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] - Nutritional and Metabolic Diseases [C18] |
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 |
To compare the changes in global longitudinal strain of the left ventricle (GLSLV) achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment. |
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E.2.2 | Secondary objectives of the trial |
To compare the changes in myocardial efficiency (%) achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment. Exploratory objectives: - To compare the changes in myocardial perfusion (ml/min/g) measured by [11C]-Acetate achieved with dapagliflozin vs. placebo after 6 weeks of double-blind treatment. - To compare the changes in myocardial fatty acid uptake (MFAU, μmol/min/g) by [18F]-FTHA) achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment. - To compare the changes in Left atrial volume (min, max) (mL), Left atrial ejection fraction (%) and transmitral flow velocity indicies (E/A (1), E (cm/s), A (cm/s) and DT (ms)), achieved with dapagliflozin versus placebo after 6 weeks of double-blind treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). - Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. - Individuals with type 2 diabetes diagnosed for at least 6 months based on the American Diabetes Association standards (ADA, 2017) and on stable dose of metformin for at least 6 weeks prior to screening and HbA1c at screening visit of ≥42 mmol/mol (6.0%) and ≤75 mmol/mol (9.0%) measured at local hospital laboratory. - Females or males ≥40 years up to 75 years of age. - No significant signs or symptoms of coronary artery disease or, if known coronary artery disease, currently free of symptoms and a) all major epicardial vessels with <50% stenosis within 12 months prior to screening, or b) if revascularized with all major epicardial vessels with <50% remaining stenosis after stenting or bypass surgery procedure determined between 3 and 12 months prior to screening. - Normal left ventricular ejection fraction (≥50%) assessed within 1 year prior to informed consent, and if applicable, after most recent acute episode of coronary artery syndrome, or at screening visit. - Body mass index (BMI) ≥ 25 kg/m2. |
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E.4 | Principal exclusion criteria |
- Blood pressure at screening that would require a change in blood pressure treatment over the study period or any of the following: systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg. - History of stroke or other clinically significant cerebrovascular disease. - Planned cardiac surgery or angioplasty within 3 months from enrolment. - Any of the following cardiovascular diseases known within 3 months prior to signing the consent at enrolment: a. Atrial fibrillation, or other unstable or severe arrhythmia affecting heart function b. Unstable heart failure or any heart failure with NYHA class III and IV c. Significant valvular disease d. Significant peripheral artery disease - Clinical diagnosis of type 1 diabetes, maturity onset diabetes of the young (MODY), secondary diabetes or diabetes insipidus. - Patients with severe hepatic impairment (Child-Pugh class C). - Unstable or rapidly progressing renal disease. - Ongoing treatment with other antidiabetic drugs than metformin. - Ongoing treatment with loop diuretics. - Ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents. - Estimated Glomerular Filtration Rate (eGFR) <45 mL/min/1.73 m2, - Women who has a positive pregnancy test at enrolment or randomization, or are breastfeeding. - Any condition when MRI and CT-PET is contraindicated such as, but not limited to, having a metallic implant (such as pacemaker or cochlear implant), permanent make up, claustrophobia or BMI ≥40 kg/m2). - Active malignancy requiring treatment at the time of visit 1 (with the exception of successfully treated basal cell or treated squamous cell carcinoma). - Plasma donation within one month of screening or any blood donation/blood loss >450 mL during the 3 months prior to screening. - Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study treatment intake. - Ongoing treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except for T2D. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in GLSLV (%). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Change from baseline in myocardial efficiency (%).
Exploratory end points: - Changes from baseline in myocardial perfusion measured by [11C]-Acetate - Changes from baseline in myocardial fatty acid uptake by [18F]-FTHA - Changes from baseline in Left atrial min volume, Left atrial max volume, Left atrial ejection fraction and transmitral flow velocity indicies (E/A, E, A and DT) |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |