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Clinical Trial Results:
MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION

Summary
EudraCT number	2014-001305-41
Trial protocol	DE
Global end of trial date	12 Dec 2018

Results information
Results version number	v1(current)
This version publication date	04 Jun 2022
First version publication date	04 Jun 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

MicroVasc-DIVA

ISRCTN number

US NCT number

NCT02164578

WHO universal trial number (UTN)

Sponsor organisation name

GWT-TUD GmbH

Sponsor organisation address

Freiberger Str. 33, Dresden, Germany, 01067

Public contact

Medical Consulting, GWT-TUD GmbH, 0049 35125933100, medical.consulting@g-wt.de

Scientific contact

Medical Consulting, GWT-TUD GmbH, 0049 35125933100, medical.consulting@g-wt.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

11 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Dec 2018

Global end of trial reached?

Yes

Global end of trial date

12 Dec 2018

Was the trial ended prematurely?

Main objective of the trial

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.

Protection of trial subjects

The conduct of this study was in compliance with the Good Clinical Practice Guidelines and under the guiding principles detailes in the Declaration of Helsinki. The study waas also carried out in keeping with applicable local law(s) and regulation(s).

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 179

Worldwide total number of subjects

179

EEA total number of subjects

179

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

From 14th Apr 2015 through 21st Dec 2017, a total of 239 patients were screened at 4 study sites in Germany. Of them, 60 patients did not meet the eligibility criteria. 188 patients were planned to enrol and 80 patients of them should included in the extension period of the study.

Screening details

179 patients were randomized to one of the two treatment groups, 89 to receive rivaroxaban and 90 to receive acetylsalicylic acid (ASA). In total, 73 patients were included in the extension period, 37 of them received rivaroxaban and 36 received ASA.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Rivaroxaban

Arm description

The arm with 5 mg b.i.d. Rivaroxaban consisted of a treatment period of 20 weeks and of an extension period of additional 32 weeks. From 72 patients 37 patients were included in the extension phase.

Arm type

Experimental

Investigational medicinal product name

Rivaroxaban

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet, Tablet

Routes of administration

Oral use

Dosage and administration details

Patients received Rivaroxaban 5 mg b.i.d. for the duration of 20 weeks. Additionally, 37 patients of the study population continued to receive the Rivaroxaban 5 mg b.i.d. for further 32 weeks (extension treatment).

Aspirin

Arm description

The arm with 100 mg q.d. Aspirin consisted of a treatment period of 20 weeks and of an extension period of additional 32 weeks. From 79 patients 36 patients were included in the extension phase.

Arm type

Active comparator

Investigational medicinal product name

Aspirin

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Patients received treatment with Aspirin 100 mg q.d. for the duration of 20 weeks. Additionally, 36 patients of the study population continued to receive the Aspirin 100 mg q.d. for further 32 weeks (extension treatment).

Number of subjects in period 1	Rivaroxaban	Aspirin
Started	89	90
Completed	72	79
Not completed	17	11
Consent withdrawn by subject	3	3
Physician decision	1	-
Adverse event, non-fatal	13	6
Protocol deviation	-	2

Baseline characteristics

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Reporting group title

Treatment period

Reporting group description

Reporting group values	Treatment period	Total
Number of subjects	179	179
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	92	92
From 65-84 years	87	87
85 years and over	0	0
Age continuous
Units: years
median (standard deviation)	65 ± 7.11	-
Gender categorical
Units: Subjects
Female	95	95
Male	84	84

End points

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Reporting group title

Rivaroxaban

Reporting group description

The arm with 5 mg b.i.d. Rivaroxaban consisted of a treatment period of 20 weeks and of an extension period of additional 32 weeks. From 72 patients 37 patients were included in the extension phase.

Reporting group title

Aspirin

Reporting group description

The arm with 100 mg q.d. Aspirin consisted of a treatment period of 20 weeks and of an extension period of additional 32 weeks. From 79 patients 36 patients were included in the extension phase.

Primary: Change in Post-ischemic Forearm Blood Flow

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End point title

Change in Post-ischemic Forearm Blood Flow

End point description

Change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml).

End point type

Primary

End point timeframe

week 20

End point values	Rivaroxaban	Aspirin
Number of subjects analysed	83	84
Units: FBF (max)
arithmetic mean (standard deviation)	3.60 ± 4.69	1.00 ± 5.27

Efficacy analysis

Comparison groups

Rivaroxaban v Aspirin

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.001

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Primary: Change in pulse wave velocity

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End point title

Change in pulse wave velocity

End point description

End point type

Primary

End point timeframe

week 52

End point values	Rivaroxaban	Aspirin
Number of subjects analysed	34	36
Units: m/s
arithmetic mean (standard deviation)	0.24 ± 0.62	0.51 ± 0.57

Efficacy analysis

Comparison groups

Rivaroxaban v Aspirin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.07

Method

ANCOVA

Confidence interval

Adverse events

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Timeframe for reporting adverse events

from day 0 to week 52

Adverse event reporting additional description

Adverse events and serious adverse events were collected from first intake of study medication and then at each visit until the end of the study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Rivaroxaban

Reporting group description

Reporting group title

Aspirin

Reporting group description

Notes
[1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
Justification: Overall, 125 out of the 179 patients (69.8%) in the SAF experienced at least one AE, 63 (70.8%) in the rivaroxaban arm and 62 (68.9%) in the ASA arm. Most of the AEs were of mild (37.0%) or moderate (52.6%) intensity. 34 AEs (10.4%) of severe intensity were documented, 22 events in the rivaroxaban arm and 12 events in the ASA arm. In total, 25.1% of the AEs were assessed as possibly or likely related to the study medication, 29.6% in the rivaroxaban arm and 19.6% in the aspirin arm.

Serious adverse events	Rivaroxaban	Aspirin
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 89 (4.49%)	6 / 90 (6.67%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cerebrovascular accident
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leiomyoma
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Foot fracture
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 89 (0.00%)	2 / 90 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Hysterectomy
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint arthroplasty
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 89 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 89 (1.12%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Rivaroxaban	Aspirin
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 89 (0.00%)	0 / 90 (0.00%)

More information

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Were there any global substantial amendments to the protocol? Yes

05 Aug 2015

Version 5.0 dated 01 Jul 2015: change in inclusion criteria, introduction of additional lab parameters; extension of screening phase

04 Aug 2016

Version 6.0 dated 07 Jul 2016: introduction of extension phase

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Post-ischemic Forearm Blood Flow

Primary: Change in Post-ischemic Forearm Blood Flow

Primary: Change in pulse wave velocity

Primary: Change in pulse wave velocity

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in Post-ischemic Forearm Blood Flow

Primary: Change in Post-ischemic Forearm Blood Flow

Primary: Change in pulse wave velocity

Primary: Change in pulse wave velocity

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
MICROVASCULAR AND ANTIINFLAMMATORY EFFECTS OF RIVAROXABAN COMPARED TO LOW DOSE ASPIRIN IN TYPE 2 DIABETIC PATIENTS WITH VERY HIGH CARDIOVASCULAR RISK AND SUBCLINICAL INFLAMMATION