SGLT2 Inhibition in Hemodialysis

Study Overview
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Brief Summary
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The study is designed as a prospective randomized, controlled, double-blinded phase II trial to examine the effect of the SGLT2 inhibitor dapagliflozin, in comparison with placebo on cardiovascular outcome parameters in kidney failure patients undergoing replacement therapy with hemodialysis. The primary endpoint is the change (∆) in left ventricular mass indexed to body surface area (LVMi) from baseline to 6 months measured by cardiac magnetic resonance imaging. Null and alternative hypotheses: H0: There is no difference in the ∆ Left Ventricular Mass indexed to BSA after six months of treatment, comparing patients having received the SGLT2-Inhibitor Dapagliflozin versus placebo. H1: There is a difference in the ∆ Left Ventricular Mass indexed to BSA comparing patients having received the SGLT2-Inhibitor Dapagliflozin versus placebo.

Detailed Description
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The parallel groups will receive dapagliflozin 10 mg vs. placebo (1:1 manner; n = 54 per group) for 6 months. Cardiological outcome parameters will include the change in left ventricular mass (LVM), left ventricular ejection fraction (EF), cardiac fibrosis and left atrial diameter (LAD) from baseline to 6 months measured by cMRI and strain echocardiography. Biochemical data will be collected prior to hemodialysis at baseline and periodically (e.g. blood gas analysis at every dialysis visit, measurements of and pre- and post- dialysis troponin T (TnT) and pro brain natriuretic peptide (proBNP) every 4 weeks). A full laboratory analysis of blood cell count, blood coagulation and clinical chemistry will be performed at baseline, 3 months, and 6 months. Additionally, body weight will be measured at all study visits to monitor changes after SGLT2 inhibitor administration. Hospitalizations and mortality will be monitored clinically. Further secondary endpoints are glucometabolic parameters (HbA1c, plasma values of insulin, c-peptide, glucagon, glucagon-Like peptide-1 (GLP1), cortisol, growth hormone, alanine, β-hydroxybutyrate (βOHB) [=ketone] and pyruvate concentration) and will be determined at baseline, 3 and 6 months. The HOMA-Indices will be calculated with the values of insulin and fasting glucose for monitoring of diabetes performed at baseline, 3 months, and 6 months. Volume status and fluid composition will be measured by bioimpedance spectroscopy at the baseline, 3 months, and end-of-study-visit. In case of hypervolemia, ultrafiltration parameters will be adapted to reach a dry weight based in synopsis of clinical status and body composition monitoring results. In terms of urinary output and tubuloglomerular feedback, a stratification by residual urine volume by 200 mL per day will be performed to elucidate study aim IV. Prior results of diabetes independent renal and cardiovascular benefit legitimate an examination of groups with and without prevalent diabetes mellitus.

Official Title
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SGLT2 Inhibition (Dapagliflozin) in Diabetic and Non-diabetic Hemodialysis Patients With and Without Residual Urine Volume: a Prospective Randomized, Placebo-controlled, Double-blinded Phase II Trial

Conditions
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Kidney Failure, Hemodialysis, Diabetes Mellitus, Type 2, Chronic Kidney Disease, Left Ventricular Hypertrophy

Intervention / Treatment
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* Drug: Dapagliflozin 10 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Maintenance hemodialysis 3×/week for ≥3 months and ≤3 years BMI <45 kg/m2 and stable weight (± 5 kg [dry weight]) over the preceding three months Signed informed consent Exclusion Criteria: Study specific: Contraindications for MRI Hypersensitivity or Intolerance of SGLT2 inhibitors Participation in another clinical trial Medical condition specific: History of diabetic ketoacidosis Interventricular septum width ≤ 11 mm Severe valvular heart disease Life expectancy < 1 year Substance abuse History of Type 1 diabetes mellitus Scheduled kidney transplant from a living donor Other significant disease or pathology, that might predispose that patient to an unacceptable risk or interferes with the study in the opinion of the investigator. Acute coronary syndrome during the last 30 days Existing treatments with SGLT2i within the last 6 months Female specific: Child bearing potential & unwilling / unable to use an acceptable method to avoid pregnancy for the entire study (estrogen and/or progesterone treatment). Pregnancy Breast feeding

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention arm<br>Hemodialysis patients receiving dapagliflozin 10 mg once daily | Drug: Dapagliflozin 10 MG<br>* administered orally once daily<br>* Other names: Forxiga 10 MG;|
| Placebo Comparator: Placebo<br>Hemodialysis patients receiving placebo oral tablet once daily | Drug: Placebo<br>* administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Δ Left ventricular mass indexed to body surface area | measured by cMRI | From baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Δ HbA1c [%] | Change in relative % | From baseline to 6 months | 
| Δ Left ventricular mass indexed to body height | measured by cMRI | From baseline to 6 months | 
| Δ Left ventricular ejection fraction | measured by cMRI | From baseline to 6 months | 
| Δ Cardiac fibrosis | measured by cMRI | From baseline to 6 months | 
| Δ Body weight [kg] | Change in kg | From baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dapagliflozin, SGLT2 inhibition