Clinical trial NCT04143581: SGLT2 Inhibitors in Glomerular Hyperfiltration
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
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Obesity
Non-diabetic Chronic Kidney Disease
Keywords: GFR decline
Glomerular hyperfiltration
SGLT2 inhibitors
Residual proteinuria
Obesity
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2019-10-29
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: OFF/ON/OFF design
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Male and female ≥ 18 years old;
2. 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;
3. Estimated GFR \> 60 ml/min/1.73m\^2 (CKD-EPI formula);
4. Female childbearing potential and non-sterile male must agree to use a method of contraception;
5. Written informed consent

Exclusion Criteria:

1. Type 1or 2 diabetic patients;
2. Concomitant treatment with insulin or oral hypoglycemic agents;
3. Nephrotic syndrome of any etiology;
4. Patients with Autosomal Dominant Polycystic Kidney Disease;
5. Symptomatic urinary tract lithiasis or obstruction;
6. Ischemic kidney disease (because of possible excess risk of acute kidney injury upon SGLT2 inhibition associated reduction in sodium pool and kidney perfusion pressure);
7. Rapidly progressive kidney disease defined by impairment of renal function within 2 weeks - 3 months (for the cohort of patients with residual proteinuria only) ;
8. Active systemic autoimmune diseases;
9. Treatment for glomerulopathies or systemic diseases with steroids or any other immunosuppressive agent within one year;
10. Specific contraindication to SGLT2 inhibitor therapy;
11. Heart failure with or without decreased systolic function;
12. Uncontrolled hypertension or symptomatic hypotension;
13. History of malignancy within 5 years of screening;
14. Inability to fully understand the possible risks and benefits related to study participation;
15. 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;
16. If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose;
17. Alcohol and drug abuse;
18. Participation in another interventional clinical trial within the 4 weeks prior to screening.

Primary outcomes:
measure: Measured Glomerular Filtration Rate (GFR)
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
Secondary outcomes:
measure: 24 hour urinary output
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary protein excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary albumin excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary urea excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary phosphate excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary sodium excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary glucose excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary potassium excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary uric acid excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour urinary creatinine excretion
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of total protein calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of albumin calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of sodium calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of potassium calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of uric acid calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Fractional clearance of free water calculated by standard formulas
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Glucose disposal rate
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Glucose tolerance
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Office blood pressure
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Office heart rate
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour (day-time and night-time) blood pressure monitoring
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: 24 hour (day-time and night-time) heart rate monitoring
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Pulse wave velocity
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: other marker of vascular stiffness
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
measure: Indices of Quality of Life: questionnaire SF-36
timeFrame: Changes from baseline to the end of one-month treatment period and one-month recovery period
Other outcomes:
Locations:
Study officials:
References: