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.

Phase 4

Terminated

Conditions: Kidney Function Tests
Diabetes Mellitus, Type 2

Interventions: Drug: Dapagliflozin

Registration Number: NCT03152084

Lead Sponsor: AstraZeneca

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

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	Dapagliflozin	T2DM subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit.
Arm 3	Dapagliflozin	Non-diabetic subjects with an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 at the Screening Visit.
Arm 2	Dapagliflozin	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.

Primary Outcome Measures

Name	Time	Method
Change in 24-hour Sodium Excretion From Baseline to Start of Treatment	From baseline (Day -3 to Day -1) to start of treatment (Day 2 to Day 4)	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.

Secondary Outcome Measures

Name	Time	Method
Change in 24-hour Sodium Excretion From Baseline to End of Treatment and From End of Treatment to Follow-up	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)	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).
Change in 24-hour Glucose Excretion From Baseline to Start of Treatment	From baseline (Day -3 to Day -1) to start of treatment (Day 2 to 4)	Average change in 24-hour glucose excretion from average baseline values to average start of treatment values (Day 2 to 4).
Change in 24-hour Glucose Excretion From Baseline to End of Treatment	From baseline (Day -3 to Day -1) to end of treatment (Day 12 to 14)	Average change in 24-hour glucose excretion from average baseline values to average end of treatment values (Day 12 to 14)
Change in 24-hour Glucose Excretion From End of Treatment to Follow-up	From end of treatment (Day 12 to 14) to follow-up (Day 15 to 17)	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).
Change in Mean 24-hour Systolic Blood Pressure From Baseline to Start of Treatment	From baseline (Day -1) to start of treatment (Day 4)	Change in mean 24-hour systolic blood pressure from baseline to start of treatment (Day 4)
Change in Mean 24-hour Systolic Blood Pressure From Baseline to End of Treatment	From baseline (Day -1) to end of treatment (Day 13)	Change in mean 24-hour systolic blood pressure from baseline to end of treatment (Day 13).
Change in Mean 24-hour Systolic Blood Pressure From End of Treatment to End of Follow-up	From end of treatment (Day 13) to end of follow-up (Day 18)	Change in mean 24-hour systolic blood pressure from end of treatment (Day 13) to end of follow-up (Day 18).
Change in Plasma Volume From Baseline to Start of Treatment	From baseline (Day 1) to start of treatment (Day 4)	Change in plasma volume from baseline to start of treatment (Day 4).
Change in Plasma Volume From Baseline to End of Treatment	From baseline (Day 1) to end of treatment (Day 14)	Change in plasma volume from baseline to end of treatment (Day 14).
Change in Plasma Volume From End of Treatment to End of Follow-up	From end of treatment (Day 14) to end of follow-up (Day 18)	Change in plasma volume from end of treatment (Day 14) to end of follow-up (Day 18).
Change in Extracellular Volume From Baseline to Start of Treatment	From baseline (Day 1) to start of treatment (Day 4)	Change in extracellular volume from baseline to start of treatment (Day 4).
Change in Extracellular Volume From Baseline to End of Treatment	From baseline (Day 1) to end of treatment (Day 14)	Change in extracellular volume from baseline to end of treatment (Day 14).
Change in Extracellular Volume From End of Treatment to End of Follow-up	From end of treatment (Day 14) to end of follow-up (Day 18)	Change in extracellular volume from end of treatment (Day 14) to end of follow-up (Day 18).
Change in 24-hour Urine Albumin:Creatinine Ratio (UACR)	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)	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).
Pharmacokinetics of Dapagliflozin on Day 4 and Day 14	At pre-dose (Day 4) and at pre-dose, 1h, 2h, 4h post-dose (Day 14)	Dapagliflozin plasma concentration on Day 4 (pre-dose) and Day 14 (pre-dose, 1h, 2h, 4h post-dose)
Number of Patients With AEs and SAEs	From Day 1 until Day 18 (Follow-up)	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.