E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
We hypothesize that hyperinsulinemia and hyperglycemia are factors that may negatively influence cardiac function, while an increased availability off free fatty acids are important for maintaining cardiac function in patients with type 2 diabetes. If so the metabolic phenotype of type 2 diabetes may be a necessary adaptation for optimal cardiac function in a hyperinsulinemic and hyperglycemic environment and thus treating hyperglycemia in an insulin independent manner that does not suppress lipid oxidation could improve myocardial function and protect the heart when stressed.
The aim of the present study is to elucidate the physiological importance of hyperglycemia, hyperinsulinemia and elevated free fatty acids for myocardial function during rest and chronotropic stress in patients with type 2 diabetes. |
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E.2.2 | Secondary objectives of the trial |
Secondarily, the study aims to characterize metabolic effects of insulin dependent and independent glucose lowering in patients with type 2 diabetes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Elegible for inclusion are male patients aged ≥18 years with T2DM who are either drug naïve (no anti-diabetes agents for ≥12 weeks prior to randomization) with HbA1c ≤10.0% or taking any background anti-diabetes therapy (except insulin) with HbA1c ≤9.0% despite diet and exercise counseling.
6.1 INCLUSION CRITERIA:
• Age ≥ 18 years
• BMI ≥ 28 kg/m2
• HbA1c ≤ 9.0% (≤10% in diet or metformin only treated patients)
• Fasting C-peptide ≥ 500 pmol/L
• Unchanged antiglycemic treatment 12 weeks prior to inclusion as assessed by investigator |
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E.4 | Principal exclusion criteria |
EXCLUSION CRITERIA:
• Insulin treatment within 3 months of informed consent
• Type 1 diabetes
• Psychiatric disorder or mental retardation
• Drug or alcohol abuse within 3 months from informed consent
• Poor compliance
• Anemia (hgb ≤ 6.4 mmol/L) or other blood dyscrasias causing hemolysis or unstable red blood cells
• Indication of liver disease, defined by serum levels of alanine amininotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit
• Impaired renal function (eGFR<45ml/min/1.73 m2)
• Treatment with anti-obesity drugs 3 months prior to informed consent
• Systemic steroid treatment within 6 weeks of informed consent
• Uncontrolled thyroid disease (prescribed changes in thyroid medication within the 6 weeks prior to informed consent)
• Any uncontrolled endocrine disorder except type 2 diabetes
• Bariatric surgery or other gastrointestinal disorders that compromises gastrointestinal absorption
• Peptic ulcer – verified by endoscopically
• Any form of planned surgery within 3 months of informed consent
• Acute coronary syndrome, stroke or TCI within 2 months prior to informed consent
• Persistent atrial fibrillation
• Inability to undergo experimental procedures including exclusion criteria for MRI scanning:
o Implantable cardioverter defibrillator/pacemaker
o Ferromagnetic clips
o Claustrophobia.
• Contraindication to glycopyrrolate infusion:
o Known closed-angle glaucoma
o known severe prostate hyperplasia
o Tachycardia (HR > 100 at rest)
o Known bladder atony
o Cardia insufficiency or non-congenital pylorus stenosis – verified endoscopically
o Known gastroparesis
• Allergy towards any of the drugs or diagnostics used in the protocol (insulin, empagliflozin, acipimox, glycopyrrolate, adenosine, gadolinium contrast enhancer).
• Any condition which in the opinion of the investigator may jeopardize subject safety or compliance with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
PRIMARY ENDPOINT:
Myocardial diastolic function (Cardiac MRI): Change in left ventricular peak filling rate (ΔLVPFR)
Change is defined as LVPFRtreatment - LVPFRbaseline. Baseline is defined as the visit during the wash-out period preceding the treatment period. Thus, if the patient is randomized to insulin first. Baseline for insulin treatment is visit 1, and baseline for empagliflozin treatment is visit 3.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The study is a 20-week prospective, interventional, comparator controlled, open label, 2-arm cross-over study where subjects are randomized to NPH insulin or Empagliflozin (25 mg once daily) treatment first for 5 weeks, followed by 3 weeks wash-out and cross-over to 5 weeks treatment with the remaining study drug. For 7 weeks preceding randomization but after inclusion, patients undergo a program of washout of pre-existing antiglycemic treatment (except metformin) and run-in of empagliflozin (see below).
At the ens of an initial wash-out period, after 5 weeks of first study drug treatment, at the end of another washout period anda again at the end of 5 weeks of treatment with second study drug. |
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E.5.2 | Secondary end point(s) |
2.4.2 KEY SECONDARY ENDPOINT:
Myocardial diastolic function: Change in left atrial passive emptying fraction
2.4.3 SECONDARY ENDPOINTS:
Myocardial systolic function (Cardiac MRI): Change in left ventricular ejection fraction (ΔLVEF)
The study design does not allow for blinding, but evaluation of primary and secondary outcomes will be performed by specialists in the field of MRI blinded to the treatment og the patients.
2.4.4 DESCRIPTIVE ENDPOINTS:
CARDIOVASCULAR ENDPOINTS:
a) VO2max – estimated from Aastrands two-point test.
b) Change in central blood volume and hematocrite.
METABOLIC ENDPOINTS:
a) Basal and postprandial AUC FFA and glycerol turnover
b) Endogenous glucose production and tissue glucose disposal (metabolic clearance of glucose)
c) Fasting and postprandial energy expenditure and respiratory quotient.
d) Glucagon/insulin ratio
e) Insulin sensitivity (Average glucose metabolic clearance rate during OGTT/average insulin concentration)
f) Beta-cell function (prehepatic insulin secretion rate (determined by deconvolution of C-peptide data) correlated to ambient glucose concentrations, glucose sensitivity).
g) Adlibitum food intake |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |