Effects of Dapagliflozin in Non-diabetic Patients With Proteinuria

Study Overview
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Brief Summary
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This study tests the hypothesis that dapagliflozin lowers proteinuria in patients with non-diabetic chronic kidney disease.

Detailed Description
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Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many patients with non-diabetic kidney disease show progressive kidney function loss, which is associated with high residual proteinuria. Novel treatment strategies are therefore required to further decrease proteinuria and to slow kidney function decline. Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of glucose and sodium in the proximal tubule. The increased natriuresis following dapagliflozin administration normalizes tubuloglomerular feedback resulting in a reduction in intra-glomerular hypertension, which is in turn manifested by acute reversible reductions in glomerular filtration rate and albuminuria. Since many etiologies of non-diabetic nephropathy are characterized by intraglomerular hypertension, we hypothesize that dapagliflozin acutely decreases GFR and proteinuria in patients without diabetes at risk of progressive kidney function loss via a glucose independent hemodynamic mechanism.

Official Title
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A Study to Assess the Renoprotective Effects of the SGLT2 Inhibitor Dapagliflozin in Non-Diabetic Patients With Proteinuria: a Randomized Double Blind 6-Weeks Cross-Over Trial

Conditions
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Chronic Kidney Diseases, Proteinuria

Intervention / Treatment
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* Drug: Dapagliflozin 10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 and ≤75 years Urinary protein excretion > 500 mg/g and ≤ 3500 mg/g in a 24-hr urine collection eGFR ≥ 25 mL/min/1.73m2 On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization Willing to sign informed consent Women of Child-Bearing Potential (WOCBP): WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized. WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug. Women must not be breast-feeding. WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal. Exclusion Criteria: Diagnosis of type 1 or type 2 diabetes mellitus Urinary protein excretion > 3500 mg/day Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis Indication for immunosuppressants as per the treating physician's judgment. Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment. Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin. Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following: History of active inflammatory bowel disease within the last six months; Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months; Pancreatic injury or pancreatitis within the last six months; Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt; Evidence of urinary obstruction of difficulty in voiding at screening History of severe hypersensitivity or contraindications to dapagliflozin Subject who, in the assessment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data Participation in any clinical investigation within 3 months prior to initial dosing. Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening. History of noncompliance to medical regimens or unwillingness to comply with the study protocol. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study. Pregnancy or breastfeeding WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after the last dose of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A Randomized Double Blind 6-Weeks Cross-over
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin 10mg Tablet<br>10 mg Green, plain, diamond shaped, film coated tablet (orally) | Drug: Dapagliflozin 10mg<br>* Tablet<br>* Other names: Placebo Matching Dapagliflozin 10mg;|
| Placebo Comparator: Placebo Matching Dapagliflozin Tablet<br>Green, plain, diamond shaped, film coated tablet. Does not contain active ingredient | Drug: Dapagliflozin 10mg<br>* Tablet<br>* Other names: Placebo Matching Dapagliflozin 10mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-hr proteinuria with dapagliflozin for six weeks relative to placebo in patients with non-diabetic kidney disease and proteinuria 500 mg/day on stable angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment. | bioequivalence | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of dapagliflozin 10 mg/d compared to placebo on Glomerular Filtration Rate (GFR) using iohexol clearance | bioequivalence | 6 weeks | 
| Effect of dapagliflozin 10 mg/d compared to placebo on systolic/diastolic blood pressure | bioequivalence | week 0, 2, 4, 5, 6, 12, 15, 18, 24 | 
| Effect of dapagliflozin 10 mg/d compared to placebo on body weight | bioequivalence | week 0, 2, 4, 5, 6, 12, 15, 18, 24 | 
| Effect of dapagliflozin 10 mg/d compared to placebo on selected neurohormones/ biomarkers | bioequivalence | week 0, 3, 6, 12, 15, 18, 24 | 
| Safety of dapagliflozin vs. placebo - the number of hypoglycemia episodes between groups and serious adverse events | safety | week 0-26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic kidney disease, non diabetic