Effects of Dapagliflozin on EChOcardiographic Measures of CarDiac StructurE and Function in Patients With CKD

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effects of dapagliflozin on echocardiographic measures of cardiac structure and function in patients with chronic kidney disease.

Detailed Description
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The study is a 6-month, investigator-initiated, randomized, double-blind, placebo-controlled clinical trial to evaluate the effects of dapagliflozin on echocardiographic measures of cardiac structure and function in patients with chronic kidney disease. The study population will consist of approximately 222 adults with chronic kidney disease - defined as a glomerular filtration rate (GFR) of 20-60 mL/min/1.73m2, in treatment with maximally tolerated ACEi or ARB. Patients will be randomized to either 10 mg dapagliflozin or placebo. Patients will be assessed by measurement of echocardiography, pulse wave velocity, blood samples, urine samples, quality of life, depressive symptoms, and cognitive function at baseline and after 6 months of treatment.

Official Title
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A 6-Month, Randomized, Double-Blind Study to Evaluate the Effect of Dapagliflozin on EChOcardiographic Measures of CarDiac StructurE and Function in Patients With Chronic Kidney Disease

Conditions
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Chronic Kidney Diseases

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: Signed informed consent ≥ 18 years of age Chronic Kidney Disease (CKD), defined as evidence of decreased eGFR (eGFR >20 and <60 mL/min/1.73 m2) at least 3 months before and at the time of screening Stable treatment with clinically appropriate doses of ACEi/ARB among CKD patients with proteinuria and uptitrated to maximal recommended or tolerated dose for at least 4 weeks before randomization, if not medically contraindicated For patients with type 2 diabetes: Stable antihyperglycemic treatment > 30 days before screening Female patients should either not be of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing one of the following methods of contraception throughout the study and for 30 days after study completion: Hormonal contraception (oral contraceptives, contraceptive implant, injectable birth control, contraceptive patch, or vaginal ring) or intrauterine device Ability to understand and read Danish Exclusion Criteria: Type 1 diabetes For patients with type 2 diabetes: History of diabetic ketoacidosis Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment Patients undergoing dialysis History of organ transplant Treatment with SGLT2 inhibitor within 8 weeks prior to enrolment Known allergy or hypersensitivity to SGLT2 inhibitors or Placebo ingredients Myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks of enrolment Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment Any condition outside the renal and cardiovascular study area with a life expectancy of <2 years based on investigator's clinical judgement Hepatic impairment (aspartate transaminase or alanine transaminase >3 times the upper limit of normal [ULN] or total bilirubin >2 times the ULN at the time of enrolment) Known blood-borne diseases, such as Hepatitis A, B, C, D, and E, and Human immunodeficiency virus (HIV) types 1 and 2, Ebola, Lassa fever virus. Female patients who are pregnant, lactating, or are considering becoming pregnant during the study or for 6 months after study completion Participation in another clinical study with an investigational product within the last month prior to enrolment Inability to understand or comply with the investigational product, procedures, and/or follow-up or any conditions that may prevent the participant to complete the study

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: Dapagliflozin 10 mg once daily<br> | Drug: Dapagliflozin 10 mg<br>* The intervention arm consists of dapagliflozin 10 mg orally once daily<br>|
| Placebo Comparator: Placebo once daily<br> | Drug: Placebo<br>* The comparator arm consists of placebo orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LV mass index assessed by echocardiography at 6 months |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in LV dimensions assessed by echocardiography at 6 months |  | 6 months | 
| Change in LVEF assessed by echocardiography at 6 months |  | 6 months | 
| Change in E-wave assessed by echocardiography at 6 months |  | 6 months | 
| Change in A-wave assessed by echocardiography at 6 months |  | 6 months | 
| Change in E/e' assessed by echocardiography at 6 months |  | 6 months | 
| Change in E/A ratio assessed by echocardiography at 6 months |  | 6 months | 
| Change in LA volume assessed by echocardiography at 6 months |  | 6 months | 
| Change in GLS assessed by echocardiography at 6 months |  | 6 months | 
| Change in LA strain assessed by echocardiography at 6 months |  | 6 months | 
| Change in RV strain assessed by echocardiography at 6 months |  | 6 months | 
| Change in high sensitivity troponin I (hs-TNI) at 6 months |  | 6 months | 
| Change in Soluble suppression of tumorigenicity 2 (sST2) at 6 months |  | 6 months | 
| Change in N-terminal pro B-type natriuretic peptide (NT-pro-BNP) at 6 months |  | 6 months | 
| Change in necrosis factor α (TNF-α) at 6 months |  | 6 months | 
| Change in copeptin at 6 months |  | 6 months | 
| Change in high sensitivity C-reactive protein (hs-CRP) at 6 months |  | 6 months | 
| Change in estimated glomerular filtration rate (eGFR) 6 months |  | 6 months | 
| Change in serum potassium at 6 months |  | 6 months | 
| Change in serum neutrophil gelatinase-associated lipocalin (sNGAL) at 6 months |  | 6 months | 
| Change in urinary neutrophil gelatinase-associated lipocalin (uNGAL) at 6 months |  | 6 months | 
| Change in urinary kidney injury molecule-1 (KIM-1) at 6 months |  | 6 months | 
| Change in insulin growth factor-binding protein-7 (IGFBP7) at 6 months |  | 6 months | 
| Change in serum cystatin C at 6 months |  | 6 months | 
| Change in uric acid at 6 months |  | 6 months | 
| Change in urinary albumin-to-creatinine ratio (UACR) at 6 months |  | 6 months | 
| Change in erythropoietin (EPO) at 6 months |  | 6 months | 
| Change in estimated plasma volume at 6 months |  | 6 months | 
| Change in hemoglobin at 6 months |  | 6 months | 
| Change in hemotocrit at 6 months |  | 6 months | 
| Change in ferritin at 6 months |  | 6 months | 
| Change in transferrin at 6 months |  | 6 months | 
| Change in iron at 6 months |  | 6 months | 
| Change in calcium at 6 months |  | 6 months | 
| Change in phosphate at 6 months |  | 6 months | 
| Change in magnesium at 6 months |  | 6 months | 
| Change in PTH at 6 months |  | 6 months | 
| Change in fibroblast growth factor 23 (FGF-23) at 6 months |  | 6 months | 
| Change in calcification propensity (T50) at 6 months |  | 6 months | 
| Change in fetuin-A (fetA) at 6 months |  | 6 months | 
| Change in bicarbonate at 6 months |  | 6 months | 
| Change in klotho at 6 months |  | 6 months | 
| Change in urine sodium at 6 months |  | 6 months | 
| Change in urine glucose at 6 months |  | 6 months | 
| Change in hemoglobin A1C at 6 months |  | 6 months | 
| Changein central blood pressure assessed by pulse wave analysis at 6 months |  | 6 months | 
| augmentation index assessed by pulse wave analysis at 6 months |  | 6 months |