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 |
To investigate the effects of 7+-1 days of of mono- and combination therapy with the SGLT2 inhibitor empagliflozin (10 mg QD) and RAS inhibitor losartan (50 mg QD) on renal hemodynamics, (glomerular filtration rate (GFR) / effective renal plasma flow (ERPF)) in metformin and/or SU-treated T2DM patients |
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E.2.2 | Secondary objectives of the trial |
What are the effects of 7+-1 days of mono- and combination therapy with the SGLT2 inhibitor empagliflozin (10 mg QD) and RAS inhibitor losartan (50 mg QD) in T2DM patients on:
1) Estimated intrarenal hemodynamic functions
2) 24-hr sodium, glucose, creatinine and albumin excretion
3) Systemic hemodynamics
4) Autonomic nervous system activity
5) Cardiovascular/metabolic biomarkers
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Caucasian*
• Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L)
• Age: 35 - 80 years
• BMI: >25 kg/m2
• HbA1c: 6.5 – 10.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 mmol/mol International Federation of Clinical Chemistry (IFCC)
• Treatment with a stable dose of metformin and/or SU therapy for at least 3 months prior to inclusion
• Written informed consent
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E.4 | Principal exclusion criteria |
• History of unstable or rapidly progressing renal disease
• Macroalbuminuria; defined as ACR of 300mg/g.
• Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (CKD-EPI) study equation)
• Only use of alpha blockers and/or beta blockers are allowed as antihypertensive background therapy. Patients using an antihypertensive agent will be considered if this agent can be stopped (i.e. blood pressure adequate to stop at screening) or replaced by an alpha and/or beta blocker. In these patients, a 4 week wash-out/run-in period will be observed prior to visit 2.
• Current/chronic use of the following medication: SGLT2 inhibitors, RAS inhibitors, TZD, GLP-1RA, DPP-4 inhibitors, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
• Volume depleted patients. Patients at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
• Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drug can be taken within a time-frame of 2 weeks prior to renal-testing
• History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
• Current urinary tract infection and active nephritis
• Recent (<6 months) history of cardiovascular disease, including:
o Acute coronary syndrome
o Chronic heart failure (New York Heart Association grade II-IV)
o Stroke or transient ischemic neurologic disorder
• Complaints compatible with neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
• Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
• (Unstable) thyroid disease; defined as fT4 outside of laboratory reference values or change in treatment within 3 months prior to screening visit
• History of or actual malignancy (except basal cell carcinoma)
• History of or actual severe mental disease
• Substance abuse (alcohol: defined as >4 units/day)
• Allergy to any of the agents used in the study
• Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
• Inability to understand the study protocol or give informed consent
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E.5 End points |
E.5.1 | Primary end point(s) |
change in GFR after 7+-1 days of treatment with empagliflozin and losartan versus losartan monotherapy, empagliflozin monotherapy or placebo as derived from the iohexol clearance test. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assesed 4 times, after every 7+-1 days of intervention |
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E.5.2 | Secondary end point(s) |
What are the effects of 7+-1 days of mono- and combination therapy with the SGLT2 inhibitor empagliflozin (10 mg QD) and RAS inhibitor losartan (50 mg QD) in T2DM patients on:
1) Estimated intrarenal hemodynamic functions
2) 24-hr sodium, glucose, creatinine and albumin excretion
3) Systemic hemodynamics
4) Autonomic nervous system activity
5) Cardiovascular/metabolic biomarkers
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints will be assesed 4 times, after every 7+-1 days of intervention |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Mechanistic - the aim of this trial is to assess the effect of 4 times 7+-1 days treatment with SGLT-2 inhibitor empagliflozin and RAS inhibitor losartan on renal hemodynamics |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |