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Trial registered on ANZCTR


Registration number
ACTRN12619000933156
Ethics application status
Approved
Date submitted
5/04/2016
Date registered
4/07/2019
Date last updated
4/07/2019
Date data sharing statement initially provided
4/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Role of Magnetic Resonance Imaging (MRI) in evaluating the impact of Empagliflozin on kidneys in patients with Type 2 diabetes.
Scientific title
Using MRI to assess impact of add-on Empagliflozin on renal physiology in Type 2 diabetic patients
Secondary ID [1] 288931 0
NONE
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 298277 0
Condition category
Condition code
Metabolic and Endocrine 298415 298415 0 0
Diabetes
Renal and Urogenital 311421 311421 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part 1: Healthy volunteers
Healthy volunteers have bloods taken to assess kidney function (estimated Glomerular Filtration rate) prior to MRI scan with injection of 0.05 mmol/kg Gadoterate meglumine (Dotarem, Aspen Pharmacare). Healthy volunteers are not required to take any medications as part of their participation, other than injection of contrast agent during the MRI scan.
The aim is to optimize a MRI protocol for comprehensive assessment to achieve high quality dynamic contrast enhanced imaging (DCE), phase contrast imaging (PC), arterial spin labelling (ASL), diffusion tensor imaging (DTI) and blood oxygen level dependent imaging (BOLD) imaging within a scan time of 1 hour.

Part 2: Patients with Type 2 Diabetes
Using a crossover design, patients will receive 12-14 weeks’ intervention with add-on oral empagliflozin 10mg tablet versus 50-100mg oral sitagliptin tablet daily in random order (n=18 commencing with empagliflozin, n=18 commencing with sitagliptin), with a 4-6 week washout period between interventions.
Empagliflozin has been dosed at 10mg daily as determined by the associate investigator Endocrinologist. Previous clinical trials have shown that patients who were prescribed Empagliflozin 10mg received the same benefits of SGLT2 inhibition as those prescribed Empagliflozin 25mg with less adverse events relating to Urinary Tract and genital infections. Patients receive one hour education face-to-face at screening and face-to-face at 5 hour study visits prior to commencement of the study drug about: the action of the drug, common, uncommon and rare adverse events, how and when to take the drug, how often to test BGL's, sign and symptoms of hypoglycaemia and how to manage a hypo., importance of maintaining adequate fluid and oral intake when taking empagliflozin due to potential for euglycaemic DKA.
In regular follow up telephone calls throughout the intervention, further education may be provided as required over the phone. A patient may be booked into diabetes clinic for endocrine review if experiencing significant adverse events.
The study nurse explains that patients are to keep the empty tablet packets to return at the following study visit. Tablet packets are then counted and documented in the patient file. The study nurse also maintains regular telephone contact with patients throughout the trial to monitor adherence and any adverse events reported. Weekly calls are maintained for the first 4 weeks of treatment, and then every 4 weeks until completion of the study drug unless in the event of adverse events. Adverse events are followed up until resolved. Weekly calls occur during the wash out phase to ensure patient does not experience uncontrolled hyperglycaemia. Following trial completion, patients are booked into the diabetes clinic within 4 weeks for medication review.

Sitagliptin will be dosed according to patients’ renal function, where 50mg sitagliptin will be prescribed to patients with eGFR less than 60ml/min/1.73m², and 100mg prescribed for patients with eGFR greater than or equal to 60ml/min/1.73m², in line with standard clinical care.

To summarise:
Visit 1 is the screening/ education visit.
Visits 2-5 are face to face 5 hour study visits where patients will undergo an MRI examination and blood tests as described in the protocol. Study drug education will be ongoing, with reinforcement regarding adverse effects, how and when to take the drug, etc. at visits 2 and 4 in particular.

With regard to the timing of the drug interventions:
Visit 2 – Baseline MRI examination/ blood tests for first drug administered (randomised to empagliflozin or sitagliptin)
Visit 3 – post drug MRI examination/ blood tests
Visit 4 – baseline MRI examination/ blood tests for second drug administered (after washout)
Visit 5 – post drug MRI examination/ blood tests
Intervention code [1] 294402 0
Treatment: Drugs
Comparator / control treatment
Sitagliptin will be used as a comparator to distinguish effects of glucose lowering on GFR from independent effects of empagliflozin. Identical testing will be performed following each intervention period.
Control group
Active

Outcomes
Primary outcome [1] 297895 0
The primary outcome measure for the clinical trial will be change in baseline MRI-derived Glomerular Filtration Rate (GFR) compared to MRI-derived Glomerular Filtration Rate (GFR) following 12-14 weeks empagliflozin to post-treatment.
Timepoint [1] 297895 0
Baseline visit and post treatment visit (Week 12) for each of empagliflozin and sitagliptin.
Secondary outcome [1] 322558 0
To evaluate effects on renal oxygen metabolism of empagliflozin using blood oxygen level dependent imaging (BOLD) derived from MRI.
Timepoint [1] 322558 0
Baseline visit and post treatment visit (Week 12) for each of empagliflozin and sitagliptin.
Secondary outcome [2] 370737 0
To study correlation of MRI-derived parameters with existing and novel markers of renal function and glycaemic control, including plasma iohexol measured GFR, Haemoglobin A1c (HbA1c), and albumin to creatinine ratio (ACR).
Timepoint [2] 370737 0
Baseline visit and post treatment visit (Week 12) for each of empagliflozin and sitagliptin.
Secondary outcome [3] 370985 0
To measure the diffusion of water through renal parenchyma, via diffusion tensor imaging, as measured by the metric fractional anisotropy (FA).
Timepoint [3] 370985 0
Baseline visit and post treatment visit (Week 12) for each of empagliflozin and sitagliptin.
Secondary outcome [4] 370986 0
To evaluate effects on renal blood flow (RBF) using Arterial Spin Labelling and DCE imaging.
ASL provides an alternative means of assessing renal haemodynamics that employs a simple free breathing acquisition..R2*, a tissue relaxation constant derived from BOLD imaging, reflects oxygenation. High medullary R2* has been demonstrated in early stage DKD in T2DM without albuminuria, possibly indicating increased oxygen consumption and a hypermetabolic state..
Timepoint [4] 370986 0
Baseline visit and post treatment visit (Week 12) for each of empagliflozin and sitagliptin.

Eligibility
Key inclusion criteria
Part 1: Healthy volunteers:
-Able to provide informed written consent
-Greater than or equal to 18 years old and less than or equal to 75 years old.

Part 2: Patients with Type 2 diabetes
- Able to provide informed written consent
- Patients greater than or equal to 18 years old and less than or equal to 75 years old, on existing diabetes treatments other than GLP1 agonists
- Patients with T2DM with normal and impaired renal function (age adjusted measured GFR of greater than or equal to 45 ml/min/1.73m²)
- Mild hyperglycaemia (HbA1c=7.0-9.0%). For patients already on sulfonylurea or insulin management of diabetes, only patients with HbA1c between 7-9.0% will be eligible, to minimise risk of hypoglycaemia.
-Patients who meet the above inclusion criteria, on existing SGLT2 inhibitors or DPP4 inhibitors, will be eligible to participate following 2 week washout of these medications.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Part 1: Healthy volunteers:
-Volunteers who are unable to provide informed consent
-Any prior history of renal disease, cardiovascular disease or diabetes
-Contraindications to MRI (e.g.: pacemaker) as identified in the MRI safety questionnaire and via repeated verbal screening at recruitment and prior to each study visit.
-Pregnant or breast feeding
-Claustrophobia
-Inability to lie still for 90 minutes
-Allergy to gadolinium-based contrast agents
-eGFR<90 ml/min/1.73m²

Part 2: Patients with Type 2 diabetes:
- Patients who are unable to provide informed consent
- Contra-indication or allergy to gadolinium based or iodine-based contrast agent
- eGFR outside specified range
- Uncontrolled hyperglycaemia, specified as overnight fasting blood glucose greater than 13.3 mmol/L
- History of Pancreatitis
- Contraindications to MRI (e.g.: pacemaker etc) as defined in the MRI safety questionnaire
- Pregnant or breast feeding
- Claustrophobia
- Inability to lie still for 1 hour
- Active drug or heavy alcohol use
- Active malignancy
- Use of warfarin, opioids, corticosteroids
- Excluded because of unacceptable adverse events from study treatment
- Haemoglobin less than 130 g/L – to remove potential confounding effect of anaemia on BOLD derived metrics

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)
a random assignment will be generated where the first 18 patient numbers (listed between 1 & 36) will be randomised to receive 12-14 weeks oral empagliflozin 10 mg (n=18) and the last 18 will receive the sitagliptin 50-100mg daily (n=18).
Following a 4-6 week washout period between interventions, patients will then crossover to receive 12-14 weeks of the alternate medication.
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Online Research Randomizer (https://www.randomizer.org/)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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] 5548 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 5549 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment postcode(s) [1] 26572 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 293283 0
Other
Name [1] 293283 0
The Royal Australian and New Zealand College of Radiologists
Address [1] 293283 0
9/51 Druitt St, Sydney NSW 2000
Country [1] 293283 0
Australia
Funding source category [2] 302857 0
Commercial sector/Industry
Name [2] 302857 0
Boehringer Ingelheim
Address [2] 302857 0
Level 1, 78 Waterloo Rd, North Ryde,
NSW 2113,
*Please note, this company is providing investigator-initiated grant funding and is not the sponsor of the study
Country [2] 302857 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road,
Heidelberg, VIC, 3084
Country
Australia
Secondary sponsor category [1] 302809 0
None
Name [1] 302809 0
Address [1] 302809 0
Country [1] 302809 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294757 0
Austin Health Human Research Ethics Committee (EC00204)
Ethics committee address [1] 294757 0
145 Studley Rd, Heidelberg VIC 3084
Ethics committee country [1] 294757 0
Australia
Date submitted for ethics approval [1] 294757 0
06/04/2016
Approval date [1] 294757 0
28/07/2016
Ethics approval number [1] 294757 0
HREC/16/AUSTIN/124

Summary
Brief summary
Our study aims to use MRI to assess the effects of empagliflozin on kidney filtration compared to another glucose-lowering medication, sitagliptin. Sitagliptin is another approved drug used to treat high glucose levels; however it is not known to affect the kidneys in the same way as empagliflozin.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64954 0
A/Prof Ruth Lim
Address 64954 0
Radiology Department
Austin Health
145 Studley Rd, Heidelberg VIC 3084
Country 64954 0
Australia
Phone 64954 0
+61394966794
Fax 64954 0
Email 64954 0
ruth.lim@austin.org.au
Contact person for public queries
Name 64955 0
Ms Julie Smith
Address 64955 0
Radiology Department
Austin Health
145 Studley Rd, Heidelberg VIC 3084
Country 64955 0
Australia
Phone 64955 0
+61394966794
Fax 64955 0
Email 64955 0
julie.smtih@austin.org.au
Contact person for scientific queries
Name 64956 0
A/Prof Ruth Lim
Address 64956 0
Radiology Department
Austin Health
145 Studley Rd, Heidelberg VIC 3084
Country 64956 0
Australia
Phone 64956 0
+61394966794
Fax 64956 0
Email 64956 0
ruth.lim@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available as sharing individual data will serve no purpose at this point.
What supporting documents are/will be available?
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 2192 0
Informed consent form
Citation [1] 2192 0
Link [1] 2192 0
Email [1] 2192 0
Other [1] 2192 0
This is the most recent Informed consent.
Type [2] 2193 0
Ethical approval
Citation [2] 2193 0
Link [2] 2193 0
Email [2] 2193 0
Other [2] 2193 0
Initial Approval, several modifications have followed.
Summary results
No Results