SGLT2 Inhibitors in Glomerular Hyperfiltration (EMPATHY)
Primary Purpose
Obesity, Non-diabetic Chronic Kidney Disease
Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Empagliflozin 10 MG
Sponsored by
About this trial
This is an interventional treatment trial for Obesity focused on measuring GFR decline, Glomerular hyperfiltration, SGLT2 inhibitors, Residual proteinuria, Obesity
Eligibility Criteria
Inclusion Criteria:
- Male and female ≥ 18 years old;
Increased risk of accelerated renal function loss because of absolute or relative hyperfiltration associated with unhealthy obesity or residual proteinuria defined as:
Unhealthy obesity:
- BMI >30 kg/m^2 or waist circumference >94 cm in males and > 80 cm in females
- Metabolic syndrome, defined as the presence of at least three of the following criteria:
- Blood pressure>140/90 mmHg or controlled blood pressure under current antihypertensive treatment
- Triglyceride levels >150 mg/dL
- HDL<40 mg/dL in males <50 mg/dL in females
- Fasting blood glucose > 100 and <125 mg/dL
Residual proteinuria:
- Urinary protein excretion >1g/24-h to <3g/24-h despite RAS inhibitor therapy with ACE inhibitors or ARBs;
- Blood pressure in recommended targets with or without blood pressure lowering medications;
- Estimated GFR > 60 ml/min/1.73m^2 (CKD-EPI formula);
- Female childbearing potential and non-sterile male must agree to use a method of contraception;
- Written informed consent
Exclusion Criteria:
- Type 1or 2 diabetic patients;
- Concomitant treatment with insulin or oral hypoglycemic agents;
- Nephrotic syndrome of any etiology;
- Patients with Autosomal Dominant Polycystic Kidney Disease;
- Symptomatic urinary tract lithiasis or obstruction;
- Ischemic kidney disease (because of possible excess risk of acute kidney injury upon SGLT2 inhibition associated reduction in sodium pool and kidney perfusion pressure);
- Rapidly progressive kidney disease defined by impairment of renal function within 2 weeks - 3 months (for the cohort of patients with residual proteinuria only) ;
- Active systemic autoimmune diseases;
- Treatment for glomerulopathies or systemic diseases with steroids or any other immunosuppressive agent within one year;
- Specific contraindication to SGLT2 inhibitor therapy;
- Heart failure with or without decreased systolic function;
- Uncontrolled hypertension or symptomatic hypotension;
- History of malignancy within 5 years of screening;
- Inability to fully understand the possible risks and benefits related to study participation;
- If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period;
- If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose;
- Alcohol and drug abuse;
- Participation in another interventional clinical trial within the 4 weeks prior to screening.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
IMP
Arm Description
Outcomes
Primary Outcome Measures
Measured Glomerular Filtration Rate (GFR)
GFR will be measured by the iohexol plasma clearance technique
Secondary Outcome Measures
24 hour urinary output
last of three consecutive collections
24 hour urinary protein excretion
mean of the measurement in three consecutive 24-hour urine collection
24 hour urinary albumin excretion
mean of the measurement in three consecutive 24-hour urine collection
24 hour urinary urea excretion
last of three consecutive collections
24 hour urinary phosphate excretion
last of three consecutive collections
24 hour urinary sodium excretion
last of three consecutive collections
24 hour urinary glucose excretion
last of three consecutive collections
24 hour urinary potassium excretion
last of three consecutive collections
24 hour urinary uric acid excretion
last of three consecutive collections
24 hour urinary creatinine excretion
last of three consecutive collections
Fractional clearance of total protein calculated by standard formulas
Fractional clearance of albumin calculated by standard formulas
Fractional clearance of sodium calculated by standard formulas
Fractional clearance of potassium calculated by standard formulas
Fractional clearance of uric acid calculated by standard formulas
Fractional clearance of free water calculated by standard formulas
Glucose disposal rate
Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index;
Glucose tolerance
Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index;
Office blood pressure
Office heart rate
24 hour (day-time and night-time) blood pressure monitoring
24 hour (day-time and night-time) heart rate monitoring
Pulse wave velocity
These parameters will be measured by tonometry
other marker of vascular stiffness
These parameters will be measured by tonometry
Indices of Quality of Life: questionnaire SF-36
By submission of validate questionnaire
Full Information
NCT ID
NCT04143581
First Posted
October 25, 2019
Last Updated
September 6, 2021
Sponsor
Mario Negri Institute for Pharmacological Research
Collaborators
Boehringer Ingelheim
1. Study Identification
Unique Protocol Identification Number
NCT04143581
Brief Title
SGLT2 Inhibitors in Glomerular Hyperfiltration
Acronym
EMPATHY
Official Title
Evaluating the Short-Term Renal and Systemic Effects of SGLT2 Inhibition in Non-Diabetic Patients at Risk of Accelerated GFR Decline Because of Glomerular Hyperfiltration: a Sequential OFF-ON-OFF Study With One-Month Empagliflozin Therapy Followed by One-Month Recovery Period
Study Type
Interventional
2. Study Status
Record Verification Date
September 2021
Overall Recruitment Status
Withdrawn
Why Stopped
Lack of funds
Study Start Date
September 3, 2021 (Actual)
Primary Completion Date
September 3, 2021 (Actual)
Study Completion Date
September 3, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mario Negri Institute for Pharmacological Research
Collaborators
Boehringer Ingelheim
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Glomerular hyperfiltration is a major risk factor for accelerated glomerular filtration rate (GFR) decline and renal and cardiovascular events despite optimized conservative therapy with blood pressure and blood glucose (in diabetics) lowering medications and inhibitors of the Renin Angiotensin System (RAS) such as Angiotensin Converting Enzyme (ACE) inhibitors and/or Angiotensin Receptor Blockers (ARBs).
Progressive GFR decline initiated and sustained by glomerular hyperfiltration in subjects with diabetes, unhealthy obesity, hypertension and other risk factors, is paralleled by progressive glomerulosclerosis and loss of functioning nephrons.
The inhibition of the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubular segments of the nephrons appears to be an ideal, specific intervention to inhibit the tubulo-glomerular feedback and ameliorate glomerular hyperfiltration in subjects with absolute or relative hyperfiltration associated with unhealthy obesity or proteinuric chronic kidney disease (CKD). Indeed, by reducing tubular sodium reabsorption, SGLT2 inhibitors may enhance sodium chloride delivery to the macula densa, restore pre-glomerular resistances and therefore limit glomerular hyperperfusion and consequent hyperfiltration. Moreover, because of its natriuretic effects, SGLT2 inhibition therapy might reduce the sodium overload and volume expansion which, along with secondary hypertension, may further contribute to kidney hyperperfusion and glomerular hyperfiltration in obesity and CKD.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity, Non-diabetic Chronic Kidney Disease
Keywords
GFR decline, Glomerular hyperfiltration, SGLT2 inhibitors, Residual proteinuria, Obesity
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
OFF/ON/OFF design
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
IMP
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Empagliflozin 10 MG
Other Intervention Name(s)
Jardiance
Intervention Description
Empagliflozin 10 mg/die for 28 days
Primary Outcome Measure Information:
Title
Measured Glomerular Filtration Rate (GFR)
Description
GFR will be measured by the iohexol plasma clearance technique
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Secondary Outcome Measure Information:
Title
24 hour urinary output
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary protein excretion
Description
mean of the measurement in three consecutive 24-hour urine collection
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary albumin excretion
Description
mean of the measurement in three consecutive 24-hour urine collection
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary urea excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary phosphate excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary sodium excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary glucose excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary potassium excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary uric acid excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour urinary creatinine excretion
Description
last of three consecutive collections
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of total protein calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of albumin calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of sodium calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of potassium calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of uric acid calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Fractional clearance of free water calculated by standard formulas
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Glucose disposal rate
Description
Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index;
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Glucose tolerance
Description
Performed by hyperinsulinemic euglycemic clamp and by standard oral glucose load and HOMA index;
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Office blood pressure
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Office heart rate
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour (day-time and night-time) blood pressure monitoring
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
24 hour (day-time and night-time) heart rate monitoring
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Pulse wave velocity
Description
These parameters will be measured by tonometry
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
other marker of vascular stiffness
Description
These parameters will be measured by tonometry
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
Title
Indices of Quality of Life: questionnaire SF-36
Description
By submission of validate questionnaire
Time Frame
Changes from baseline to the end of one-month treatment period and one-month recovery period
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male and female ≥ 18 years old;
Increased risk of accelerated renal function loss because of absolute or relative hyperfiltration associated with unhealthy obesity or residual proteinuria defined as:
Unhealthy obesity:
BMI >30 kg/m^2 or waist circumference >94 cm in males and > 80 cm in females
Metabolic syndrome, defined as the presence of at least three of the following criteria:
Blood pressure>140/90 mmHg or controlled blood pressure under current antihypertensive treatment
Triglyceride levels >150 mg/dL
HDL<40 mg/dL in males <50 mg/dL in females
Fasting blood glucose > 100 and <125 mg/dL
Residual proteinuria:
Urinary protein excretion >1g/24-h to <3g/24-h despite RAS inhibitor therapy with ACE inhibitors or ARBs;
Blood pressure in recommended targets with or without blood pressure lowering medications;
Estimated GFR > 60 ml/min/1.73m^2 (CKD-EPI formula);
Female childbearing potential and non-sterile male must agree to use a method of contraception;
Written informed consent
Exclusion Criteria:
Type 1or 2 diabetic patients;
Concomitant treatment with insulin or oral hypoglycemic agents;
Nephrotic syndrome of any etiology;
Patients with Autosomal Dominant Polycystic Kidney Disease;
Symptomatic urinary tract lithiasis or obstruction;
Ischemic kidney disease (because of possible excess risk of acute kidney injury upon SGLT2 inhibition associated reduction in sodium pool and kidney perfusion pressure);
Rapidly progressive kidney disease defined by impairment of renal function within 2 weeks - 3 months (for the cohort of patients with residual proteinuria only) ;
Active systemic autoimmune diseases;
Treatment for glomerulopathies or systemic diseases with steroids or any other immunosuppressive agent within one year;
Specific contraindication to SGLT2 inhibitor therapy;
Heart failure with or without decreased systolic function;
Uncontrolled hypertension or symptomatic hypotension;
History of malignancy within 5 years of screening;
Inability to fully understand the possible risks and benefits related to study participation;
If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period;
If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose;
Alcohol and drug abuse;
Participation in another interventional clinical trial within the 4 weeks prior to screening.
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
SGLT2 Inhibitors in Glomerular Hyperfiltration
We'll reach out to this number within 24 hrs