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Trial registered on ANZCTR


Registration number
ACTRN12619000887178
Ethics application status
Approved
Date submitted
2/06/2019
Date registered
26/06/2019
Date last updated
26/06/2019
Date data sharing statement initially provided
26/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study examining the effects of empagliflozin (Jardiance®), a tablet for treatment of diabetes on autonomic nervous system and heart function in patients with type 2 diabetes.
Scientific title
Effects of Empagliflozin on Autonomic Nervous System Function and Cardiac Function in Patients with Type 2 Diabetes.
Secondary ID [1] 298391 0
Nil known
Universal Trial Number (UTN)
U1111-1234-5592
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 313081 0
Condition category
Condition code
Metabolic and Endocrine 311568 311568 0 0
Diabetes
Cardiovascular 311681 311681 0 0
Normal development and function of the cardiovascular system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
3 months treatment with empagliflozin 25 mg oral tablet once daily in patients with type 2 diabetes. Adherence to the intervenstion will be monitored by indirect methods (self-reports, pill counts and patient diaries).
Intervention code [1] 314634 0
Treatment: Drugs
Comparator / control treatment
3 months treatment with placebo oral tablet in patients with type 2 diabetes. Placebo tablets contain microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 320273 0
Change in VO2peak from baseline in patients with type 2 diabetes taking empagliflozin compared with placebo.
A ramp protocol peak exercise test will be performed on a bicycle ergometer to assess VO2peak
Timepoint [1] 320273 0
Baseline and 3 months
Primary outcome [2] 320274 0
Change in muscle sympathetic nerve activity (MSNA) from baseline in patients with type 2 diabetes taking empagliflozin compared with placebo.
Resting multiunit MSNA activity will be measured by microneurography via a tungsten microelectrode inserted into a muscle nerve fascicle of the right peroneal nerve.
Timepoint [2] 320274 0
Baseline and 3 months
Secondary outcome [1] 371045 0
Changes in Ventilatory efficiency (VE/VCO2 slope) from baseline in patients taking empagliflozin compared with placebo.
Analysis of VE and VCO2 will be conducted using metabolic cart. VE and VCO2 responses throughout exercise will be used to calculate the VE/VCO2 slope via least squares linear regression.
Timepoint [1] 371045 0
Baseline visit and 3 months
Secondary outcome [2] 371922 0
Changes in heart rate during exercise echocardiography from baseline in patients taking empagliflozin compared with placebo.
Timepoint [2] 371922 0
Baseline visit and 3 months
Secondary outcome [3] 371923 0
Changes in blood pressure during exercise echocardiography from baseline in patients taking empagliflozin compared with placebo.
Timepoint [3] 371923 0
Baseline visit and 3 months

Eligibility
Key inclusion criteria
- Adults with established Type 2 diabetes > 12 months on any anti-hyperglycaemic agents except for SGLT-2 inhibitors
- HbA1c 7.1-10.0%
- Estimated glomerular filtration rate (e-GFR) > 45 ml/min
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- History of sodium glucose transporter-2 (SGLT2) inhibitor treatment in the past 3 months or intolerance
- Age > 75 years
- Known heart failure or established cardiac disease
- Treatment with beta blockers or centrally acting sympathetic blockers
- Unable to perform moderate cycloergometric exercise
- Chronic kidney disease stage IIIB or above (e-GFR <45)
- History of recurrent genital infections and Urinary Tract Infections
- Hypoglycaemia requiring third party assistance in the previous 3 months
euglycaemic diabetic ketoacidosis in the previous 6 months

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An external company will provide encapsulated tablets of placebo and Empagliflozin. Investigators and patients will both be blinded.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed by a random number generator.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
In a middle-aged cohort of type 2 diabetes subjects without significant other comorbidities, we observed an average VO2peak of 32 +/- 10 ml/min/kg11.. An increase of 3.5ml/min/kg (1 metabolic equivalent) in VO2peak would be clinically meaningful and has previously been associated with a 15% improvement in 10-year mortality and improvements in quality of life (QOL).
Using a repeated measures design with exercise capacity as a within subject factor, a sample size of 26 subjects would be expected to identify an increase in VO2peak from 32 to 35.5 ml/min/kg with 80% power (alpha=0.05). Allowing a 30% drop-out rate due to drugintolerance and other factors, we will aim to enrol 30 subjects into the Empagliflozin treatment arm.
In addition, 30 control subjects randomised to placebo will undergo the same testing with the expectation that exercise capacity and cardiac function will remain largely unchanged. There would thus be adequate power to demonstrate a significant interaction between change in VO2peak and treatment assignment.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13884 0
Baker Heart and Diabetes Institute - Melbourne
Recruitment postcode(s) [1] 26656 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 302931 0
Charities/Societies/Foundations
Name [1] 302931 0
diabetes australia
Address [1] 302931 0
Level 1, 101 Northbourne Ave, Turner ACT 2612
Country [1] 302931 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Baker Heart and Diabetes Institute
Address
99 Commercial Road, Melbourne, VIC, 3004
Country
Australia
Secondary sponsor category [1] 302892 0
None
Name [1] 302892 0
Address [1] 302892 0
Country [1] 302892 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303495 0
Bellberry Limited
Ethics committee address [1] 303495 0
123 Glen OsmondRoad, Eastwood, SA, 5063
Ethics committee country [1] 303495 0
Australia
Date submitted for ethics approval [1] 303495 0
10/02/2019
Approval date [1] 303495 0
22/05/2019
Ethics approval number [1] 303495 0
HREC2019-02-107

Summary
Brief summary
The overall aims are to assess changes in cardiac function and sympathetic nervous system activity at rest and during exercise with empagliflozin in patients with type 2 diabetes without established heart disease. We hypothesised that:
- 3 months treatment with empagliflozin will be associated with a measurable improvement in exercise capacity as reflected by peak oxygen consumption during maximal exercise (VO2peak) in addition to key physiological variables during exercise (heart rate reserve, blood pressure and ventilatory efficiency) in type 2 diabetes subjects without overt clinical heart failure.
- Empagliflozin is associated with changes in sympathetic nervous system activity that may cause changes in cardiovascular function.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93858 0
A/Prof Neale Cohen
Address 93858 0
Baker Heart and Diabetes Institute
75 Commercial Road, Melbourne, VIC, 3004
Country 93858 0
Australia
Phone 93858 0
+61385321800
Fax 93858 0
Email 93858 0
neale.cohen@baker.edu.au
Contact person for public queries
Name 93859 0
Dr Amin Sharifi
Address 93859 0
Baker Heart and Diabetes Institute
Level 4, 99 Commercial Road, Melbourne, VIC, 3004
Country 93859 0
Australia
Phone 93859 0
+61385321800
Fax 93859 0
Email 93859 0
amin.sharifi@baker.edu.au
Contact person for scientific queries
Name 93860 0
Dr Amin Sharifi
Address 93860 0
Baker Heart and Diabetes Institute
Level 4, 99 Commercial Road, Melbourne, VIC, 3004
Country 93860 0
Australia
Phone 93860 0
+61385321800
Fax 93860 0
Email 93860 0
amin.sharifi@baker.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results