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Clinical Trial Results:
A study of the effects of dapagliflozin on ambulatory aortic pressure, arterial stiffness and urine albumin excretion in patients with type 2 diabetes.

Summary
EudraCT number	2015-005288-17
Trial protocol	GR
Global end of trial date	10 Jun 2019

Results information
Results version number	v1(current)
This version publication date	09 Apr 2022
First version publication date	09 Apr 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

ESR-15-10964

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Hellenic Society for Medical Education

Sponsor organisation address

Tsimiski 44, Thessaloniki, Greece,

Public contact

Asterios Karagiannis, President of the Hellenic Society for Medical Education, Hellenic Society for Medical Education, 0030 2310992845, astkar@med.auth.gr

Scientific contact

Asterios Karagiannis, President of the Hellenic Society for Medical Education, Hellenic Society for Medical Education, 0030 2310992845, astkar@med.auth.gr

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

04 Dec 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

10 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

10 Jun 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of the present study was to investigate the effect of dapagliflozin on ambulatory aortic pressure in patients with type 2 DM.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Greece: 85

Worldwide total number of subjects

EEA total number of subjects

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

The trial was conducted across 3 sites in Thessaloniki. The first subject was recruited in Sep 2016; with the last subject last visit planned for Sep 2019, on Feb 2019 Astra-Zeneca notified the sponsor/investigators of its intention to terminate the financial support, leading to premature trial termination with last randomized patient in Mar 2019.

Screening details

A total of 123 participants consented to participate in the study, of which 38 were screen failures; 85 participants were finally randomized (43 to dapagliflozin and 42 to placebo).

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst, Carer, Assessor

Blinding implementation details

The Sponsor, the CRO, investigators, study staff, and the patients were blinded to study drug assignment during the double-blind period of the trial, from the time of randomization until the database lock. The following methods were used to ensure the blinding: a)Randomization data were kept confidential until the time of unblinding and were not accessible by anyone else involved in the study, b) the identity of the treatments was concealed by the use of study drugs that were all identical.

Are arms mutually exclusive

Yes

Dapagliflozin

Arm description

Arm type

Experimental

Investigational medicinal product name

dapagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Dapagliflozin for oral administration was supplied as a 10 mg film-coated tablet (green, plain, diamond shaped) containing dapagliflozin propanediol monohydrate equivalent to 10 mg of dapagliflozin. The dosage was dapagliflozin 10 mg (p.o.) q24h for 12 weeks.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo for oral administration was supplied as a film-coated tablet of identical color and texture (i.e. green, plain, diamond shaped). The dosage was Placebo (p.o.) q24h for 12 weeks

Number of subjects in period 1	Dapagliflozin	Placebo
Started	43	42
Completed	41	39
Not completed	2	3
Consent withdrawn by subject	1	3
Refuse to perform 24-h ABPM at study-end	1	-

Baseline characteristics

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Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Dapagliflozin	Placebo	Total
Number of subjects	43	42	85
Age categorical
Units: Subjects
Adults (18-64 years)	29	28	57
From 65-84 years	14	14	28
Age continuous
Units: years
arithmetic mean (standard deviation)	61.74 ± 6.73	60.64 ± 9.35	-
Gender categorical
Units: Subjects
Female	20	21	41
Male	23	21	44

End points

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Reporting group title

Dapagliflozin

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

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End point title

The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

End point description

End point type

Primary

End point timeframe

Basline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: mmHg
arithmetic mean (standard deviation)	-4.12 ± 8.00	-0.65 ± 7.77

Primary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.046

Method

t-test, 2-sided

Confidence interval

Notes
[1] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

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End point title

The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: mmHg
arithmetic mean (standard deviation)	-1.63 ± 5.23	0.16 ± 5.99

Secondary endpoint

Comparison groups

Placebo v Dapagliflozin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.144

Method

t-test, 2-sided

Confidence interval

Notes
[2] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

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End point title

The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: mmHg
arithmetic mean (standard deviation)	-5.80 ± 9.48	-0.10 ± 8.70

Secondary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.005

Method

t-test, 2-sided

Confidence interval

Notes
[3] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

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End point title

The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: mmHg
arithmetic mean (standard deviation)	-2.23 ± 5.26	0.10 ± 5.70

Secondary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.054

Method

t-test, 2-sided

Confidence interval

Notes
[4] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

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End point title

The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: m/sec
arithmetic mean (standard deviation)	-0.16 ± 0.32	0.02 ± 0.27

Secondary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.007

Method

t-test, 2-sided

Confidence interval

Notes
[5] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

Top of page

End point title

The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: mg/g
median (inter-quartile range (Q1-Q3))	0.02 (-3.63 to 3.71)	-0.73 (-2.74 to 2.18)

Secondary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.447

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[6] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Secondary: The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

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End point title

The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

End point description

End point type

Secondary

End point timeframe

Baseline and study-end (12 weeks).

End point values	Dapagliflozin	Placebo
Number of subjects analysed	43	42
Units: percent
arithmetic mean (standard deviation)	-0.57 ± 0.74	-0.09 ± 0.66

Secondary endpoint

Comparison groups

Dapagliflozin v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.002

Method

t-test, 2-sided

Confidence interval

Notes
[7] - Analysis of study outcomes included all randomized participants (intention-to-treat principle). We used the last observation carried forward method to handle missing data

Adverse events

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Timeframe for reporting adverse events

Adverse events (AEs) were followed as appropriate during the study (from baseline to study-end).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Dapagliflozin group

Reporting group description

Reporting group title

Placebo group

Reporting group description

Serious adverse events	Dapagliflozin group	Placebo group
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 43 (2.33%)	0 / 42 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Skin and subcutaneous tissue disorders
Basal cell carcinoma
subjects affected / exposed	1 / 43 (2.33%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Dapagliflozin group	Placebo group
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 43 (23.26%)	10 / 42 (23.81%)
Cardiac disorders
Hypotension
subjects affected / exposed	0 / 43 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1
Oedema peripheral
subjects affected / exposed	0 / 43 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 43 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	2
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 43 (4.65%)	0 / 42 (0.00%)
occurrences all number	2	0
Immune system disorders
Rhinitis allergic
subjects affected / exposed	1 / 43 (2.33%)	1 / 42 (2.38%)
occurrences all number	1	1
Gastrointestinal disorders
Gastrointestinal disorder
subjects affected / exposed	1 / 43 (2.33%)	1 / 42 (2.38%)
occurrences all number	1	1
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection
subjects affected / exposed	1 / 43 (2.33%)	1 / 42 (2.38%)
occurrences all number	1	1
Lower respiratory tract infection
subjects affected / exposed	0 / 43 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 43 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	3 / 43 (6.98%)	0 / 42 (0.00%)
occurrences all number	3	0
Prostatic specific antigen increased
subjects affected / exposed	1 / 43 (2.33%)	0 / 42 (0.00%)
occurrences all number	1	0
Lithiasis
subjects affected / exposed	0 / 43 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 43 (2.33%)	0 / 42 (0.00%)
occurrences all number	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

25 Oct 2016

Following the changes in the labeling of the investigational product (dapagliflozin), the appropriate changes in inclusion criteria [(a) from "Age >18 and <70 years old" to "Age >18 and <75 years old" and (b) from "Patients on stable dose of metformin of at least 1500 mg for the past 3 months" to "Patients on monotherapy or combination of two of the following type of antidiabetic agents: metformin, sulphonylurea, DDP-4 inhibitor, or insulin for the past 3 months")] and exclusion criteria (from "Patients on antidiabetic drugs other than metformin" to "Patients on GLP-1 receptor agonist or pioglitazone") were made.

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:
A study of the effects of dapagliflozin on ambulatory aortic pressure, arterial stiffness and urine albumin excretion in patients with type 2 diabetes.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Primary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

Secondary: The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Iceland
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Outside EU/EEA

Clinical trials

Clinical Trial Results: A study of the effects of dapagliflozin on ambulatory aortic pressure, arterial stiffness and urine albumin excretion in patients with type 2 diabetes.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Primary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour systolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour diastolic aortic pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial systolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour brachial diastolic blood pressure recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of 24-hour pulse wave velocity recorded with the Mobil-O-Graph device at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of albumin/creatinine ratio at study-end.

Secondary: The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

Secondary: The difference between the groups of dapagliflozin and placebo in the change of glycosylated hemoglobin at study-end

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A study of the effects of dapagliflozin on ambulatory aortic pressure, arterial stiffness and urine albumin excretion in patients with type 2 diabetes.