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Trial registered on ANZCTR


Registration number
ACTRN12617000490370
Ethics application status
Approved
Date submitted
30/03/2017
Date registered
5/04/2017
Date last updated
5/12/2018
Date data sharing statement initially provided
5/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of empagliflozin on the sympathetic nervous system in people with type 2 diabetes.
Scientific title
Elucidating the effect of empagliflozin on the cardiac and renal sympathetic outflows in patients with type 2 diabetes
Secondary ID [1] 291527 0
Boehringer Ingelheim 1245.145
Universal Trial Number (UTN)
U1111-1184-5780
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 302615 0
Cardiovascular disease 302616 0
Condition category
Condition code
Metabolic and Endocrine 302138 302138 0 0
Diabetes
Cardiovascular 302139 302139 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Empagliflozin. Dose = 25 mg once a day, Duration = 12 weeks. Mode of administration = oral tablet.
Adherence will be monitored at study visits by empty drug packet return and pill counting of any returned study drug.
Intervention code [1] 297597 0
Treatment: Drugs
Comparator / control treatment
Placebo. Dose = once a day. Duration = 12 weeks. Mode of administration = oral tablet.
The placebo will contain matching excipients to the intervention. The tablet contains microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 301569 0
Whole body norepinephrine spillover rate
This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy.
Timepoint [1] 301569 0
12 weeks after randomisation
Secondary outcome [1] 333060 0
Cardiac norepinephrine spillover rate
This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy.
Timepoint [1] 333060 0
12 weeks after randomisation
Secondary outcome [2] 333061 0
Renal norepinephrine spillover rate
This is assessed by assay of blood collected at catheterisation and determination of noradrenaline concentration by HPLC and liquid scintillation spectroscopy.
Timepoint [2] 333061 0
12 weeks after randomisation
Secondary outcome [3] 333062 0
Resting muscle sympathetic nerve activity
This is assessed by microneurography in a muscle fascicle of the peroneal nerve at the fibular
head.
Timepoint [3] 333062 0
12 weeks after randomisation
Secondary outcome [4] 333064 0
Left atrial pressure (pulmonary artery wedge pressure)
This is measured using a Swan-Ganz catheter with a pressure transducer.
Timepoint [4] 333064 0
12weeks after randomisation
Secondary outcome [5] 333065 0
Systolic and diastolic blood pressure
This is measured by sphygmomanometry.
Timepoint [5] 333065 0
12 weeks after randomisation
Secondary outcome [6] 333066 0
Ankle brachial pressure index
This is measured with a vascular profiler which has limb cuffs, phonocardiogram, ECG and electronic pressure transducers
Timepoint [6] 333066 0
12 weeks after randomisation
Secondary outcome [7] 333067 0
Left ventricular volumes
This is measured by echocardiogram.
Timepoint [7] 333067 0
12 weeks after randomisation
Secondary outcome [8] 333068 0
Hba1c
This is measured by assay on venous whole blood..
Timepoint [8] 333068 0
12 weeks after randomisation
Secondary outcome [9] 333069 0
24 hour urine glucose
Timepoint [9] 333069 0
12 weeks after randomisation
Secondary outcome [10] 333070 0
VO2max
This is measured by cycle ergometer maximum exercise capacity test.
Timepoint [10] 333070 0
12 weeks after randomisation
Secondary outcome [11] 333071 0
Questionnaire scores for quality of life, SF-36,
Timepoint [11] 333071 0
12 weeks after randomisation
Secondary outcome [12] 333072 0
Coronary arterial-venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay.
Timepoint [12] 333072 0
12 weeks after randomisation
Secondary outcome [13] 333073 0
Epigenetics –DNA methylation , transcriptome and microRNA
These will be assessed using epigenomic profiling of PBMCs using Illumina sequencing technology; RNA-seq to perform unbiased measurement of all expressed genes in the specimens; microRNA sequencing to detect all expressed small RNAs; whole genome DNA methylation analysis using MBD-seq and bisulfite sequencing; polymerase chain reaction experiments to validate methylation and gene expression signatures.
These analyses will review patterns. One of the pathways to be examined will be the MTOR pathway.
Timepoint [13] 333073 0
12 weeks after randomisation
Secondary outcome [14] 333432 0
Pulse wave velocity
This is measured with a vascular profiler which has limb cuffs, phonocardiogram, ECG and electronic pressure transducers.
Timepoint [14] 333432 0
12 weeks
Secondary outcome [15] 333433 0
Left ventricular ejection fraction
This is measured by echocardiogram.
Timepoint [15] 333433 0
12 weeks
Secondary outcome [16] 333434 0
Left ventricular global longitudinal strain
This is measured by echocardiogram with speckle tracing.
Timepoint [16] 333434 0
12 weeks
Secondary outcome [17] 333435 0
Fasting plasma glucose
This is measured on blood collected in fluoride oxalate tube.
Timepoint [17] 333435 0
12 weeks
Secondary outcome [18] 333439 0
24 hour urine electrolytes
Timepoint [18] 333439 0
12 weeks
Secondary outcome [19] 333440 0
24 hour urine albumin
Timepoint [19] 333440 0
12 weeks
Secondary outcome [20] 333444 0
Questionnaire scores for depression: Beck Depression Inventory–II.
Timepoint [20] 333444 0
12 weeks
Secondary outcome [21] 333445 0
Questionnaire scores for anxiety: Spielberger’s State & Trait Anxiety Inventory (STAI Form Y-1 and STAI Form X-2)
Timepoint [21] 333445 0
12 weeks
Secondary outcome [22] 333448 0
Renal arterial-venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay.
Timepoint [22] 333448 0
12 weeks
Secondary outcome [23] 333449 0
Splanchnic arterial-venous neurotransmitter, neuromodulator and metabolite gradients measured by serum assay.
Timepoint [23] 333449 0
12 weeks

Eligibility
Key inclusion criteria
1) Capable of understanding the content of and able voluntarily to provide a personally signed and dated written informed consent form.
2) Stated willingness to comply with all study procedures and availability for the duration of the study.
3) Male or female, aged 18-85 years inclusive.
4) Diagnosed with type 2 diabetes.
5) HbA1c between 7.0% (53 mmol/mol) and 10.0% (86 mmol/mol) inclusive, at Visit 1.
6) Antidiabetic therapy has to be unchanged for 12 weeks before Visit 1.
a) If insulin is part of the background therapy, this means no change in the dose of insulin in excess of ±10% of the average daily dose.
b) For oral antidiabetic medications, this means no change in the number or class of glucose-lowering drugs, and no change in excess of ±20% of the average daily dose.
c) For GLP-1 receptor agonists, this means no change in dose of the average daily dose.
7) eGFR greater than or equal to 45 mL/min/1.73 m2, as calculated by the CKD-EPI creat formula, at Visit 1.
8) Body mass index between 20-40 kg/m2 inclusive, at Visit 1.
9) In addition to the above described criteria, participants must have high cardiovascular risk, defined as at least one of the following: A] confirmed history of coronary artery disease, or B] age greater than or equal to 30 years with documented symptomatic atherosclerotic non-coronary cardiovascular events, or C] age greater than or equal to 50 years with 2 or more defined risk factors identified at the screening visit.
A] Confirmed history of coronary artery disease is defined as at least one of the following:
a) Confirmed history of myocardial infarction (>2 months prior to Visit 1).
b) Evidence of multivessel coronary artery disease, in 2 or more major coronary arteries, irrespective of the revascularisation status, i.e.
i) Either the presence of a significant stenosis (imaging evidence of at least 50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced computed tomography angiography), in 2 or more major coronary arteries,
or
ii) a previous revascularisation (percutaneous transluminal coronary angioplasty with or without stent, or coronary artery bypass grafting) at least 2 months ago, in 2 or more major coronary arteries,
or
iii) the combination of previous revascularisation in one major coronary artery at least 2 months ago (percutaneous transluminal coronary angioplasty with or without stent, or coronary artery bypass grafting), and the presence of a significant stenosis in another major coronary artery (imaging evidence of at least 50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced computed tomography angiography),
Note: A disease affecting the left main coronary artery is considered as a 2-vessel disease.
c) Evidence of a single vessel coronary artery disease with:
i) The presence of a significant stenosis i.e. the imaging evidence of at least 50% narrowing of the luminal diameter of one major coronary artery in participants not subsequently successfully revascularised (measured during a coronary angiography or a multi-sliced computed tomography angiography)
ii) And at least one of the following (either (1) or (2) below):
(1) A positive non-invasive stress test, confirmed by either:
• A positive exercise tolerance test in participants without a complete left bundle
branch block, Wolff-Parkinson-White syndrome, or paced ventricular rhythm,
or
• A positive stress echocardiography showing regional systolic wall motion abnormalities,
or
• A positive scintigraphic test showing stress-induced ischaemia, i.e. the development of transient perfusion defects during myocardial perfusion imaging;
(2) Participant discharged from hospital with a documented diagnosis of
unstable angina within 12 months prior to Visit 1.

d) Last episode of unstable angina >2 months prior to Visit 1, with confirmed evidence of coronary multivessel or single vessel disease as defined above.
B] Age greater than or equal to 30 years with documented symptomatic atherosclerotic non-coronary cardiovascular events, defined as at least one of the following: stroke, peripheral revascularisation (angioplasty or surgery); symptomatic with documented haemodynamically-significant carotid or peripheral vascular disease.
C] Age greater than or equal to 50 years with 2 or more of the following risk factors at Visit 1: duration of type 2 diabetes greater or equal to 10 years; participant is on at least one anti-hypertensive medication and the average of 3 readings of systolic blood pressure at Visit 1 is > 140 mm Hg; documented albuminuria within 12 months of Visit 1 (defined as at least one urine albumin to creatinine ratio greater than or equal to 3 mg/mmol in the last 12 months, with at least one other abnormal albumin to creatinine ratio greater than or equal to 3 mg/mmol documented in the history); documented HDL-cholesterol < 1.0 mmol/L within 12 months of Visit 1.
10) Willing to practice highly effective methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during the screening period, while taking investigational product and for at least 90 days after the last dose of investigational product is ingested. Women of childbearing potential are female participants who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), and are not postmenopausal for at least 1 year. Furthermore, male study participants must also not donate sperm from day of randomisation until 90 days after the last dose of investigational product.
11) The only permitted antidepressant medications are serotonin and norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs).
a) If on antidepressant medication SSRI or SNRI as part of background therapy, the dose has to be unchanged for 12 weeks before Visit 1.
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) History of type 1 diabetes.
2) Uncontrolled hyperglycaemia with fasting plasma glucose level > 13.3 mmol/L during screening and confirmed by a second measurement performed on a separate day.
3) History of 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalisation within the 6 months prior to Visit 1.
4) Ongoing therapy with an SGLT2 inhibitor or pioglitazone.
5) Previously intolerant of an SGLT2 inhibitor.
6) Acute coronary syndrome, stroke or TIA within 2 months prior to Visit 1.
7) On monoamine oxidase inhibitors or tricyclic antidepressants.
8) Diagnosed hypertrophic obstructive cardiomyopathy, dilated cardiomyopathy or restrictive cardiomyopathy.
9) New York Heart Association class III or IV heart failure.
10) Valvular heart disease, moderate or severe, i.e. Stage B moderate or severe, Stage C or Stage D, as defined by the current American Heart Association clinical guidelines9.
11) Current smoker.
12) Indication of liver disease, defined by serum levels of either ALT, AST, or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 or bilirubin above 1.5 x the ULN measured at Visit 1.
13) Planned cardiac surgery or angioplasty within 19 weeks of Visit 1
14) Bariatric surgery within the past two years, or history of other gastrointestinal surgeries that induce chronic malabsorption.
15) Treatment with anti-obesity drugs 3 months prior to Visit 1 (e.g. orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, naltrexone, either alone or in combination for the purpose of weight loss) or any other treatment at the time of screening (e.g. aggressive diet regimen, etc.) leading to unstable body weight. Unstable body weight is defined as more than 5 kg self-reported change within the 3 months before Visit 1.
16) Have any haematological condition that may interfere with HbA1c measurement (e.g. haemolytic anaemias, haemoglobinopathy).
17) History of an active or untreated malignancy, or in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinoma of the cervix, or in situ prostate cancer) for less than 5 years prior to Visit 1, or are receiving or planning to receive therapy for cancer, at Visit 1.
18) Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, intra-ocular, intranasal, or inhaled preparations) or have received such therapy within 4 weeks of Visit 1.
19) Change in dosage of thyroid replacement hormone within 6 weeks prior to Visit 1.
20) Other endocrine disorder, with the exception of type 2 diabetes and hypothyroidism on stable thyroid replacement dose.
21) Pre-menopausal women (last menstruation less than or equal to 1 year prior to informed consent) who:
a) are nursing or pregnant or
b) are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and for 30 days after end of treatment, and do not agree to submit to periodic pregnancy testing during participation in the trial.
22) Inadequately controlled arterial blood pressure, defined as SBP >160 mmHg at Visit 1 or DBP > 100 mm Hg at Visit 1.
23) Current genito-urinal infection or history of genito-urinal infection within 2 weeks prior to Visit 1 (but not simple asymptomatic bacteriuria).
24) The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Visit 1, or known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
25) Patients with any rare hereditary condition of galactose intolerance, e.g. galactosaemia.
26) Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation.
27) Administration of any investigational product within 30 days or within 5 half-lives of the investigational agent (whichever is longer) of Visit 1, or currently participating in another trial (involving an investigational drug and/or follow-up).
28) Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation. This includes participants unlikely to comply with the study protocol (e.g. an inability and unwillingness to participate in adequate training, an uncooperative attitude, inability to return for follow-up visits, or unlikelihood of completing the study).
29) Persons employed by the Sponsor, Boehringer Ingelheim.
30) Persons who are Investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or adopted.
31) Participants who, in the opinion of the investigator and based on the participant’s comorbid profile, are likely to have a change in dose of GLP-1 receptor agonist during the study.

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation table was created by the Stata 15 (StataCorp LP, Texas, USA) ralloc command using random permuted blocks,
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)
Pharmacodynamics
Statistical methods / analysis
The assumptions for the power calculations were based on the following. The intra-assay coefficient of variation was 1.3% for norepinephrine, 2.3% for [3H]norepinephrine; interassay coefficients of variation were 3.8% and 4.5% respectively. The SD for whole body norepinephrine spillover was 10-13%. Esler and colleagues had previously shown that a sample size of 17 per group had 80% power with a 2 sided alpha of 0.05 to demonstrate group differences of greater than or equal to 10% in log norepinephrine spillover and greater than or equal to 25% in MSNA. The estimated dropout rate is 5% and estimated screen fail rate is 15%. For each arm, 18 people will need to be randomised to achieve 17 participants reaching the end of the treatment period. Therefore, up to 43 people will need to be screened.


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] 7765 0
Baker Heart and Diabetes Institute - Melbourne
Recruitment postcode(s) [1] 15650 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 296015 0
Commercial sector/Industry
Name [1] 296015 0
Boehringer Ingelheim Pty Ltd
Address [1] 296015 0
Level 1, 78 Waterloo Rd, North Ryde, NSW 2113, Australia
Country [1] 296015 0
Australia
Primary sponsor type
Other
Name
Baker Heart and Diabetes Institute
Address
75 Commercial Road, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 294976 0
None
Name [1] 294976 0
None
Address [1] 294976 0
None
Country [1] 294976 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297277 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 297277 0
Old Baker Building, Level 1, 55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 297277 0
Australia
Date submitted for ethics approval [1] 297277 0
25/01/2017
Approval date [1] 297277 0
04/04/2017
Ethics approval number [1] 297277 0

Summary
Brief summary
This study will help to better understand the effect of empagliflozin on the sympathetic nervous system in people who have pre­existing cardiovascular disease. The sympathetic nervous system regulates heart rate, controls blood pressure, regulates sweating and release of glucose from the liver.
The primary aim is to answer this question:
*What effect does empagliflozin have overall on the sympathetic nervous system? The secondary aims are to answer these questions:
*What effects does empagliflozin have on the sympathetic nervous system activity in the heart, kidney, muscle and sweat gland?
*What effects does empagliflozin have on pressure in the heart and on heart muscle contraction and relaxation?
*What effects does empagliflozin have on glucose and metabolite levels?
The study is a randomised trial with 18 people per arm:
*Group 1 ­ empagliflozin
*Group 2 ­ placebo
Total length of study participation will be approximately 19 weeks, i.e. a screening period and baseline assessment period that will last up to 3 weeks, a treatment period lasting 12 weeks, and a safety follow­up period lasting 4 weeks. There will be up to 9 study visits.
During this study, there will be medical history and medication reviews, physical examination, assessment of blood pressure, heart rate and weight, collection of blood and urine. To answer the primary aim, there will be baseline and end of treatment kidney and heart noradrenaline spillover studies and arteriovenous metabolite gradient sampling. This involves sampling from a vein in the back of the hand or arm, from a small tube in the artery in the arm, and from a catheter placed via a vein in the arm, to sample the blood in the heart vein, kidney vein and liver vein. To assess accurately the rate of noradrenaline release from the heart and the kidneys into the bloodstream, a small amount of a radioactive substance will be infused continuously at a low rate through the tube in the arm vein. In the same tube, there will be infused a chemical called para aminohippuric acid (PAH) to measure the kidney blood flow.
To answer the secondary aims, there will be baseline and end of treatment tests of electrocardiogram, echocardiogram (heart ultrasound), questionnaires on general health, anxiety and depression, Sudoscan (nerve activity related to sweating), ankle brachial index (which assesses the blood pressure in all 4 limbs), nerve activity testing in the calf muscle, and a maximum exercise capacity test on a stationary bicycle.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73554 0
Prof David Kaye
Address 73554 0
Level 3, Alfred East Block, Alfred Hospital, 55 Commercial Rd Melbourne, VIC 3004
Country 73554 0
Australia
Phone 73554 0
+61 3 9076 3265
Fax 73554 0
Email 73554 0
david.kaye@baker.edu.au
Contact person for public queries
Name 73555 0
Prof David Kaye
Address 73555 0
Level 3, Alfred East Block, Alfred Hospital, 55 Commercial Rd Melbourne, VIC 3004
Country 73555 0
Australia
Phone 73555 0
+61 3 9076 3265
Fax 73555 0
Email 73555 0
david.kaye@baker.edu.au
Contact person for scientific queries
Name 73556 0
Prof Jonathan Shaw
Address 73556 0
Level 4, Alfred Centre, 99 Commercial Road, Melbourne VIC 3004
Country 73556 0
Australia
Phone 73556 0
+61 3 8532 1800
Fax 73556 0
Email 73556 0
jonathan.shaw@baker.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
subject to confidentiality agreements.
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable