The Study Will Evaluate Average 24-hr Sodium Excretion During Dapagliflozin Treatment in Patients With Type 2 Diabetes Mellitus With Preserved or Impaired Renal Function or Non-diabetics With Impaired Renal Function.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate how dapagliflozin mechanism of action is impacted by Type 2 Diabetes Mellitus status and kidney function

Official Title
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DAPASALT: An Open Label, Phase IV, Mechanistic, Three-Arm Study to Evaluate the Natriuretic Effect of 2-Week Dapagliflozin Treatment in Type 2 Diabetes Mellitus Patients With Either Preserved or Impaired Renal Function and Non-Diabetics With Impaired Renal Function

Conditions
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Diabetes Mellitus, Type 2, Kidney Function Tests

Intervention / Treatment
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* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures Female and/or male aged between 18 years and ≤80 years In the diabetic arms - a diagnosis of T2DM with HbA1c ≥6.5% (≥48 mmol/mol) and <10% (<86 mmol/mol); and eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 or between >90 and ≤130 mL/min/1.73m2 for patients aged 59 years or younger, between >85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69 years, and between >75 and ≤130 mL/min/1.73m2 for patients aged 70 years or older at the Screening Visit (Visit 1) In the non-diabetic arm, HbA1c <6.5% (<48 mmol/mol) and an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit (Visit 1) Patient specific optimal antihypertensive dose of an angiotensin receptor blocker at least 6 weeks before study treatment In the diabetic arm (Group 2) an appropriate stable dose of metformin, or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks before study treatment Stable urinary sodium excretion on 2 successive 24-hr urinary sodium excretion measurements. In the diabetic arm with impaired renal function (Group 1), a stable insulin dosing (intermediate, long-acting, premixed insulin, basal bolus insulin) for the last 12 weeks prior to Visit 4 (Day 1), as judged by the Investigator. Metformin or sulphonylurea, or metformin+sulphonylurea together with insulin would be accepted, but is not mandatory. If used, stable dose of metformin or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to Visit 4 (Day 1) is required. Exclusion Criteria: Diagnosis of Type 1 Diabetes Mellitus Any of the following cardiovascular/vascular diseases within 3 months prior to signing the consent; myocardial infarction, cardiac surgery or revascularization, unstable angina, unstable heart failure, heart failure NYHA Class IV, transient ischemic attack or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia Symptoms/complaints suggestive of established neurogenic bladder and/or incomplete bladder emptying History of bladder cancer, diagnosis of polycystic kidney disease, history or current lupus nephritis or unstable or rapidly progressing renal disease UACR >1000 mg/g at screening Current/chronic use of the following medications: any anti-diabetic medication with the exception of metformin, sulphonylurea, angiotensin converting enzyme inhibitors, insulin (insulin only allowed in Group 1), oral glucocorticoids, non-steroidal anti-inflammatory drugs, immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants and monoamine oxidase inhibitors Receiving immunosuppressive or other immunotherapy for primary or secondary renal disease within 6 months prior to screening Current treatment or treatment within the last 2 weeks prior to screening with diuretics including loop diuretics, thiazides, and mineralocorticoid antagonists

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>T2DM subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit. | Drug: Dapagliflozin<br>* The study consists of a 2-week, open label, dapagliflozin (10mg) treatment period.<br>|
| Experimental: Arm 2<br>T2DM subjects with an eGFR (CKD-EPI) between >90 and ≤130 mL/min/1.73m2 for patients aged 59 or younger, between >85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69, and between >75 and ≤130 mL/min/1.73m2 for patients aged 70 or older at the Screening Visit. | Drug: Dapagliflozin<br>* The study consists of a 2-week, open label, dapagliflozin (10mg) treatment period.<br>|
| Experimental: Arm 3<br>Non-diabetic subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit. | Drug: Dapagliflozin<br>* The study consists of a 2-week, open label, dapagliflozin (10mg) treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-hour Sodium Excretion From Baseline to Start of Treatment | Change in 24-hour sodium excretion during dapagliflozin treatment between baseline and average of Days 2 to 4 within each study group in patients with T2DM with preserved kidney function and in non-diabetics with impaired kidney function was assessed. | From baseline (Day -3 to Day -1) to start of treatment (Day 2 to Day 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-hour Sodium Excretion From Baseline to End of Treatment and From End of Treatment to Follow-up | Average change in 24-hour sodium excretion from average baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17). | From baseline (Day -3 to Day -1) to end of treatment (Day 12 to 14); and from end of treatment (Day 12 to 14) to follow-up (Day 15 to 17) | 
| Change in 24-hour Glucose Excretion From Baseline to Start of Treatment | Average change in 24-hour glucose excretion from average baseline values to average start of treatment values (Day 2 to 4). | From baseline (Day -3 to Day -1) to start of treatment (Day 2 to 4) | 
| Change in 24-hour Glucose Excretion From Baseline to End of Treatment | Average change in 24-hour glucose excretion from average baseline values to average end of treatment values (Day 12 to 14) | From baseline (Day -3 to Day -1) to end of treatment (Day 12 to 14) | 
| Change in 24-hour Glucose Excretion From End of Treatment to Follow-up | Average change in 24-hour glucose excretion from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17). | From end of treatment (Day 12 to 14) to follow-up (Day 15 to 17) | 
| Change in Mean 24-hour Systolic Blood Pressure From Baseline to Start of Treatment | Change in mean 24-hour systolic blood pressure from baseline to start of treatment (Day 4) | From baseline (Day -1) to start of treatment (Day 4) | 
| Change in Mean 24-hour Systolic Blood Pressure From Baseline to End of Treatment | Change in mean 24-hour systolic blood pressure from baseline to end of treatment (Day 13). | From baseline (Day -1) to end of treatment (Day 13) | 
| Change in Mean 24-hour Systolic Blood Pressure From End of Treatment to End of Follow-up | Change in mean 24-hour systolic blood pressure from end of treatment (Day 13) to end of follow-up (Day 18). | From end of treatment (Day 13) to end of follow-up (Day 18) | 
| Change in Plasma Volume From Baseline to Start of Treatment | Change in plasma volume from baseline to start of treatment (Day 4). | From baseline (Day 1) to start of treatment (Day 4) | 
| Change in Plasma Volume From Baseline to End of Treatment | Change in plasma volume from baseline to end of treatment (Day 14). | From baseline (Day 1) to end of treatment (Day 14) | 
| Change in Plasma Volume From End of Treatment to End of Follow-up | Change in plasma volume from end of treatment (Day 14) to end of follow-up (Day 18). | From end of treatment (Day 14) to end of follow-up (Day 18) | 
| Change in Extracellular Volume From Baseline to Start of Treatment | Change in extracellular volume from baseline to start of treatment (Day 4). | From baseline (Day 1) to start of treatment (Day 4) | 
| Change in Extracellular Volume From Baseline to End of Treatment | Change in extracellular volume from baseline to end of treatment (Day 14). | From baseline (Day 1) to end of treatment (Day 14) | 
| Change in Extracellular Volume From End of Treatment to End of Follow-up | Change in extracellular volume from end of treatment (Day 14) to end of follow-up (Day 18). | From end of treatment (Day 14) to end of follow-up (Day 18) | 
| Change in 24-hour Urine Albumin:Creatinine Ratio (UACR) | Average change in mean 24-hour urine albumin:creatinine ratio (UACR) from average baseline to Day 4; and from average baseline values to average end of treatment values (Day 12 to 14). | From baseline (Day -3 to Day -1) to start of treatment (Day 4); and from baseline (Day -3 to Day-1) to end of treatment (Day 12 to 14) | 
| Pharmacokinetics of Dapagliflozin on Day 4 and Day 14 | Dapagliflozin plasma concentration on Day 4 (pre-dose) and Day 14 (pre-dose, 1h, 2h, 4h post-dose) | At pre-dose (Day 4) and at pre-dose, 1h, 2h, 4h post-dose (Day 14) | 
| Number of Patients With AEs and SAEs | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. SAE is an AE that results in any untoward medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a significant medical event. | From Day 1 until Day 18 (Follow-up) |