoglobin, hematocrit, platelets, ALAT, ASAT, creatinine, GFR (calculated), blood cell count 
(leucocytes, erythrocytes), total bilirubin, sodium, potassium, hsCRP, PAI1, eGFR 
 
efficacy laboratory for endothelial function and coagulation: 
VCAM-1, ICAM-1, E-Selectin, P-Selectin, CD40L, von Willebrand factor, ADMA, nitrotyrosin, 
microalbuminuria, eGFR, UACR, creatinin (serum), fibrinogen (immunolog), prothrombin 
fragment 1 and 2, TAT, D-Dimer, (protein C, protein S) 
 
Original wording, page 37 (section 4.14.2): 
responsible laboratory 
parameters to be determined 
Labor Studienzentrum Professor Hanefeld  
GWT-TUD GmbH 
Fiedlerstr. 34,  
01307 Dresden 
 
HbA1c, hsCRP, PAI-1, MCP-1, MPO, 
IL-6, 
IL-8, 
MMP-9, 
eGFR,  
Microalbuminuria, LDL-C, HDL-C, 
trigylceride, Crea (PAPP), HbA1c, 
UACR 


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Tel:  +49 (0)351 4400 5970 
Fax: +49 (0)351 4400 581 
 
 
Universitätsklinikum Dresden 
Institut für klinische Chemie und Laboratoriumsmedizin 
Fetscherstr. 74 
01307 Dresden 
Tel:  +49(0) 351 458 2109  
Fax: +49(0) 351 458 4332  
Prothrombin fragment 1, 2; PAP, 
TAT, Protein C, Protein S, D-Dimer, 
VCAM-1, ICAM-1, E-Selectin, P-
Selectin, Fibrinogen, CD40L, von 
Willebrand 
factor, 
ADMA, 
Nitrotyrosin 
 
Revised wording, page 37, (section 4.14.2) 
responsible laboratory 
parameters to be determined 
Labor Studienzentrum Professor Hanefeld  
GWT-TUD GmbH 
Fiedlerstr. 34,  
01307 Dresden 
 
Tel:  +49 (0)351 4400 5970 
Fax: +49 (0)351 4400 581 
HbA1c, hsCRP, PAI-1, MCP-1, MPO, 
IL-6, 
IL-8, 
MMP-9, 
eGFR,  
Microalbuminuria, LDL-C, HDL-C, 
trigylceride, Crea (PAPP), UACR, 
ALAT, ASAT 
 
Universitätsklinikum Dresden 
Institut für klinische Chemie und Laboratoriumsmedizin 
Fetscherstr. 74 
01307 Dresden 
Tel:  +49(0) 351 458 2109  
Fax: +49(0) 351 458 4332 
Prothrombin fragment 1and 2; TAT, 
Protein C, Protein S, D-Dimer, 
VCAM-1, ICAM-1, E-Selectin, P-
Selectin, Fibrinogen immunolog., 
CD40L, 
von 
Willebrand factor, 
ADMA, Nitrotyrosin, 
12.2.1.1.3 
Changes in section 5.5 Labeling of IMP 
Original wording, page 43 (section 5.5): 
The IMP will be used in its commercially available form. Special labeling for the present study is 
not necessary according to GCP-V §5 (8) as treatment is unblinded. However, to avoid 
unauthorized usage the package (cartons) will be marked as containing study medication 
according to GCP by central pharmacy. […] 
 
Revised wording, page 43 (section 5.5): 
The IMP will be used in its commercially available form. Special labeling for the present study is 
not necessary according to GCP-V §5 (8) as treatment is unblinded. However, to avoid 
unauthorized usage the package (primary and secondary packaging) will be marked as containing 
study medication according to GCP by central pharmacy. […] 


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12.3 Amendment 2 
12.3.1 
Overview of changes Amendment 2 (Version 3.0) 
On request of the independent ethics committee (EK) the general aspect of the withdrawal of 
aspirin before randomization in patients with an indication for taking the medication has been 
revised (section 4.2.1 and 5.9). Accordingly, the visits (screening visit and baseline visit) have been 
revised (section 4.12.2 and 5.7). 
Due to the comments of the EK the patient population was adjusted to the effect of inclusion of 
patients with a high cardiovascular risk instead of cardiovascular disease. Please note for general 
information: in the Protocol, the definition of "cardiovascular disease" was replaced by "high 
cardiovascular risk". Therefore the inclusion criteria and the major exclusion criterion were 
adapted and in the inclusion criteria the statement tot he patient's insurance was deleted (section 
4.11.1) 
Furthermore the process for establishment of a DSMB was adapted (section 3.6).  
Section5.2.1wasadjusted according to the approved indication of the IMP Rivaroxaban 2.5 mg. 
 
12.3.1.1 
Changes to the protocol text Amendment 2 (Version 3.0) 
In this section, all protocol sections affected by Amendment 2 are detailed and sequence of the 
sections follows the structure of the original protocol (version 2.0 of 08.07.2014).  
The amendment comprises changes to the following sections: sections 4.11and 4.14 and 5.5.  
12.3.1.1.1 
Changes of study title 
Original wording, page: 
Microvascular and antiinflammatory Effects of Rivaroxaban compared to low dose aspirin in type 
2 diabetic patients with cardiovascular disease and subclinical inflammation 
 
Revised wording, page: 
Microvascular and antiinflammatory Effects of Rivaroxaban compared to low dose aspirin in type 
2 diabetic patients with very high cardiovascular risk and subclinical inflammation  
12.3.1.1.2 
Adaption of Risk-Benefit-Assessment 
Original wording, page 20 (section 2.5): 
[…] 
However, since all patients have documented CVD and therefore the indication for secondary 
prevention of cardiovascular damage with aspirin 100 mg as standard care, even the control 
group (which receives standard treatment) has a slightly increased bleeding risk. To minimize 
these risks for the patients we will conduct four safety visits during the treatment of 20 weeks of 


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study medication and will not include patients with an increased risk of bleeding as stated in the 
exclusion criteria.  
In conclusion there is clear evidence, that patients with a high cardiovascular risk in a state of 
secondary prevention need a treatment. The standard treatment today is low dose aspirin, but in 
our point of view considering the expected advantages of rivaroxaban at a low dose would 
outweigh the possible increased risk of bleeding. 
 
Revised wording, page 20 (section 2.5): 
[…] 
Since all patients of our planned investigation have a high risk for cardiovascular disease a primary 
prevention of CV events with aspirin 100 mg is recommended by several guidelines (14) however, 
this recommendation is not so strong as the indication for aspirin in the case of secondary 
prevention. In Germany the therapeutic costs for a primary prevention with aspirin 100 mg even 
in high risk patients are not covered by general health insurance, therefore a lot of patients do 
not get a prescription of this medication. The inclusion of this patients with a high CV risk but 
without a major CV event in medical history would offer the possibility to cover high risk patients 
with a recommended treatment for the duration of the study. To minimize the bleeding risk for 
the patients we will conduct four safety visits during the treatment of 20 weeks of study 
medication and will not include patients with an increased risk of bleeding as stated in the 
exclusion criteria.  
In conclusion there is scientific evidence, that patients with a very high cardiovascular risk in a 
state of primary prevention and with a low risk for bleeding should be treated. The standard 
recommended treatment today is low dose aspirin, but in our point of view considering the 
expected advantages of rivaroxaban at a low dose would outweigh the possible increased risk of 
bleeding. 
 
12.3.1.1.3 
Changes in the Inclusion criteria 
Original wording, page 27 (section 4.11.1): 
 
Type 2 diabetes duration between 2 and 20 years 
 
one of the following documented atherosclerotic CVD:  
- 
major cardiovascular event in medical history (myocardial infarction, stroke, 
peripheral artery disease or invasive vascular procedure (balloon angioplasty or 
bypass grafting)) or 
- 
coronary angiography showing a coronary artery stenosis of > 50 % or 
- 
carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or 
- 
left ventricular hypertrophy or 
- 
macroalbuminuria in the absence of other renal diseases than diabetic nephropathy 
 
increased hsCRP (> 2 mg/l but < 10 mg/l) and/or increased PAI 1 (> 15 ng/ml) 
 
age 40 – 75 years at the first screening visit 


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 
stable treatment with statines (if tolerated) 
 
the informed consent form must be signed before any study specific tests or procedures 
are done 
 
cornfirmation od the subject´s health insurance coverage prior to the first screening visit 
 
ability to understand and follow study-related instructions 
 
Revised wording, page 27 (section 4.11.1): 
 
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 n 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) and/or increased PAI 1 (> 15 ng/ml) 
 
age 40 – 75 years at the first screening visit 
 
stable treatment with statines (if tolerated) 
 
the informed consent form must be signed before any study specific tests or procedures 
are done 
 
ability to understand and follow study-related instructions 
 
The changes were made in the same way in the synopsis. 
12.3.1.1.4 
Changes in the exclusion criteria – section 4.11.2 
Original wording, page 28 (section 4.11.2): 
 
CV event with need for oral anticoagulation or dual platelet inhibitor therapy or acute 
coronary syndrome < 12 month before study entry 
[…] 
Revised wording, page 28 (section 4.11.2): 
 
major CV event with need for oral anticoagulation or platelet inhibitor therapy or acute 
coronary syndrome < 12 month before study entry 
[…] 
The changes were made in the same way in the synopsis. 


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12.3.1.1.5 
Changes of withdraw of aspirin treatment before randomization (section  4.2.1 
and 5.9)-  
Original wording, page 23 (section 4.2.1): 
[…] 
Concomitant aspirin treatment for secondary prevention of CVD must be stopped at least 10 days 
before randomization. 
[…] 
 
Revised wording, page 23 (section 4.2.1): 
Sentence deleted. 
 
Original wording, page 45 (section 5.9): 
[…] 
Rivaroxaban will be administered according to the described instructions. Dosage and frequency 
of aspirin treatment applied in this study will follow the general specifications of the given SmPC. 
Subjects who are treated with aspirin for prophylaxis of recurrent cardiovascular event (as 
indicated see 5.3) must stop this treatment at least 10 days before intake of the study drug. 
 
Revised wording, page 45 (section 5.9): 
[…] 
Sentence deleted. 
12.3.1.1.6 
Revision of timelines of screening and baseline visit (section 4.12.1 / and  5.7)-  
The treatment changes before the randomization (no suspension of ASS therapy) result in an 
adjustment of the timelines of the screening and baseline visit. 
Original wording, page 31 (section 4.12.2): 
VISIT 
V0 
V1 
V2 
V3 (TV) 
V4 
V5 (TV) 
V6 
WEEK 
-2 
(+/- 7 d) 
0 
 
2 
(+/- 2 d) 
4 
(+/- 2 d) 
8 
(+/- 2 d) 
12 
(+/- 2 d) 
20 
(+/- 2 d) 
 
SCREEN 
BASELINE 
TREAT 
TREAT 
TREAT 
TREAT 
EOT 
[…] 
 
Revised wording, page 31 (section 4.12.2): 
VISIT 
V0 
V1 
V2 
V3 (TV) 
V4 
V5 (TV) 
V6 
WEEK 
day -10 
 
day 0 
(+/- 4 d) 
2 
(+/- 2 d) 
4 
(+/- 2 d) 
8 
(+/- 2 d) 
12 
(+/- 2 d) 
20 
(+/- 2 d) 
 
SCREEN 
BASELINE 
TREAT 
TREAT 
TREAT 
TREAT 
EOT 


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[…] 
 
Original wording, page 44 (section 5.7): 
Visit 
Week 
V0 
-2 
V1 
0 ±2d 
V2 
2 ±2d 
V3 (TV) 
4 ±2d 
V4 
8 ±2d 
V5 (TV) 
12 ±2d 
V6 
20 ±2d 
Dispensed 
medication 
[...] 
[...] 
 
[…] 
[...] 
 
 
Revised wording, page 44 (section 5.7): 
Visit 
Week 
V0 
day -10 
V1 
day 0 ±4d 
V2 
2 ±2d 
V3(TV) 
4 ±2d 
V4 
8 ±2d 
V5(TV) 
12 ±2d 
V6 
20 ±2d 
Dispensed 
medication 
[...] 
[...] 
 
[…] 
[...] 
 
 
In section 4.12 / page 4.12Figure 1: Trail overview was adapted accordingly. 
12.3.1.1.7 
Changes in section 3.6 – Data and Safety Monitoring Board 
Original wording, page 21 (section 3.6): 
A Data and Safety Monitoring Board is deemed not to be necessary for this study as this is a multi-
center, open-label study with a low risk for participating subjects, i.e. subjects are expected to 
experience only minor side effects, and interim analyses are not crucial for the protection of the 
subjects. 
 
Revised wording, page 21 (section 3.6): 
A Data Safety Monitoring Board (DSMB) of independent experts will be set up. It will consist of 
two physicians and one statistician who are not involved in the conduct of the trial. The task of 
the DSMB is to oversee the safety of the trial subjects in the clinical trial by periodically assessing 
the safety and efficacy of the trial therapy and to monitor the integrity and validity of the data 
collected and the conduct of the clinical trial. 
Throughout this process of surveillance, the DSMB will provide the sponsor with 
recommendations with regard to continuing the trial (e.g. termination or modification) based on 
the data collected. The data necessary for the DSMB to fulfill this function will be provided by the 
sponsor as determined by the DSMB charter. 
12.3.1.1.8 
Changes in section 5.2.1 – Therapeutic indication of Rivaroxaban 2.5 mg 
Original wording, page 40 (section 5.2.1): 
Prophylaxis of venous thromboembolism in adult patients after hip or knee joint replacement. 


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Revised wording, page 40 (section 5.2.1): 
Rivaroxaban, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or 
ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an 
acute coronary syndrome (ACS) with elevated cardiac biomarkers. 
12.4 Amendment 3 
12.4.1 
Overview of changes Amendment 3 (Version 4.0) 
The changes in this amendment relate to the specification of laboratory parameters (section 4.14) 
and are not substantial. These changes do not require the approval of the ethics committee and 
the competent authority (BfArM) but will be e submitted to the authorities for information.  
 
Section 2 - Objectives of the clinical trial 
Original wording, page 19 (section 2.3) and synopsis: 
[…] 
Secondary objectives 
 
[….] 
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin 
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes 
 
metabolic 
marker: 
fasting 
plasma 
glucose, 
HbA1c,  
lipids: triglycerides, LDL-C, HDL-C 
 
Revised wording, page 19 (section 2.3): 
[...] 
Secondary objectives 
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8 
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C 
 
coagulation: von Willebrand-Factor, Fibrinogen, Prothrombinfragment 1 + 2, D-Dimer, 
Protein C, Protein S, TAT 
 
Section 4 – Trial conduct 
Revised and additional wording, page 31 (section 4.12.2): 
Addition and definition of screening laboratory and specification of randomization after screening 
visit. 
Inflammation laboratory will be done at baseline visit (V1) 


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Additional wording, page 33 (section 4.13.1): 
[…] 
 
screening laboratory for check of in- and exclusion criteria containing measurement of 
HDL, triglycerides, urinary albumin/creatinin ratio and creatinine 
 
Additional wording, page 33 (section 4.13.1): 
[…] 
 
patients are randomized in one of two treatment groups (Arm A or Arm B). Randomization 
can be performed when all in- and exclusion criteria were examined (Results of screening 
laboratory must be available). Randomization can be performed between baseline and 
randomization 
 
Original wording, page 33 (section 4.13.2) 
[…] 
 
check previous medication (medication history); all medication used within the last 
12 weeks […] 
 
Revised wording, page 33 (section 4.13.2)- Deletion of this paragraph due to repetition 
[…] 
 
check previous medication (medication history); all medication used within the last 
12 weeks […] 
 
 
Section 4.14 - Evaluation of laboratory parameters 
Original wording, page 36 (section 4.14) and synopsis: 
safety laboratory contains:  
hemoglobin, hematocrit, platelets, ALAT, ASAT, creatinine, GFR (calculated), blood cell count 
(leucocytes, erythrocytes), total bilirubin, sodium, potassium, hsCRP, PAI1, eGFR 
 
INFLAMMATION LABORATORY:  
hsCRP, PAI-1, MCP-1, MPO, IL-6, IL-8, MMP-9, fibrinogen, leucocytes, platelets 
[...] 
 
Revised and additional wording, page 36 (section 4.14): 
[…] 


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screening laboratory 
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR, HDL-C, triglycerides, 
cholesterine, urinary albumin/creatinin ratio, creatinine urine, hsCRP, PAI1 (optional), urine 
pregnancy test 
 
safety laboratory contains:  
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR 
 
inflammation laboratory:  
hsCRP, PAI-1, MCP-1, MPO, IL-6, IL-8, MMP-9, fibrinogen 
 
efficacy laboratory for endothelial function and coagulation: 
VCAM-1, ICAM-1, E-Selectin, P-Selectin, CD40L, von Willebrand factor, ADMA, nitrotyrosin, 
urinary albumin/creatinin ratio, eGFR, UACR, creatinin (serum), fibrinogen (immunolog), 
prothrombin fragment 1 and 2, TAT, D-Dimer, (protein C, protein S) 
 
metabolic marker: 
HbA1c, triglycerides, LDL-C, HDL-C, cholesterine 
 
Original wording, page 37 (section 4.14.2) and synopsis : 
[…] 
responsible laboratory 
parameters to be determined 
Labor Studienzentrum Professor Hanefeld  
GWT-TUD GmbH 
Fiedlerstr. 34,  
01307 Dresden 
 
Tel:  +49 (0)351 4400 5970 
Fax: +49 (0)351 4400 581 
HbA1c, hsCRP, PAI-1, MCP-1, MPO, 
IL-6, 
IL-8, 
MMP-9, 
eGFR,  
Microalbuminuria, LDL-C, HDL-C, 
trigylceride, Crea (PAPP), UACR, 
ALAT, ASAT 
 
Universitätsklinikum Dresden 
Institut für klinische Chemie und Laboratoriumsmedizin 
Fetscherstr. 74 
01307 Dresden 
Tel:  +49(0) 351 458 2109  
Prothrombin fragment 1 and 2; TAT, 
Protein C, Protein S, D-Dimer, 
VCAM-1, ICAM-1, E-Selectin, P-
Selectin, Fibrinogen immunolog., 


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Fax: +49(0) 351 458 4332  
CD40L, 
von 
Willebrand factor, 
ADMA, Nitrotyrosin 
[…] 
 
Revised and wording, page 37 (section 4.14.2): 
responsible laboratory 
parameters to be determined 
Labor Studienzentrum Professor Hanefeld  
GWT-TUD GmbH 
Fiedlerstr. 34,  
01307 Dresden 
 
Tel:  +49 (0)351 4400 5970 
Fax: +49 (0)351 4400 581 
HbA1c, hsCRP, PAI-1, MCP-1, MPO, 
IL-6, 
IL-8, 
MMP-9, 
eGFR,  
Microalbumine, 
LDL-C, 
HDL-C, 
trigylceride, Crea (PAP methode), 
UACR, VCAM-1, ICAM-1, E-Selectin, 
P-Selectin, ADMA, 
Nitrotyrosin, 
CD40L 
 
Universitätsklinikum Dresden 
Institut für klinische Chemie und Laboratoriumsmedizin 
Fetscherstr. 74 
01307 Dresden 
Tel:  +49(0) 351 458 2109  
Fax: +49(0) 351 458 4332 
Prothrombin fragment 1 and 2; 
TAT, Protein C, Protein S, D-Dimer, 
Fibrinogen 
immunolog., 
von 
Willebrand factor  
[…] 
12.5 Amendment 4 
12.5.1 
Overview of changes Amendment 4 (Version 5.0) 
The changes in this amendment relate to the specification of one Inclusion criterion (the 
timepoint of an increased hsCRP measurement) and the evaluation of additional laboratory 
parameters (section 4.14) as well as additional central laboratory. Changes of the In- and Exclusion 
criteria require the approval of the ethics committee and the competent authority (BfArM). The 
changes in this amendment relate to t. The changes modify one inclusion criterion but are not 
relevant for safety issues. 
 
Specification of the inclusion criterion:  In- and exclusion criteria of the trial (4.11 / 4.11.1) 
Original wording Synopsis and chapter 4.11.1 
 
increased hsCRP (> 2 mg/l but < 10 mg/l) and/or increased PAI 1 (> 15 ng/ml)  
 
Revised wording: Synopsis and chapter 4.11.1 
 
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 


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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) 
 
Specification and addition of laboratory  
Original wording:  Synopsis, Secondary and other objectives (section 2.3),  
 
coagulation: von Willebrand-Factor, Fibrinogen, Prothrombinfragment 1 + 2, D-Dimer, 
Protein C, Protein S, TAT 
 
Additional wording: Synopsis, Secondary and other objectives (2.3) 
 
coagulation: von Willebrand-Factor, Fibrinogen, Prothrombinfragment 1 + 2, D-Dimer, 
Protein C, Protein S, TAT, Quick, aPTT 
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Addition of assessment of cardiovascular marker in Visit 1 and Visit 6 (section 4.13.2 and 4.13.5) 
and addition of Visit schedule (section 4.12.2). 
 
Addition of central laboratory for evaluation of cardiovascular marker (section 4.14.2) 
Universitäres Herzzentrum Hamburg 
Biomarker Labor (AG Zeller) 
Gebäude O48/4. OG 
Martinistrasse 52 
20246 Hamburg / Germany 
Phone:   
+49(0) 40 7410 56575 
Fax: 
+49 (0) 40 7410 40194 
NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Expansion of the screening period to 28 days. Changes were made in the following sections:  
Original wording: section 4.2.2, section 4.12.2 and section 4.13.1 
Visit  
specification 
V0 
screening 
V1 
baseline 
V2 
 
V3  
telephone 
V4 
 
V5  
telephone 
V6 
EOT 
week 
day -10 
day 0 
2 
4 
8 
12 
20 
timeframe 
 
+/- 4 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
 
Revised Wording: section 4.2.2, section 4.12.2 and section 4.13.1 
Visit  
specification 
V0 
screening 
V1 
baseline 
V2 
 
V3 
telephone 
V4 
 
V5 
telephone 
V6 
EOT 
week 
day -28 
day 0 
2 
4 
8 
12 
20 
timeframe 
 
+/- 4 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 


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12.7 Amendment 5 
12.7.1 
Overview of changes Amendment 5 (Version 6.0) 
The changes in this amendment relate to the extended trial duration for 80 of 188 patients 
included into the study. Due to the extension of treatment, a second primary endpoint variable 
will be included into the protocol.  
Changes of the trial duration require the approval of the ethics committee and the competent 
authority (BfArM). The changes did not modify inclusion or exclusion criteria however, the subject 
information and informed consent form were affected. The changes are not relevant for safety 
issues. 
 
Synopsis  
Original wording Synopsis Treatment period and Timeplan (4.1) 
Treatment period 
20 weeks 
Time plan 
First patient first visit (FPFV): 
January 2014 
Last patient first visit (LPFV): 
May 2016 
Last patient last visit (LPLV): 
February 2017 
DataBase Lock: 
December 2017 
Final study report: 
March 2018 
 
Revised wording Synopsis Treatment period and Timeplan:  
Treatment period 
20 weeks  
+ additional 32 weeks (extension study for 80 patients) 
Time plan 
First patient first visit (FPFV): 
April 2015 
Last patient first visit (LPFV): 
July 2017 
Last patient last visit (LPLV): 
August 2018 
Database Lock: 
December 2018 
Final study report: 
April 2019 


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Original wording Synopsis primary objectives and 2.2: 
Study objectives 
Primary objectives 
Difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 20 weeks 
treatment between rivaroxoban and aspirin therapy  
 
 
Revised wording Synopsis primary objectives and 2.2:  
Study objectives 
Primary objectives 
Difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 20 weeks 
treatment between rivaroxoban and aspirin therapy  
Additionally the difference of arterial stiffness after the end of the extension 
study (week 52) between rivaroxoban and aspirin therapy will be evaluated. 
 
 
Original wording Synopsis secondary objectives and 2.3: 
Study objectives 
Secondary objectives 
 
change of peripheral skin microcirculatory function (measured by 
laserdopplerfluxmetry; LDF) 
 
LDF baseline 
 
LDF after ischemia (endothelial function) 
 
arterial stiffness measured by Mobilograph (IEM Inc.) 
 
laboratory markers for endothelial function  
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
Microalbuminuria, eGFR 
 
composite of biomarkers of inflammation  
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8 
 
side effects: major bleeding according to ISTH, symptomatic 
thromboembolic events 
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C 
 
coagulation: von Willebrand-Factor, Fibrinogen, 
Prothrombinfragment 1 + 2, D-Dimer, Protein C, Protein S, TAT, 
Quick, aPTT 
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 


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Revised wording Synopsis secondary objectives and 2.3:  
Study objectives 
Secondary objectives 
 
change of peripheral skin microcirculatory function (measured by 
laserdopplerfluxmetry; LDF) after 20 and 52 weeks of treatment 
 
LDF baseline 
 
LDF after ischemia (endothelial function) 
 
arterial stiffness measured by Mobilograph (IEM Inc.) after 20 weeks 
of tretament 
 
laboratory markers for endothelial function  
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
Microalbuminuria, eGFR 
 
composite of biomarkers of inflammation  
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8 
 
side effects: major bleeding according to ISTH, symptomatic 
thromboembolic events 
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C 
 
coagulation: von Willebrand-Factor, Fibrinogen, 
Prothrombinfragment 1 + 2, D-Dimer, Protein C, Protein S, TAT, 
Quick, aPTT 
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Additional secondary objective for extension period: 
 
Difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 52 
weeks treatment 
 
 
Original wording Synopsis Study endpoints and 6.1.1 and 6.1.2:  
Study end points 
Primary variable 
 
change of maximal postischemic forearm blood flow during reactive 
hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at 
EOT 


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MicroVasc-DIVA_study protocol_final_V6.0_07.07.2016 
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Study end points 
Secondary variables 
 
change of the area under the postischemic FBF curve over 10 cycles 
of intermittent venous congestion (compared to baseline) 
 
maximal postischemic skin blood flow (arbitrary units) during 
reactive hyperaemia after 5 min of forearm ischemia at EOT using 
LDF 
 
change of postischemic skin blood flow (compared to baseline) using 
LDF 
 
Pulse wave velocity at EOT compared to baseline 
 
laboratory parameter (see above) at EOT 
 
 
Revised wording Synopsis Study Endpoints and 6.1.1 and 6.1.2:  
Study end points 
Primary variable 
 
change of maximal postischemic forearm blood flow during reactive 
hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at 
20 weeks 
 
Additional primary variable for extension period: 
 
pulse wave velocity at EOT after 52 weeks 
Study end points 
Secondary variables 
 
change of the area under the postischemic FBF curve over 10 cycles 
of intermittent venous congestion (compared to baseline) after 20 
weeks and EOT Extension 
 
maximal postischemic skin blood flow (arbitrary units) during 
reactive hyperaemia after 5 min of forearm ischemia at 20 weeks and 
EOT Extension using LDF 
 
change of postischemic skin blood flow (compared to baseline) using 
LDF 
 
Pulse wave velocity at 20 weeks compared to baseline 
 
laboratory parameter (see above) at 20 weeks and EOT Extension 
 
Additional secondary variable for extension period: 
 
change of maximal postischemic forearm blood flow during reactive 
hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml) at 
EOT after 52 weeks (EOT Extension) 
 


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Original wording Synopsis Statistical methods and 3.5: 
Statistical methods 
Efficacy:  
The statistical analysis will be done in the intention to treat and per protocol 
set. The primary parameter will be the maximum FBF at EOT (assessed with 
venous occlusion plethysmography after forearm ischemia) using an analysis 
of covariance (ANCOVA) controlling for baseline FBF. Independent t-test will 
be used to test the parameters between the groups at the time point baseline 
and EOT as well as the change between baseline and EOT.  
 
Safety:  
Analysis of bleeding events and safety parameters is required. 
Statistical methods 
Sample Size Estimation: 
The primary variable is change of forearm blood blow with venous occlusion 
plethysmography (ΔFBF) after forearm ischemia after 20 weeks treatment. 
The sample size calculation is based on the following assumptions: 
H0: ΔFBFRiva ≤ ΔFBFASS 
H1: ΔFBFRiva > ΔFBFASS 
 
 
Type I error: α = 0.05, one-tailed t-test for independent samples 
 
Power: 1-ß = 0.90 
 
Estimated dropout rate : 25 % 
 
Minimum of expected clinical relevant difference between the 
groups in changes of maximal forearm blood flow (ΔFBF) = 1.2 
ml/100ml with an estimated standard deviation (SD) of σ = 2.4 
ml/100ml [Pistrosch, F. et al. Diabetes Care 27: 484-490, 2004] 
 
Sample size should be N = 188 Patients (N1/2 = 94 patients per arm) for a 
valid number of 141 patients for per protocol analysis. This sample size may 
also provide enough power for further analyses. 
 
 
Revised wording Synopsis Statistical methods and 3.5: 
 


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MicroVasc-DIVA_study protocol_final_V6.0_07.07.2016 
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Statistical methods 
Efficacy:  
The statistical analysis will be done in the intention to treat and per protocol 
set. The primary parameter will be the maximum FBF at 20 weeks (assessed 
with venous occlusion plethysmography after forearm ischemia) controlling 
for baseline FBF and the Pulse Wave Velocity (PWV) at EOT (extended 
treatment period after 52 weeks) assessed with a sphygmograph 
(Mobilograph®, IEM) using an analysis of covariance (ANCOVA). Independent 
t-test will be used to test the parameters between the groups at the time 
point as well as the change between baseline and 20 weeks of treatment.  
Additionally, measurements will be also compared to an extended treatment 
up to 52 weeks (EOT Extension). 
 
Safety:  
Analysis of bleeding events and safety parameters is required. 
Statistical methods 
Sample Size Estimation: 
[…] 
 
Additionally, the second primary variable is the difference of PWV between 
treatment groups at EOT Extension (after 52 week of treatment). The sample 
size calculation is based on the following assumptions:  
 
H0: PWVRiva=PWVASS 
H1: PWVRiva≠PWVASS 
 
Type I error: α = 0.05, t-test for independent samples  
 
Power: 1-ß = 0.80  
 
Estimated dropout rate : 20 %  
 
Minimum of expected clinical relevant difference between the 
groups in PWV = 0.7 m/s with an estimated standard deviation (SD) 
of σ = 1.0 m/s  
 
Sample size should be N=80 patients (40 patients per arm) for a valid number 
of 66 patients for per protocol analysis. 
 
In summary the necessary sample size would be N=188 patients for the study 
up to week 20 including 80 patients for the extension up to week 52. 
 
 


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Additional wording Introduction (section 1): 
[…] 
Previous studies demonstrated a fast response of forearm blood flow to interventions (10) 
however; forearm blood flow is marker of endothelial (dys)function and did not measure 
structural changes of large conductive arteries or the microvascular bed. In contrast to forearm 
blood flow changes which occur within a few weeks after an intervention, these structural 
adaptation of the vascular wall usually require a longer time span.  
There are few investigational studies of microvascular skin blood flow in patients with type 2 
diabetes which described significant changes during treatment with glucose lowering drugs after 
36 weeks (11). However; an extrapolation from the capillary bed to structural changes of large 
arteries should be difficult due to the different anatomy of the vascular wall. Pulse wave velocity 
(PWV) as marker of arterial stiffness is an independent predictor of cardiovascular events and 
mortality (12, 13). 
Changes of PWV during medical intervention usually required a longer time span. This had been 
demonstrated in studies with antihypertensive agents (14) as well as in studies with lipid lowering 
medication (15) which required treatment periods of at least 12 months to demonstrate an 
improvement of PWV. We believe that a structural remodeling of the vascular wall in the present 
investigation also need that period of time. 
 
Changed wording of organizational and administrative aspects (section 3.2): 
Coordinating Principal Investigator 
PD Dr. Frank Pistrosch 
GWT, Study centre, Blasewitzer Str. 43, 01307 
Dresden 
Tel.: 
+49 351 4400580 
Fax No: 
+49 351 4400581 
 
Deletion of Substitute Coordination investigator. 
 
Original wording Treatment groups (section 4.2.1): 
Arm A: treatment group 
Rivaroxaban  
Patients will receive Rivaroxaban 5 mg b.i.d. for the 
duration of 20 weeks. 
Arm B: control group  
aspirin  
Patients will receive treatment with aspirin 100 mg q.d. for 
the duration of 20 weeks.   
7 study visits will be performed during the study. Subjects are obliged to come to the study center 
for 5 visits. Visits will take place at week –2 (screening – V1), day 0 (randomization – V1), at week 


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2 (V3), 4 (V4), 8 (V5), 12 (safety/compliance – V6) and week 20 (end of treatment – V7). Visit 4 
and Visit 6 will be conducted as a telephone visit.  
Measurements of FBF, LDF and pletysmography at baseline-visit and EOT-visit can be done up to 
3 days after the visits in the corresponding study location that provides these measurements. 
Patients will be informed of the procedure by the physician. 
 
Revised wording Treatment groups (section 4.2.1): 
Arm A:treatment group 
Rivaroxaban  
Patients will receive Rivaroxaban 5 mg b.i.d. for the 
duration of 20 weeks. 
Additionally, 80 patients of the study population receive 
the Rivaroxaban 5 mg b.i.d. for a duration of 52 weeks 
(extension treatment). 
Arm B: control group  
Aspirin  
Patients will receive treatment with Aspirin 100 mg q.d. for 
the duration of 20 weeks.   
Additionally, 80 patients of the study population receive 
the Aspirin 100 mg q.d. for a duration of 52 weeks 
(extension treatment). 
 
7 study visits will be performed during the study. Subjects are obliged to come to the study center 
for 5 visits. Visits will take place at week –2 (screening – V0), day 0 (randomization/baseline – V1), 
at week 2 (V2), 4 (V3), 8 (V4), 12 (safety/compliance – V5) and week 20 (end of treatment for the 
first study period with vascular function test – V6).). Visit 3 and Visit 5 will be conducted as a 
telephone visit.  
Additionally, 80 patients of the study population will perform 7 additional visits during the 
extension period. These visits will start after week 20. Patients attending the extension period will 
perform at all 14 study visits for 8 of these visits they will come to the study center whereas at all 
6 visits are performed as telephone visits. The additional visits take place at week 24 (V7), week 
28 (V8), week 32 (V9), week 36 (V10), week 40 (V11), week 44 (V12) and week 52 (end of 
treatment extension - V13). Visit 7, 9, 11 and 12 will be conducted as a telephone visit. 
Measurements of FBF, LDF and pletysmography at baseline-visit, visit week 20 (V6) and EOT-visit 
(V13) can be done up to 3 days after the visits in the corresponding study location that provides 
these measurements. Patients will be informed of the procedure by the physician. 
 


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Additional wording Visit schedule (section 4.2.2): 
Visit  
specification 
V7 
telephone 
V8 
 
V9 
telephone 
V10 
 
V11 
telephone 
V12 
telephone 
V13 
EOT 
week 
24 
28 
32 
36 
40 
44 
52 
timeframe 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
+/- 2 d 
 
Original Flowchart (section 4.2.2): 
 
 
Changed Flowchart (section 4.2.2): 
 


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Additional Visit description (section 4.12.3): 
VISIT 
V7 (TV) 
V8 
V9 (TV) 
V10 
V11 (TV) 
V12 (TV) 
V13 
WEEK 
24 
(+/- 2 d) 
28 
(+/- 2 d) 
32 
(+/- 2 d) 
36 
(+/- 2 d) 
40 
(+/- 2 d) 
44 
(+/- 2 d) 
52 
(+/- 2 d) 
 
TREAT 
TREAT 
TREAT 
TREAT 
TREAT 
TREAT 
EOT 
EXTENSIO
N 
STUDY INFORMED CONSENT 
FOR EXTENSION PERIOD 
 
 
 
 
 
 
 
VITAL SIGNS (RADIAL PULSE, 
BLOOD PRESSURE) 
 
 
 
 
 
 
 
BODY HEIGHT 
 
 
 
 
 
 
 
WAIST/HIP CIRCUMFERENCE 
BODY WEIGHT 
 
 
 
 
 
 
 
CONCOMITANT MEDICATION/ 
ACUTE DISEASES 
 
 
 
 
 
 
 
ARTERIAL STIFFNESS 
 
 
 
 
 
 
 
FOREARM BLOOD FLOW 
 
 
 
 
 
 
 
INFLAMMATION LABORATORY(1) 
 
 
 
 
 
 
 
SAFETY LABORATORY(3) 
 
 
 
 
 
 
 
EFFICACY LABORATORY(2) 
 
 
 
 
 
 
 
METABOLIC MARKER(4) 
 
 
 
 
 
 
 
LDF INVESTIGATIONS 
 
 
 
 
 
 
 
ADVERSE EVENT REPORTING 
 
 
 
 
 
 
 
DISPENSING/RETURN OF 
MEDICATION/ 
DRUG ACCOUNTABILITY 
 
 
 
 
 
 
 
 
Additional wording of visit description (section 4.14): 
Visit 7, Visit 9, Visit 11 and Visit 12 – Extended treatment phase (telephone visits) 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
assessment of adverse events  
 
questioning for concomitant medication  
Visit 8 and Visit 10 – Extended treatment phase on site visit 
The following actions/measures will be performed for patients of Arm A and Arm B: 


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 
assessment of adverse events 
 
questioning for concomitant medication 
 
clinical examination for potential bleeding sides 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
return of study medication and drug accountability 
 
dispense of new study medication 
 
safety laboratory parameter 
Visit EoT of extended treatment period (end of study visit) 
The following actions/measures will be performed for patients of Arm A and Arm B: 
 
questioning for adverse events and concomitant medication 
 
measurement of blood pressure and heart rate (after resting for at least 3 min in supine 
position) 
 
measurement of forearm blood flow 
 
laserdopplerfluxometry (LDF) 
 
measurement of arterial stiffness 
 
efficacy laboratory parameter for endothelial function and coagulation: 
 
efficacy laboratory for composite of biomarkers of inflammation  
 
safety laboratory parameter 
 
assessment of metabolic marker  
 
return of study drug / drug accountability 
 
advice patient for further treatment after end of study 
 
Original wording Dispensing of IMP (section 5.7): 
Visit 
Week 
V0 
day -28 
V1 
day 0 ±4d 
V2 
2 ±2d 
V3 (TV) 
4 ±2d 
V4 
8 ±2d 
V5 (TV) 
12 ±2d 
V6 
20 ±2d 
Dispensed 
medication 
Rivaroxa-
ban 
- 
90 
(3 Packs) 
210 
(7 Packs) 
- 
330 
(11 Packs) 
- 
- 
630 
aspirin 
- 
50 
(1 Pack) 
50 
(1 Pack) 
- 
50 
(1 Pack) 
- 
- 
150 


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Revised wording Dispensing of IMP (section 5.7): 
Visit 
Week 
V0 
day -28 
V1 
day 0 ±4d 
V2 
2 ±2d 
V3(TV) 
4 ±2d 
V4 
8 ±2d 
V5(TV) 
12 ±2d 
V6 
20 ±2d 
Dispensed 
medication 
Rivaroxa-
ban 
- 
90 Tabl. 
(3 Packs) 
210 Tabl. 
(7 Packs) 
- 
330 Tabl. 
(11 
Packs) 
- 
270 Tabl. 
(9 Packs) 
630 (+270) 
Tabl. = 21 
(+9) Packs 
Aspirin 
- 
50 Tabl. 
(1 Pack) 
50 Tabl. 
(1 Pack) 
- 
50 Tabl. 
(1 Pack) 
- 
100 Tabl. 
(2 Packs) 
150 (+100) 
Tabl. = 3 
(+2) Packs 
TABLE 12: DRUG DISPENSE FOR FIRST TREATMENT PERIOD (1 PACK RIVAROXABAN CONTAINING 30 TABLETS; 1 PACK ASPIRIN 
CONTAINING 50 TABLETS);  
 
OPTIONAL: DISPENSE OF IMP AT V6 FOR PATIENTS PARTICIPATIONS TO EXTENDED TREATMENT PERIOD 
 
Visit 
Week 
V7 (TV) 
24 ±2d 
V8 
28 ±2d 
V9 (TV) 
32 ±2d 
V10 
36 ±2d 
V11 
(TV) 
40 ±2d 
V12 
(TV) 
44 ±2d 
V13 
52 ±2d 
Dispensed 
medication 
Rivaroxa-
ban 
- 
210 Tabl. 
(7 Packs) 
- 
510 Tabl. 
(17 
Packs) 
- 
- 
- 
720 Tabl. = 
24 Packs  
Aspirin 
- 
50 Tabl.  
(1 Pack) 
- 
150 Tabl. 
(3 Packs) 
- 
- 
- 
200 Tabl. = 
4 Packs 
TABLE 13: DRUG DISPENSE FOR EXTENDED TREATMENT PERIOD (80 OF 188 PATIENTS) (1 PACK RIVAROXABAN CONTAINING 
30 TABLETS; 1 PACK ASPIRIN CONTAINING 50 TABLETS) 
 
 
 
 


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REFERENCES 
1. Grundy, S.M. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin. Endocrinol. 
Metab. 2007. 92:399-404. 
2. Gawaz, M., Langer, H. and May, A.E. Platelets in inflammation and atherogenesis. J.Clin.Invest 
. 2005. 115:3378-84. 
3. Randriamboavonjy, V. and I., Fleming. Platelet function and signaling in diabetes mellitus. 
Curr.Vasc.Pharmacol. 2012. 10:532-38. 
4. M.R., Patel, et al. ROCKET AF Investigators: Rivaroxaban versus warfarin in nonvalvular atrial 
fibrillation. N Engl J Med. . 2011. 365(10):883-91. 
5. Mega, J.L., et al. ATLAS ACS 2–TIMI 51 Investigators: Rivaroxaban inpatients with a recent acute 
coronary syndrome. N Engl J Med. 2012. 366(1):9-19. 
6. Wolzt, M., et al. Open-label, randomized study of the effect of rivaroxaban with or without 
acetylsalicylic acid on thrombus formation in a perfusion chamber. Thromb Res. 2013. 132(2):240-
7. 
7. Costopoulos, C., et al. Novel oral antico-agulants in acute coronary syndrome. Int J Cardiol. 
2013. 167(6):2449-55. 
8. Wilkinson, I.B. and Webb, D.J. Venous occlusion plethysmography in cardiovascular research: 
methodology and clinical applications. Br J Clin Pharmacol. 2001. 52(6):631-46. 
9. Perticone, F., et al. Prognostic significance of endothelial dysfunction in hypertensive patients. 
Circulation. 2001. 104(2):191-6. 
10. Pistrosch, F., et al. In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates 
endothelial dysfunction independent of glucose control. Diabetes Care. 2004. 27(2):484-90. 
11. Pistrosch F et al. Effects of insulin glargine versus metformin on glycemic variability, 
microvascular and beta-cell function in early type 2 diabetes. Acta Diabetol. 2013 Aug;50(4):587-
95 
12. van Sloten TT, et al. Carotid stiffness is associated with incident stroke: a systematic review 
and individual participant data meta-analysis. J Am Coll Cardiol. 2015 Nov 10;66(19):2116-25.  
13. Cavalcante JL, et al. Aortic stiffness: current understanding and future directions. J Am Coll 
Cardiol. 2011 Apr 5;57(14):1511-22 
14. Peng F, et al. The impact of angiotensin receptor blockers on arterial stiffness: a meta-analysis. 
Hypertens Res. 2015 Sep;38(9):613-20.  
15. Davenport C,et al. The Effects of Atorvastatin on Arterial Stiffness in Male Patients with Type 
2 Diabetes. J Diabetes Res. 2015;2015:846807 
16. Baigent, C., Blackwell, L. and Collins, R. et al. Aspirin in the primary and secondary prevention 
of vascular disease: collaborative meta-analysis of individual participant data from randomised 
trials. Lancet. 2009. 373:1849-60. 


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17. Seshasai, S.R., Wijesuriya, S. and Sivakumaran, R. et al. Effect of aspirin on vascular and 
nonvascular outcomes: meta-analysis of randomized controlled trials . Arch.Intern.Med. 2012. 
172:209-16. 
18. Mega, J.L., et al. Comparison of the efficacy and safety of two rivaroxaban doses inacute 
coronary syndrome (from ATLAS ACS 2-TIMI 51). Am J Cardiol. 2013. 112(4):472-8. 
19. American Diabetes Association. Executive Summary: Standards of Medical Care in Diabetes. 
Diabetes Care 2011; 34: 
 
 
 
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan (SAP) 
MicroVasc-DIVA 
 
Version 1.0 
 
 
 
Confidential                                          Version 1.0, September 19, 2018  
page 1 of 38 
 
  
Microvascular and anti-inflammatory effects of Rivaroxaban compared to 
low dose aspirin in type 2 diabetic patients with very high cardiovascular 
risk and subclinical inflammation (MicroVasc-DIVA) 
 
Statistical Analysis Plan (SAP) 
 
 
Primary trial objective: 
Evaluation of efficacy defined as the difference of change 
of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia 
after 20 weeks treatment between rivaroxoban and aspirin 
therapy.   
 
Additionally the difference of arterial stiffness after 52 
weeks treatment (extension study) between rivaroxoban 
and aspirin therapy will be evaluated. 
 
Trial design: 
Multicenter, prospective, active controlled, 
randomized, 2 parallel arms, open 
interventional clinical trial 
 
Investigational 
Rivaroxaban 
Comparator: 
Aspirin 
medicinal product: 
Clinical study phase: 
Phase IIIb 
Date: 
19.09.2018 
EudraCT No.: 
  2014-001305-41 
Version: 
1.0 
Principal Coordinating 
PD Dr.  
Sponsor: 
GWT-TUD GmbH 
Investigator: 
Frank Pistrosch 
Dresden - 
Germany 
Statistician: 
Dr. Dorothea Schipp 
 
  
 
Confidential 
 
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation. Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
 
 
 
This SAP is produced on a word-processing system and bears no signatures. 
 
The approval of the SAP is documented in a separate Signature Document. 
 
  


Statistical Analysis Plan (SAP)
MicroVasc-DIVA
Signatures
Version 1.0
Sponsor:
GWT-TUD GmbH
Freiberger Strasse 33
01067 Dresden/Germany
Phone: +49 (0) 351 25933 100
Fax:
+49 (0) 351 25933 111
E-mail: contact@gwtonline.de
Signature of Sponsor‘s Representative
f__)
/
E‘b
c-rc-. -j ijEj
%o.
Date
Printed Name of Representative
Signature of Principle Coordinating
Investigator
Printed Name of Principle Coordinating
1 nvestigator
. 1/iP
Signature of statisticiaij t
. co4L cl4tpp
Printed Name ofStatistician
II
Date
&I.3J
Date
Confidential
Version 1.0, September 19, 2018
page 2of38


Statistical Analysis Plan (SAP)
MicroVasc-DIVA
Signatures
Version 1.0
Sponsor:
GWT-TUD GmbH
Freiberger Strasse 33
01067 Dresden/Germany
Phone: +49 (0) 351 25933 100
Fax:
+49 (0) 351 25933 111
E-mail: contact@gwtonline.de
Signature of Sponsor‘s Representative
Date
Printed Name of Representative
Signature of Principle Coordinating
Investigator
‘:7)3
Printed Name of Principle Coordinating
)nvestigator
Signature of Statistician
Printed Name ofStatistician
Date
Date
Confidential
Version L0, September 19, 2018
page 2 of 38


 
 
 
Statistical Analysis Plan (SAP) 
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Version 1.0 
 
 
 
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Table of Contents 
Signatures ..................................................................................................................................................... 2 
1 
Rational of the statistical analysis plan ................................................................................................. 6 
2 
Investigational Plan ............................................................................................................................... 6 
2.1 
Study design .................................................................................................................................. 6 
2.2 
Visit schedule ................................................................................................................................ 7 
2.3 
Study objectives ............................................................................................................................ 8 
2.3.1 
Primary objectives ................................................................................................................. 8 
2.3.2 
Secondary objectives ............................................................................................................ 9 
2.3.3 
Explorative study objective(s) ............................................................................................... 9 
2.4 
Sample size calculation ................................................................................................................. 9 
3 
Analysis Sets ........................................................................................................................................ 10 
3.1 
Full Analysis Set (FAS) ................................................................................................................. 10 
3.2 
Safety Analysis Set (SAF) ............................................................................................................. 10 
3.3 
Per-Protocol Set (PPS) ................................................................................................................. 10 
4 
Analysis Variables ................................................................................................................................ 10 
4.1 
Demographics ............................................................................................................................. 10 
4.2 
Medical history ........................................................................................................................... 10 
4.3 
Concomitant medication and acute diseases ............................................................................. 11 
4.4 
Drug administration .................................................................................................................... 11 
4.5 
Efficacy Variables ........................................................................................................................ 11 
4.6 
Laboratory Variables ................................................................................................................... 11 
4.7 
Safety Variables ........................................................................................................................... 12 
4.7.1 
Vital Signs ............................................................................................................................ 12 
4.7.2 
Safety laboratory ................................................................................................................. 12 
4.7.3 
Adverse Events and Serious Adverse Events ...................................................................... 12 
4.8 
Definition of derived variables .................................................................................................... 12 
4.8.1 
Primary variable .................................................................................................................. 12 
4.8.2 
Secondary variables ............................................................................................................ 13 
5 
Efficacy Endpoints ............................................................................................................................... 13 
5.1 
Primary endpoint ........................................................................................................................ 13 
5.2 
Secondary endpoints .................................................................................................................. 13 
6 
Statistical Methods ............................................................................................................................. 13 
6.1 
Data Handling .............................................................................................................................. 13 
6.2 
Descriptive or summary statistics ............................................................................................... 13 
6.3 
Hypothesis Testing ...................................................................................................................... 13 
6.4 
Subject Disposition ...................................................................................................................... 14 
6.5 
Demographics ............................................................................................................................. 14 


 
 
 
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6.6 
Medical History ........................................................................................................................... 14 
6.7 
Concomitant medication and Acute Diseases ............................................................................ 15 
6.8 
Compliance ................................................................................................................................. 15 
6.9 
Treatment exposure and observation period ............................................................................. 15 
6.10 
Analysis of baseline characteristics ............................................................................................. 15 
6.11 
Analysis of Efficacy Endpoints ..................................................................................................... 15 
6.11.1 
Analysis of Primary Endpoint .............................................................................................. 15 
6.11.2 
Analysis of Secondary Endpoints ........................................................................................ 16 
6.12 
Analysis of Safety Data ................................................................................................................ 16 
6.12.1 
Vital Signs ............................................................................................................................ 16 
6.12.2 
Safety Laboratory Measurements ...................................................................................... 16 
6.12.3 
Adverse Events .................................................................................................................... 16 
6.12.4 
Bleedings ............................................................................................................................. 17 
6.13 
Interim analysis ........................................................................................................................... 17 
6.14 
Reporting conventions ................................................................................................................ 17 
7 
Appendix: Mock-Up tables, figures and listings .................................................................................. 18 
7.1 
Subjects Disposition .................................................................................................................... 18 
7.2 
Demographics ............................................................................................................................. 20 
7.3 
Medical History ........................................................................................................................... 21 
7.3.1 
Medical History ................................................................................................................... 21 
7.3.2 
Concomitant medication..................................................................................................... 21 
7.3.3 
ECG and Pregnancy Test ..................................................................................................... 21 
7.4 
Compliance ................................................................................................................................. 22 
7.5 
Treatment exposure and observation period ............................................................................. 23 
7.6 
Efficacy Endpoints ....................................................................................................................... 24 
7.6.1 
Forearm Blood Flow (FBF) ................................................................................................... 24 
7.6.2 
Pulse Wave Analysis ............................................................................................................ 26 
7.6.3 
Laser Doppler fluxometry (LDF) .......................................................................................... 29 
7.7 
Efficacy Laboratory ..................................................................................................................... 30 
7.7.1 
Inflammation Laboratory .................................................................................................... 30 
7.7.2 
Laboratory for Endothelian Function and Coagulation ...................................................... 31 
7.8 
Safety Variables ........................................................................................................................... 33 
7.8.1 
Vital Signs ............................................................................................................................ 33 
7.8.2 
Safety Laboratory ................................................................................................................ 35 
7.8.3 
Adverse Events .................................................................................................................... 36 
7.8.4 
Bleedings ............................................................................................................................. 36 
 
 
 
 
 


 
 
 
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Abbreviations 
Abbreviation 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
b.i.d. 
(Bis in Die) twice a day 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CRNM 
Clinical Relevant Non-Major 
CSV 
Clinically significant value 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronical Case Report Form 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FBF 
Forearm Blood Flow 
GmbH 
Gesellschaft mit beschränkter Haftung 
ICH 
International Council for Harmonization 
LDF 
Laser Doppler Fluxometry 
LLOQ 
Lower Limit of Quantification 
Max 
Maximum 
Min 
Minimum 
OR 
Odds Ratio 
PCSV 
Potentially clinically significant value 
PPS 
Per Protocol Set 
PT 
Preferred Term 
PWA 
Pulse Wave Analysis 
PWV 
Pulse Wave Velocity 
q.d. 
(quaque die) daily 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety Analysis Set 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
STD 
Standard Deviation 
vs. 
versus 
 
 
 


 
 
 
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1 Rational of the statistical analysis plan 
 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results by pre-
specifying statistical approaches for the analysis of study. The SAP is intended to be a comprehensive 
and detailed description of strategy and statistical techniques to be used to realize the analysis of data 
for the MicroVasc-DIVA study.  
This plan may be revised during the study to accommodate protocol amendments and to adapt to 
unexpected issues in study execution or data that affect planned analyses. These revisions will be based 
on blinded review of the study and data. 
 
2 Investigational Plan 
  
2.1 
Study design 
This will be a multicenter, open-label, controlled study with two treatment arms running in parallel. A 
total of 188 patients of both genders and older than 18 years with type 2 diabetes and documented high 
cardiovascular risk and low grade inflammation will be randomly assigned to one of two treatment 
groups:   
Arm A: treatment group:  
Rivaroxaban (5 mg b.i.d for the duration of 20 weeks, 52 weeks 
               
 
 
duration for patients participating in the extension) 
Arm B: control group:   
Aspirin (100 mg q.d. for the duration of 20 weeks, 52 weeks 
               
 
 
duration for patients participating in the extension) 
 
 
 
 
Figure 1: Trial overview 
 


 
 
 
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2.2 
Visit schedule 
7 visits will be performed during the study. Visits will take place at week –2 (screening – V0), day 0 
(randomization/baseline – V1), at week 2 (V2), 4 (V3), 8 (V4), 12 (safety/compliance – V5) and week 20 
(end of treatment for the first study period with vascular function test – V6).  
 
Additionally, 80 patients of the study population will perform 7 additional visits during the extension 
period. These visits will start after week 20. Patients attending the extension period performed a total of 
14 study visits. The additional visits will take place at week 24 (V7), week 28 (V8), week 32 (V9), week 36 
(V10), week 40 (V11), week 44 (V12) and week 52 (end of treatment extension - V13).  
 
 
Table 1: Study visits and parameters 
 


 
 
 
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Table 2: Study visits and parameters of extended treatment period 
 
2.3 
Study objectives 
Objectives of this clinical trial are the in vivo assessment of microvascular function using different non-
invasive techniques and the in vitro assessment of biomarkers of endothelial damage, inflammation and 
coagulation/fibrinolysis before and after treatment with either aspirin or rivaroxaban in type 2 diabetic 
patients with high cardiovascular risk and inflammation. Furthermore possible functional interactions 
between mononuclear blood cells and platelets as well as expression of mRNA (and protein) within 
these cells before and after treatment in vitro will be assessed. 
 
2.3.1 Primary objectives 
 
Primary objective is the difference of change of forearm blood flow with venous occlusion 
plethysmography at baseline and after forearm ischemia after 20 weeks treatment between 
rivaroxoban and aspirin therapy.  
Additionally the difference of arterial stiffness after 52 weeks treatment (extension study) between 
rivaroxoban and aspirin therapy will be evaluated. 


 
 
 
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2.3.2 Secondary objectives 
 
 
Change of peripheral skin microcirculatory function (measured by Laser Doppler fluxometry; 
LDF) after 20 and 52 weeks of treatment 
 
LDF baseline  
 
LDF after ischemia (endothelial function)  
 
arterial stiffness measured by Mobilograph (IEM Inc.) after 20 weeks of treatment  
 
laboratory markers for endothelial function   
 
VCAM, ICAM, E-Selectin, ADMA, Nitrotyrosin, P-Selectin, CD40-L 
 
Microalbuminuria, eGFR  
 
composite of biomarkers of inflammation   
 
hsCRP, PAI-1, MCP-1, MMP-9, fibrinogen, leucocytes, MPO, IL-6, IL-8  
 
side effects: major bleeding according to ISTH, symptomatic thromboembolic events  
 
metabolic marker: HbA1c, lipids: triglycerides, LDL-C, HDL-C  
 
coagulation: von Willebrand-Factor, Fibrinogen, Prothrombinfragment 1 + 2, D-Dimer, Protein C, 
Protein S, TAT, Quick, aPTT  
 
cardiovascular marker: NT-proBNP, hs-Tnl, GDF-15, MR-ANP 
 
Additional secondary objective for extension period: 
 
Difference of change of forearm blood flow with venous occlusion plethysmography at baseline 
and after forearm ischemia after 52 weeks treatment. 
 
2.3.3 Explorative study objective(s) 
 
Assessment of platelet activation, measurement of mitogenic potential and risk benefit assessment. 
 
2.4 
Sample size calculation 
The first primary variable is the change of forearm blood flow with venous occlusion plethysmography 
(ΔFBF) after forearm ischemia after 20 weeks of treatment. The sample size calculation is based on the 
following assumptions:  
 
Hypotheses: 
H0: µΔFBF, Riva ≤ µΔFBF, ASS  
H1: µΔFBF, Riva > µΔFBF, ASS 
 
Application of t-test for independent samples  
 
Type I error: α = 0.05  
 
Power: 1-ß = 0.90 
 
Estimated dropout rate: 25 %  
 
Minimum of expected clinical relevant difference between the groups in changes of maximal 
forearm blood flow (ΔFBF) = 1.2 ml/100ml with an estimated standard deviation (STD) σ = 2.4 
ml/100ml  
  
Sample size should be at least N = 188 Patients (i.e. N/2 = 94 patients per arm) in order to achieve a 
valid number of 141 patients  (per protocol analysis).  
  
Additionally, the second primary variable is the difference of PWV between treatment groups at EOT 
Extension (after 52 week of treatment). The sample size calculation is based on the following 
assumptions:   
 
H0: µPWV, Riva = µPWV, ASS  


 
 
 
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 
H1: µPWV, Riva ≠ µPWV, ASS  
 
Type I error: α = 0.05, t-test for independent samples   
 
Power: 1-ß = 0.80   
 
Estimated dropout rate: 20 %   
 
Minimum of expected clinical relevant difference between the groups in PWV = 0.7 m/s with an 
estimated standard deviation (STD) of σ = 1.0 m/s   
  
Sample size should be N=80 patients (40 patients per arm) to achieve a valid number of 66 patients for 
per protocol analysis.  
  
In summary the necessary sample size would be N=188 patients for the study up to week 20 including 
80 patients for the extension up to week 52. 
 
3 Analysis Sets 
 
For the analysis, patients not fulfilling the selection criteria of the trial ("all randomized") will be 
excluded from the statistical analysis. Only casuistic reports will be provided for this group.  
3.1 
Full Analysis Set (FAS) 
For the analysis, patients not fulfilling the selection criteria of the trial ("all randomized") will be 
excluded from the statistical analysis. Only casuistic reports will be provided for this group. All other 
patients will primarily be evaluated in an intent-to-treat analysis (ITT, FAS). 
3.2 
Safety Analysis Set (SAF) 
All patients having received at least one application of study medication are generally evaluable for 
safety and will be included in the safety analysis set. 
3.3 
Per-Protocol Set (PPS) 
Analyses of efficacy endpoints will be performed on the per protocol analysis set (PPS) defined as the 
subset of subjects of the FAS who have provided complete data of the target variable of interest at the 
first (V1) and last visit (V6/V13) and who have no major protocol deviations thought to impact the 
efficacy conclusions of the trial. The classification of protocol violation as major and minor will be done 
in a data review meeting that will take place after the database is clean. 
4 Analysis Variables 
4.1 
Demographics  
The following demographic characteristics will be summarized at baseline day 0:  
age (year), gender, race. 
4.2 
Medical history  
Information on following diagnostics will be recorded at baseline day 0: 
Pregnancy Test (done yes/no), result of pregnancy test (pregnant yes/no),  
ECG (yes/no), if “yes”, ECG result (“normal”, “minor findings”, “major findings”) 
Duration of diabetes 
In- and exclusion criteria 


 
 
 
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4.3 
Concomitant medication and acute diseases  
Medications taken will be recorded from the day of informed consent until the EOT visit (day 0-week 
52). Patients who received a concomitant medication at any point of time will be counted in the 
category “yes”. All patients who did not receive any concomitant medication in the course of the study 
will be counted in the category “no”. 
4.4 
Drug administration  
The drug amount dispensed and returned will be recorded. Compliance (proportion of drug taken 
compared to drug dispensed) will be monitored. 
4.5 
Efficacy Variables 
Efficacy variables will be measured at day 0, weeks 20 and week 52: 
 
Forearm blood flow (FBF) (mL/100mL): IR baseline, IR post-ischemic, IR post-ischemic (AUC) 
 
Extension: 
Arterial stiffness measured by pulse wave analysis: Pulse wave velocity (m/s), index of augmentation 
(%), peripheric and central blood pressure systolic/diastolic (mmHg) 
 
Skin blood flow (measured by Laser Doppler): 
Depth pre-ischemic blood flow (U), depth post-ischemic blood flow (U), shallow pre-ischemic blood flow 
(U) and shallow post-ischemic blood flow (U) 
 
4.6 
Laboratory Variables 
Several categories of laboratory variables are assessed: 
 
 
screening laboratory (day -28): 
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR, HDL-C, triglycerides, 
cholesterine, urinary albumin/creatinin ratio, creatinine urine, hsCRP (if not available before 
screening visit according to in- and exclusion criteria), PAI1 (optional), urine pregnancy test  
 
 
inflammation laboratory  (day 0, weeks 20, 52):   
hsCRP, PAI-1, MCP-1, MPO, IL-6, IL-8, MMP-9, fibrinogen  
 
 
efficacy laboratory for endothelial function and coagulation (day 0, weeks 20, 52):  
VCAM-1, ICAM-1, E-Selectin, P-Selectin, CD40L, von Willebrand factor, ADMA, nitrotyrosin, 
urinary albumin/creatinin ratio, eGFR, UACR, creatinin (serum), fibrinogen (immunolog), 
prothrombin fragment 1 and 2, TAT, D-Dimer, protein C, protein S, Quick, aPTT  
 
 
metabolic markers (day 0  (if not available, using of values at screening visit), weeks 20, 52):  
HbA1c, triglycerides, LDL-C, HDL-C, total cholesterine 
 
 
cardiovascular markers: NT-proBNP, hs-Tnl, GDF-15, MR-ANP  
 
bioassay data (subpopulation at day 0 and week 20): Thrombocytic micro-particles, vasodilator-
stimulated phoshoprotein (VASP), serine-positive thrombocytes und thrombocyte proliferation 
rate. 


 
 
 
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4.7 
Safety Variables 
4.7.1 Vital Signs  
Vital Signs will be collected in terms of:  
Height (cm)  
 
 
 
 
 
 
(day 0, week 52) 
Weight (kg), BMI (kg/m2), Waist and Hip circumference (cm)  
(day 0, weeks 2, 8, 20, 28, 36, 52) 
Radial pulse (bpm), systolic/diastolic blood pressure (mmHg) 
(day 0, weeks 2, 8, 20, 28, 36, 52) 
4.7.2 Safety laboratory 
Safety laboratory variables will be monitored (day 0, weeks 2, 8, 20, 28, 36, 52):   
hemoglobin, hematocrit, ALAT, ASAT, creatinine (PAP method), blood cell count (leucocytes, 
erythrocytes, platelets), total bilirubin, sodium, potassium, eGFR  
 
4.7.3 Adverse Events and Serious Adverse Events  
Adverse events and serious adverse events will be collected from first intake of study medication and 
then at each visit until the end of the study (day 0-week 52). 
 
Bleedings (yes/no). If “yes” bleeding is classified as: 
 
major bleeding (“major”) 
 
clinically relevant non-major bleeding (“CRNM”) 
 
Patients with major bleeding at any time in the course of the study will be counted in the category 
“major”. All patients with CRNM but never “major” at any time will be counted in the category “CRNM”. 
Only patients with minor bleedings but never CRNM are counted in the category “minor”. 
 
Adverse events: 
All AE/SAE will be assessed and documented by the investigator according to the categories detailed 
below.  
 
Seriousness (yes/no): 
Patients with SAE at any time in the course of the study will be counted in the category SAE. All 
patients with AE but not serious at any time will be counted in the category AE. 
 
Intensity (mild, moderate, severe)  
 
Causal relationship (yes/no)  
 
Action taken with study treatment (drug withdrawn, drug interrupted, dose reduced, dose not 
changed, dose increased, not applicable, unknown) 
 
Other specific treatments (none, remedial drug therapy, other) 
 
Outcome (recovered/resolved, recovered/resolved with sequelae, not recovered/not resolved, 
life-threatening, fatal, unknown)  
4.8 
Definition of derived variables 
4.8.1 Primary variable 
 
∆FBF:  
∆FBF (ml/100ml) will be composed of 5 IR baseline measurements and 8 measurements of post-
ischemic blood flow. Repeated measurements for IR baseline per visit will be summarized by arithmetic 
mean.  
Changes in FBF (ml/100ml) will be calculated as IR post-ischemic – IR baseline (mean).  
  


 
 
 
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4.8.2 Secondary variables 
 
Skin blood flow (LDF): 
∆ Depth: 
 post-ischemic blood flow (depth) – pre-ischemic blood flow (depth) 
∆ Shallow: 
 post-ischemic blood flow (shallow) – pre-ischemic blood flow (shallow) 
 
5 Efficacy Endpoints 
 
5.1 
Primary endpoint 
 
Comparison of treatment groups for ∆FBF at week 20   
Additional primary variable for extension period:  
 
Comparison of treatment groups for pulse wave velocity at week 52 
 
5.2 
Secondary endpoints 
 
Comparisons of groups and changes from baseline per treatment group for the following 
variables:  
o PWV at week 52 
o Maximal difference between baseline and post-ischemic skin blood flow FBF 
o Change of area under the FBF curve over 10 cycles of venous congestion (compared to 
baseline/day 0) at week 20 and EoT extension  
o Index of augmentation at weeks 20 and 52 
o pulse wave velocity at 20 weeks and EoT Extension compared to baseline  
o change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 
min of forearm ischemia (FBF max. ml/100ml) at EOT after 52 weeks (EOT Extension) 
o laboratory parameters (see above) at weeks 20 and 52   
6 Statistical Methods 
6.1 
Data Handling 
Concentrations below the lower limit of quantification will be set to zero by laboratory.  In case a set of 
continuous data contains zeros, an analysis in log scale (as described in 6.3) will be omitted.  
6.2 
Descriptive or summary statistics 
All continuous variables will be summarized by treatment group using the following statistics: n (non-
missing sample size), number of missing values (Missing), arithmetic mean (Mean), standard deviation, 
(STD), median (Median), maximum (Max) and minimum (Min).  
Tables for original (untransformed) data will be provided as well as tables for differences from baseline 
by visit. Boxplots will be presented for illustration. 
For nominal or categorical data, frequencies and percentages (based on the non-missing sample size) 
will be tabulated for each category.  
6.3 
Hypothesis Testing 
Unless otherwise specified all hypotheses will be tested at a 5% level of significance against two-sided 
alternative hypotheses.  


 
 
 
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Continuous variables will be analyzed by the following test procedures: 
First of all the assumption of normally distributed data will be checked with Shapiro-Wilk test by 
treatment group. If the hypothesis of normally distributed data cannot be rejected for both treatment 
groups treatments will be compared by an ANCOVA procedure which includes “treatment” as the main 
factor and “baseline value” as covariate. T-Tests for independent samples will be used to compare 
groups at baseline. 
In the event that the normality assumption is not warranted, data will be log-transformed and normality 
assumption of the transformed data will be checked by Shapiro-Wilk test. In case of non-rejection of the 
hypothesis of normally distributed data for both treatment groups, ANCOVA procedure and t-tests as 
described above will be performed on the basis of log-transformed data.  
Point estimates and 95% CI of the difference in (adjusted) mean change from baseline will be provided if 
data are evaluated on basis of an ANCOVA procedure. 
Otherwise Mann-Whitney´s-U test on the basis of original data will be applied for comparison of groups 
at baseline. Mann-Whitney´s-U test on the basis of intra-individual differences to baseline will be 
applied for treatment comparison per visits after baseline. Wilcoxon´s signed rank test will be applied to 
evaluate changes from baseline per treatment group.  
Categorical variables with 2 categories will be analyzed using Fisher´s exact test (with Yates correction) 
to compare proportions between treatment groups. Variables with more than 2 categories will be 
compared by Pearson’s Chi-square test. Additionally for each category, the proportions of treatment 
groups are compared using an (asymptotic) z test. Significant differences in proportions will be flagged, 
p-values for the z-test will not be shown. 
Missing values will not be imputed.  
If necessary, modifications of this general procedure will be described in the following sections of 
chapter 6. 
6.4 
Subject Disposition 
Subject disposition analyses will be based on all enrolled subjects. The following summaries will be 
provided:  
 
Subject disposition, as the number of subjects screened, randomized and completed treatment 
will be summarized.  
The following listings will be provided:  
 
Listing of subjects withdrawn or dropped out: date of baseline visit, date of the last visit,  
discontinued by reason 
 
If there are any protocol deviations, including violation of inclusion/exclusion criteria, and post-
enrollment deviations which will impact assessment of efficacy and safety endpoints, a listing 
will be generated. 
6.5 
Demographics 
Demographic characteristics will be summarized in total and by treatment groups (and center) on the 
basis of FAS, PPS and SAF. Listings of demographic characteristics will be presented. 
6.6 
Medical History  
Medical history will be summarized for FAS, PPS and SAF by each treatment group. Frequency tables will 
be provided for pregnancy test and ECG results.  


 
 
 
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6.7 
Concomitant medication and Acute Diseases  
Medications taken will be recorded from the day of informed consent until the EOT visit (day 0-week 
52). Patients who received a concomitant medication at any point of time will be counted in the 
category “yes”. All patient who did not receive any concomitant medication in the course of the study 
will be counted in the category “no”. Number and proportion of subjects taking prior/concomitant 
medication will be summarized. 
6.8 
Compliance 
The overall treatment compliance will be calculated as: [1- (overall amount of drug dispensed – overall 
amount of drug returned) / (overall amount of drug dispensed)]x 100%. 
In addition to the overall compliance, the treatment compliance will be presented by the following 
specific ranges for each treatment group: <50%, <80%,  ≥80%.  
Analysis of compliance will be based on FAS. 
6.9 
Treatment exposure and observation period 
The duration of treatment exposure period during the study is calculated as:  
(last drug administration date – first drug administration date) + number of days to next visit after last 
drug administration. 
The duration of observation period during the study is calculated as:  
last contact date – randomization date +1.  
The duration of exposure and the duration of observation period will be summarized for each treatment 
group (FAS, PPS and SAF). 
6.10 Analysis of baseline characteristics 
Baseline data including demographics, anamnestic data, vital signs and laboratory values will be 
summarized by treatment group. Analyses will be repeated in SAF, FAS and PPS. 
6.11 Analysis of Efficacy Endpoints 
All efficacy endpoints will be assessed for FAS, PPS and SAF. 
6.11.1 Analysis of Primary Endpoint 
Primary study endpoint: 
The hypothesis H0 is tested against the one-sided alternative hypothesis H1 
H0: µ∆FBF,Riva, week 20 ≤ µ∆FBF, ASS, week 20  
vs. 
H1: µΔFBF, Riva, week 20 > µΔFBF, ASS, week 20 
by test procedures for continuous data. In case of non-rejection of the normality hypothesis an ANCOVA 
procedure for repeated measurements will be applied. For repeated measurements per subject an 
AR(1)-covariance-structure will be specified. Otherwise ANCOVA for repeated measurements will be 
based on (Blom-transformed) rank data. 
Primary endpoint for the extension period: 
The hypotheses 
H0: µPWV, Riva, week 52 = µPWV, ASS, week 52  
vs. 
H1: µPWV, Riva, week 52 ≠ µPWV, ASS, week 52 
will be tested by procedure for continuous data.  


 
 
 
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Age, gender and duration of diabetes might represent confounding factors and could thus be included 
as covariates in the statistical model. Models incorporating different combinations of covariates are 
compared with respect to their model fit. The best fitting model according to the QIC (Quasi-Likelihood 
information) -criterion will be finally chosen for analysis.  
Correction procedures for multiple comparisons are not necessary due to the fact that both primary 
endpoints consist in single comparisons addressing different variables.  
 
6.11.2 Analysis of Secondary Endpoints 
 
All secondary endpoints will be analyzed according to the procedure for continuous variables.  
Correlations (original data and changes from baseline) might be calculated.  
6.12 Analysis of Safety Data 
The summary of safety will be performed based on the SAF. 
6.12.1 Vital Signs  
Summaries of vital sign variables will include original data and change from baseline by visit.  
 
Blood pressure will be analyzed only by PWA because these measurements are regarded as more 
precise.  
 
6.12.2 Safety Laboratory Measurements 
 
Summaries of safety laboratory variables will include:  
 
Descriptive statistics of original values and differences from baseline 
 
The number (n) and percentage (%) of subjects with CSVs during study, depending on data. 
 
6.12.3 Adverse Events 
 
Individual listings of treatment-emergent adverse events will be generated. The incidence of treatment-
emergent adverse events, respectively, will be summarized using WHO SOC terms. Analysis of adverse 
events will be based on the SAF. 
 
Listings of AEs, SAEs, ADRs and SADRs will be generated.  The following variables will be included in the 
listing:  
 
Patient ID 
 
Treatment group  
 
Age/gender/race 
 
Verbatim Term 
 
AE start date and end date/ongoing 
 
AE Duration  
 
Study day onset  
 
Intensity 
 
Relationship of AE to study drug: unrelated or related  
 
Action taken  
 
Treatment 
 
Outcome 
Listing of SADRs resulting in death and study discontinuation will also be generated.  
 


 
 
 
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6.12.4 Bleedings 
The results for major, CRNM, minor and total bleeding will be documented. Total bleeding includes any 
bleeding event (including CRNM, minor and major bleeding). These analyses will be performed on SAF 
and PPS.  
6.13 Interim analysis 
Interim analyses are not planned. 
6.14 Reporting conventions 
P-values ≥ 0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as “< 
0.001”. The mean, standard deviation and any other statistics other than quantiles, will be reported to 
one decimal place greater than the original data. Quantiles, such as median, or min and max will use the 
same number of decimal places as the original data. Estimated parameters, not on the same scale as 
raw observations (e.g. regression coefficients) will be reported to 3 digits. 
    


 
 
 
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7 Appendix: Mock-Up tables, figures and listings 
7.1 
Subjects Disposition 
Patients 
Frequencies 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
Enrolled 
 
 
 
 
 
 
Screening failures 
 
 
 
 
 
 
Randomized 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
Treated 
 
 
 
 
 
 
Did not complete study 
 
 
 
 
 
 
Completed study 
 
 
 
 
 
 
 
Analysis Set 
Frequencies 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
FAS 
 
 
 
 
 
 
SAF 
 
 
 
 
 
 
PPS 
 
 
 
 
 
 
 
Exclusions 
Frequencies 
Total 
Rivaroxaban 
Aspirin 
from  
N 
% 
N 
% 
N 
% 
FAS 
 
 
 
 
 
 
SAF 
 
 
 
 
 
 
PPS 
 
 
 
 
 
 
 
 
 


 
 
 
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Reasons for Exclusion from FAS 
(Screening Failures) 
Frequencies 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
(all screening failures) 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
Non-Compliance 
 
 
 
 
 
 
Data not complete 
 
 
 
 
 
 
 
Reasons for Exclusion from SAF  
Frequencies 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
Screening Failure 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
…. further reasons ….. 
 
 
 
 
 
 
 
Reasons for Exclusion from PPS  
Frequencies 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
Screening Failure 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
Non-Compliance 
 
 
 
 
 
 
Withdrawal of consent 
 
 
 
 
 
 
Study drug never administered 
 
 
 
 
 
 
Data not complete 
 
 
 
 
 
 
…….. further reasons ….. 
 
 
 
 
 
 
 
 


 
 
 
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7.2 
Demographics  
 
Demographics 
Frequencies 
Hypothesis Testing 
Total 
Rivaroxaban 
Aspirin 
Comparison of 
Proportions 
Variable 
Category 
N 
% 
N 
% 
N 
% 
p-Value 
Gender 
Female 
 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
Race 
European 
 
 
 
 
 
 
 
Asian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
Age 
 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
- 
- 
- 
- 
 
 
 


 
 
 
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7.3 
Medical History 
7.3.1 Medical History 
Duration of Diabetes 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
7.3.2 Concomitant medication  
Concomitant 
medication 
Frequencies 
Comparison of 
Proportions 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
p-Value 
yes 
 
 
 
 
 
 
 
no 
 
 
 
 
 
 
 
7.3.3 ECG and Pregnancy Test 
Medical History 
Frequencies 
Total 
Rivaroxaban 
Aspirin 
Variable 
Category 
N 
% 
N 
% 
N 
% 
ECG 
yes 
Normal 
 
 
 
 
 
 
Abnormal, clinically not significant 
 
 
 
 
 
 
Abnormal, clinically significant 
 
 
 
 
 
 
total 
 
 
 
 
 
 
no 
 
 
 
 
 
 
 
Pregnancy 
test done 
yes 
 
 
 
 
 
 
 
no 
 
 
 
 
 
 
 
 
 
 


 
 
 
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7.4 
Compliance 
Compliance [%] 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
Week 2 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 4 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 8 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 28 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 36 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Overall 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Total Compliance 
Frequencies 
Comparison of 
Proportions 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
p-Value 
< 50% 
 
 
 
 
 
 
 
≥ 50% and < 80% 
 
 
 
 
 
 
≥ 80%  
 
 
 
 
 
 
 


 
 
 
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7.5 
Treatment exposure and observation period 
Duration 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups 
 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
Treatment 
exposure 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Observation 
period 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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7.6 
Efficacy Endpoints 
7.6.1 Forearm Blood Flow (FBF) 
FBF 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Value 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
∆ FBF 
 
Day 0 
Post1-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post2-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post3-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post4-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post5-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post6-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post7-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Post8-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 
20 
 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 
52 
 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
FBF 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
 
Max. 
IR post-
ischemic 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
IR post-
ischemic 
(AUC) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
∆ FBF 
(Differenzen zu V0) 
 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Visit 
Value 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
Week 20 
Post1-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post2-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post3-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post4-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post5-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post6-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post7-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Post8-
baseline 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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FBF 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Visit 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
Max. 
IR post-
ischemic 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
IR post-
ischemic 
(AUC) 
Week 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.6.2 Pulse Wave Analysis 
PWA 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
Pulse Wave 
Velocity 
(m/s)  
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Index of 
Augmentation 
 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Peripheral 
Systolic Blood 
Pressure  
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Peripheral 
Diastolic 
Blood 
Pressure 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Central 
Systolic Blood 
Pressure  
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Central 
Diastolic 
Blood 
Pressure 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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PWA 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Visit 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
Pulse 
Wave 
Velocity 
(m/s) 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Index of 
Augmenta-
tion 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Peripheral 
Systolic 
Blood 
Pressure 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Peripheral 
Diastolic 
Blood 
Pressure 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Central 
Systolic 
Blood 
Pressure 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Central 
Diastolic 
Blood 
Pressure 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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7.6.3 Laser Doppler fluxometry (LDF) 
LDF 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
∆ Depth 
 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
∆ Shallow 
 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
LDF 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Visit 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
∆ Depth 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
∆ Shallow 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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7.7 
Efficacy Laboratory 
7.7.1 Inflammation Laboratory  
Inflammation Laboratory 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
hsCRP 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
PAI-1 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
……. further variables….. 
 
Inflammation Laboratory 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Changes 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
hsCRP 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
PAI-1 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 


 
 
 
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……. further variables….. 
7.7.2 Laboratory for Endothelian Function and Coagulation 
Efficacy Laboratory for Endothelial 
Function and Coagulation 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
VCAM-1 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
ICAM-1 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
……. further variables….. 
 
Efficacy Laboratory for Endothelial 
Function and Coagulation 
Changes from Baseline Day 0 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Changes 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
VCAM-1 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
ICAM-1 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
……. further variables….. 


 
 
 
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….. similar table for Metabolic Markers and bioassay data …… 
 
 


 
 
 
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7.8 
Safety Variables 
7.8.1 Vital Signs 
Vital Signs 
Original Data 
Descriptive Statistics 
Normality 
Comparison of Groups at Baseline 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
p-Value 
Effect 
p-Value 
95% CI 
 
Height 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
 
Weight 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Radial Pulse 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 2 
Rivaroxaban 
 
 
 
 
 
 
 
 
- 
- 
- 
Aspirin 
 
 
 
 
 
 
 
 
Week 8 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 28 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 36 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
…… further variables…… 
 


 
 
 
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Vital Signs 
Changes from Baseline V1 
Descriptive Statistics 
Comparison to Baseline 
Comparison of Groups 
Variable 
Visit 
Treatment 
N 
Missing 
Mea
n 
Median 
STD 
Min 
Max 
Effect 
p-Value 
95% CI 
Effect 
p-Value 
95% CI 
 
Weight 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
 
Radial 
Pulse 
Week 2 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 8 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 28 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 36 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
 
…. further variables ……… 
 
 
 
 


 
 
 
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7.8.2 Safety Laboratory  
Safety Laboratory 
Original Data 
 
Descriptive Statistics 
Comparison of Groups 
Variable 
Visit 
Treatment 
N 
Missing 
Mean 
Median 
STD 
Min 
Max 
Effect 
p-value 
95% CI 
 
Hemoglobin 
Day 0 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 2 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 8 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 20 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 28 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 36 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
Week 52 
Rivaroxaban 
 
 
 
 
 
 
 
 
 
 
Aspirin 
 
 
 
 
 
 
 
 
 
Safety Laboratory CSV’s 
Frequencies 
Comparison of 
Proportions* 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
p-Value 
Total 
Number of Patients 
 
 
 
 
 
 
 
Number of Events 
 
 
 
 
 
 
 
Hemoglobin 
Number of Patients 
 
 
 
 
 
 
 
Number of Events 
 
 
 
 
 
 
 
……. further variables….. 
*can only be calculated for number of patients 
 
 


 
 
 
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7.8.3 Adverse Events 
 
Adverse Events 
Frequencies 
Comparison of 
Proportions 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
p-Value 
Number of 
Patients 
AE 
 
 
 
 
 
 
 
SAE 
 
 
 
 
 
 
ADR 
 
 
 
 
 
 
SADR 
 
 
 
 
 
 
Number of 
Events 
AE 
 
 
 
 
 
 
- 
SAE 
 
 
 
 
 
 
ADR 
 
 
 
 
 
 
SADR 
 
 
 
 
 
 
 
7.8.4 Bleedings 
 
Bleedings 
Frequencies 
Comparison of 
Proportions 
Total 
Rivaroxaban 
Aspirin 
N 
% 
N 
% 
N 
% 
p-Value 
Number of 
Patients 
Major 
 
 
 
 
 
 
 
CRNM 
 
 
 
 
 
 
Minor 
 
 
 
 
 
 
Total Bleeding 
 
 
 
 
 
 
 
Number of 
Events 
Major 
 
 
 
 
 
 
- 
CRNM 
 
 
 
 
 
 
Minor 
 
 
 
 
 
 
Total Bleeding 
 
 
 
 
 
 
-