| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus |
| Type 2 Diabetes Mellitus |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 determine the effects of 8-week empagliflozin (SGLT-2 inhibitor) monotherapy (10 mg QD), followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor) combination therapy (10/5 mg QD) versus 8-week linagliptin monotherapy (5 mg QD), followed by 8-week linagliptin and empagliflozin combination therapy (5/10 mg QD) versus 8-week gliclazide (Sulfonylurea) monotherapy (30 mg QD), followed by 8-week gliclazide intensification (30 mg BID) on renal hemodynamics in both the fasting and postprandial state in metformin-treated T2DM patients, measured as:
• GFR (measured by the iohexol-clearance technique)
• Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid (PAH) clearance technique) |
|
| E.2.2 | Secondary objectives of the trial |
- Renal Tubular Function
-Renal damage
-Blood Pressure and heart rate
-Body anthropometrics and Body fat content
-Glycemic variables, Lipid spectrum, Inflammation, Biochemistry and
Hematology
-Arterial stiffness (PWA)
-Systemic hemodynamics
-CANS function
Exploratory objectives:
-Biomarkers and gut microbiome
-DNA
-Insulin sensitivity
-Beta-cell function
-Microvascular function |
|
| 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 - 75 years
• BMI: >25 kg/m2
• HbA1c: 7.0 – 9.5% Diabetes Control and Complications Trial (DCCT) or 53 - 80 mmol/mol International Federation of Clinical Chemistry (IFCC)
• Treatment with a stable dose of metformin monotherapy for at least 3 months prior to inclusion
• Hypertension should be controlled, i.e. ≤140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months.
• Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months.
• Written informed consent
* In order to increase homogeneity
|
|
| E.4 | Principal exclusion criteria |
• Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in Renal Disease (MDRD) study equation)
• Current urinary tract infection and active nephritis
• History of unstable or rapidly progressing renal disease
• Macroalbuminuria; defined as ACR of 300 mg/g.
• Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs).
• Patients on diuretics will only be excluded when these drugs cannot be stopped 3 months prior randomization and for the duration of the study.
• 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 drugs can be taken within a time-frame of 2 weeks prior to renal-testing
• Pregnancy
• History of or actual severe mental disease
• History of or actual severe somatic disease (e.g. systemic disease)
• History of or actual malignancy (except basal cell carcinoma)
• History of or actual pancreatic disease
• (Unstable) thyroid disease
• Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
• Recent (<6 months) history of cardiovascular disease, including
o Acute coronary syndrome
o Stroke or transient ischemic neurologic disorder or chronic heart failure (NYHA grade II-IV)
• Complaints compatible with or established neurogenic bladder and/or incomplete bladder emptying (as determined by ultrasonic bladder scan)
• Substance abuse (alcohol: defined as >3 units alcohol/day)
• History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
• Recent blood donation (< 6 months)
• Allergy to any of the agents used in the study
• Inability to understand the protocol and/or give informed consent
• 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Renal hemodynamics, measured as:
• Glomerular filtration rate (GFR; measured by the iohexol-clearance
technique)
•Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid (PAH) clearance technique) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Renal hemodynamics are assessed at baseline, 8 weeks and 16 weeks of
treatment. |
|
| E.5.2 | Secondary end point(s) |
To investigate the effects of the above-indicated interventions on:
• Renal damage markers (Week 0, 2, 8, 10, 16):
o 24-hour urinary albumin excretion (glomerular)
o Albumin-creatinine ratio (glomerular)
• Renal tubular function (Week 0, 8, 16), measured as:
o Fractional and cumulative (24-hour urine collection) sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid, bicarbonate-, ammonium- and urea excretion
o Urinary glucose excretion
o Urine osmolality
o Urinary pH
• GFR trajectory (Week 0, 2, 8, 10, 16), measured by:
o Creatinine clearance (24-hour urine collection)
• Systemic hemodynamics, measured by:
o Week 0, 2, 8, 10, 16: SBP, DBP, MAP and heart rate, measured by automated oscillometric blood pressure monitor (Dinamap®)
o Week 0, 8, 16: SBP, DBP, MAP, heart rate (HR), stroke volume (SV), cardiac output (CO)/-index (CI), and total systemic vascular resistance (TSVR)) derived from non-invasive beat-to-beat finger blood pressure measurements (Finger photoplethysmography, Nexfin®)
• Autonomic nervous system activity (Week 0, 8, 16), measured by:
o Heart rate variability derived from automated, beat-to-beat blood pressure and ECG recording monitor (Finger photoplethysmography, Nexfin®)
• Vascular function (Week 0, 8, 16), measured as:
o Arterial stiffness (Pulse Wave Analysis), measured by radial artery applanation tonometry (SphygmoCor®)
• Metabolic biomarkers
o Glycated hemoglobin (HbA1c), and fasting and postprandial glucose, lipids (triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and free fatty acids (FFA)), insulin, glucagon.
• Body anthropometrics
o Height, weight, BMI and waist/hip circumference
o Body fat content, total body water (TBW) and body cell mass (BCM) measured by body impedance analysis (BIA) (Soft Tissue Analyzer®)
Exploratory Objectives
(The extent of these complementary measurements is conditional to feasibility and available budget)
To investigate the effects of the above-indicated interventions on:
• Complementary markers of renal function / damage (NGAL, KIM-1, plasma cystatin C, fibroblast growth factor -23 (FGF-23), parathyroid hormone (PTH), soluble Klotho, urinary transforming growth factor-β1 (TGF-β1), collagen type IV, nephrin, podocin, urinary microparticles, 8-hydroxy-2' -deoxyguanosine (8-OHdG), Calcitriol, Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α))
• (Cardiovascular)-biomarkers (N-terminal pro-B-Type Natriuretic Peptide (NT-proBNP), Brain Natriuretic Peptide (BNP), Atrial Natriuretic Peptide (ANP), plasma renin activity (PRA), angiotensin II, angiotensin 1-7, aldosterone, urinary angiotensinogen, endothelin, catecholamines, soluble receptor for advanced glycation end products (sRAGE), zonulin, fructosamine, uric acid, ketone bodies, FGF-21, isoprostanes, urinary adenosine, plasma co-peptin, urinary cortisol, urinary dopamine
• Additional markers of inflammation (hsCRP, interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1))
• Deoxyribonucleic acid (DNA) (to study the influence of genetic factors on the parameters measured and the response to DPP-4 inhibitor and / or SGLT-2 inhibitor) This will only be performed after specific and separate consent by the participant.
• DDP-4 substrates (GLP-1, GIP, substance-P, Neuropeptide Y (NPY), Stromal cell-derived factor 1 (SDF-1α), erythropoietin) and DPP-4 activity.
• 24h ambulatory blood pressure monitor (not mandatory, assed only when feasible (i.e. extra visit to pick up monitor; distance to CRU and willingness participant. Office blood pressure will also be measured after 1 hour rest in semi-recumbent position)
• Gut microbiome composition from fecal samples.
• Insulin sensitivity (M-value ) as derived from the glucose infusion rate during the euglycemic clamp (23)
• Insulin sensitivity (OGIS (24) , Matsuda index (25)) as derived from the meal tolerance test
• Beta-cell function measures as derived from HOMA-B (26), insulinogenic index and ratio of postprandial glucose and C-peptide area under the curve (24)
Safety Objectives
• To evaluate the safety and tolerability of empagliflozin, linagliptin and their combination, compared to gliclazide, in the target patient population (Hb, Ht, erythrocytes, leucocytes, thrombocytes, sodium, potassium, AST, GGT, creatinine and urine screening). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary and exploratory end points are assessed at baseline and after 8 weeks and
16 weeks of treatment. |
|
| 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 is to assess changes in renal physiology using a DPP-4I versus a SGLT-2I versus a SU derivative and combined SGLT-2 / DPP-4I versus intensified SU derivative |
|
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
Print
