Efficacy of Double vs Standard Empapagliflozin Dose for METabolic syndromE tReatment

Study Overview
=================
Brief Summary
-----------------
The DEMETER - SIRIO 11 study is a phase III, multicenter, randomized, open-labled, investigator-initiated clinical trial with a 6 month follow-up. The study population will include 200 subjects with diagnosis of metabolic syndrome. All enrolled patients (nn=200) will be randomly assigned in 1:1 ratio to one of the two study arms: Empagliflozin 20 mg - experimental arm Empagliflozin 10 mg - control arm. Primary co-endpoints of the study include: BMI and HbA1c. Secondary endpoints include: LDL-C, triglycerides, CRP, NT-proBNP, LVEF (echocardiography), body composition, VO2max (ergospirometry), waist-hip ratio (WHR), liver steatosis assessment (LSA) by computed tomography (CT), major adverse cardiovascular events - MACE (based on medical history: heart attack, stroke, death), cardiovascular hospitalizations.

Detailed Description
-----------------
The DEMETER - SIRIO 11 study is a phase III, multicenter, randomized, open-labled, investigator-initiated clinical trial with a 6 month follow-up. The study population will include 200 subjects with diagnosis of metabolic syndrome. All enrolled patients (nn=200) will be randomly assigned in 1:1 ratio to one of the two study arms: Empagliflozin 20 mg - experimental arm Empagliflozin 10 mg - control arm. Primary co-endpoints of the study include: BMI and HbA1c. Secondary endpoints include: LDL-C, triglycerides, CRP, NT-proBNP, LVEF (echocardiography), body composition, VO2max (ergospirometry), waist-hip ratio (WHR), liver steatosis assessment (LSA) by computed tomography (CT), major adverse cardiovascular events - MACE (based on medical history: heart attack, stroke, death), cardiovascular hospitalizations. Other variables that are scheduled to be analyzed: central arterial pressure, pulse wave propagation speed, ABPM (ambulatory blood pressure monitoring), endothelial function assessment by Endopath, autonomic nervous system assessment (ANSA) by Task Force Touch CARDIO (TFTC), exercise tolerance, thickness of the adipose tissue (skin fold), blood samples: blood count, serum creatinine and eGFR, ALT, AST, GGTP, total cholesterol, HDL-C, uric acid, plasma concentration of calcium, phosphate, parathormon, 25-OH-D3, cystatin C, erythropoietin; morning urine: N-acetyl-beta-D-glucosaminidase, sodium/creatinine ratio, calcium/creatinine ratio, albumin/creatinine ratio. Moreover, functioning in chronic disease and adherence to medication and diet will be assessed with dedicated questionairies (FCIS, ACDS, ACDS diet).

Official Title
-----------------
Efficacy of Double vs Standard Empapagliflozin Dose for METabolic syndromE tReatment (DEMETER - SIRIO 11) Study

Conditions
-----------------
Metabolic Syndrome

Intervention / Treatment
-----------------
* Drug: Empagliflozin 20 mg
* Drug: Empagliflozin 10 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: diagnosis of metabolic syndrome as follows: the presence of obesity (waist circumference ≥ 88 cm in women; ≥102 cm or body mass index (BMI) ≥30 kg/m2) and two of the three following criteria: high blood pressure (systolic blood pressure - in-office measurement: ≥ 130 and/or diastolic blood pressure ≥85 mm Hg or systolic blood pressure - ambulatory measurement: ≥130 and/or diastolic blood pressure ≥ 80 mm Hg) or on anti-hypertensive treatment; impaired glucose metabolism (fasting glucose ≥100 mg/dL or ≥ 140 mg/dL after 120 min in oral glucose tolerance test or HbA1c ≥5.7%) or on glucose-lowering drug treatment; elevated non-high-density lipoprotein (non-HDL ≥130 mg/dL) cholesterol level (atherogenic dyslipidemia) or on lipid-lowering drug treatment Exclusion Criteria: current treatment with SGLT2 inhibitor chronic kidney disease with estimated glomerular filtration rate (eGFR) &lt; 30 mL/min or on dialysis severely impaired liver function known hypersensitivity to the active empagliflozin or to any of the excipients contained in Jardiance history of ketoacidosis diabetes treated with insulin pregnancy decompensated heart failure acute coronary syndrome active thromboembolic disease current treatment for neoplastic disease active inflammatory disease within 1 month prior to enrollment expected lifetime <1 year non-cooperative patients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin 20 mg<br>Patients receiving empagliflozin 20 mg daily | Drug: Empagliflozin 20 mg<br>* Patients receiving empagliflozin 20 mg daily - experimental arm<br>|
| Active Comparator: Empagliflozin 10 mg<br>Patients receiving empagliflozin 10 mg daily | Drug: Empagliflozin 10 mg<br>* Patients receiving empagliflozin 10 mg daily - control arm<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMI (Body Mass Index) | change in BMI between study arms | 0-6 months | 
| concentration of HbA1c (glycated hemoglobin) | change in glycated hemoglobin plasma concentration between study arms | 0-6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| concentration of LDL-C (low density cholesterol serum concentration) | change in low density cholesterol serum concentration between study arms | 0-6 months | 
| concentration of triglycerides | change in triglycerides serum concentration between study arms | 0-6 months | 
| concentration of CRP (c-reactive protein) | change in CRP serum concentration between study arms | 0-6 months | 
| concentration of NT-proBNP | change in NT-pro BNP serum concentration between study arms | 0-6 months | 
| LVEF - left ventricle ejection fraction (echocardiography) | change in LVEF (presented in percentage) between study arms | 0-6 months | 
| body composition analysis - body fat mass [kg] | evaluation of body fat mass [kg] change throughout the study | 0-6 months | 
| body composition analysis - body fat mass [%] | evaluation of body fat mass [%] change throughout the study | 0-6 months | 
| body composition analysis - lean body mass [kg] | evaluation of lean body mass [kg] change throughout the study | 0-6 months | 
| body composition analysis - lean body mass [%] | evaluation of lean body mass [%] change throughout the study | 0-6 months | 
| body composition analysis - skeletal muscle mass [kg] | evaluation of skeletal muscle mass [kg] change throughout the study | 0-6 months | 
| body composition analysis - total body water [liters] | evaluation of total body water [liters] change throughout the study | 0-6 months | 
| body composition analysis - total body water [%] | evaluation of total body water [%] change throughout the study | 0-6 months | 
| body composition analysis - extracellular water [liters] | evaluation of extracellular water [liters] change throughout the study | 0-6 months | 
| body composition analysis - extracellular water [%] | evaluation of extracellular water [%] change throughout the study | 0-6 months | 
| body composition analysis - hydration [%] | evaluation of hydration [%] change throughout the study | 0-6 months | 
| body composition analysis - visceral fat level [liters] | evaluation of visceral fat level [liters] change throughout the study | 0-6 months | 
| level of maximal oxygen uptake (VO2max) measured in ergospirometry | change in VO2 max between study arms | 0-6 months | 
| waist-hip ratio (WHR) | change in waist-hip ratio between study arms | 0-6 months | 
| liver steatosis assessment (LSA) by computed tomography (CT) | evaluation of liver steatosis assessment (LSA) assessed with computed tomography (CT), between study arms throughout the study | 0-6 months | 
| major adverse cardiovascular events - MACE | rate of MACE (based on medical history: heart attack, stroke, death) between study arms throughout the study | 0-6 months | 
| cardiovascular hospitalizations | rate of cardiovascular hospitalizations between study arms | 0-6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metabolic syndrome, empagliflozin, adherence