A Study to Evaluate the Effect of Dapagliflozin With and Without Saxagliptin on Albuminuria, and to Investigate the Effect of Dapagliflozin and Saxagliptin on HbA1c in Patients With Type 2 Diabetes and CKD

Phase 2

Completed

Conditions: Type 2 Diabetes Mellitus, CKD and Albuminuria

Interventions: Drug: Dapagliflozin 10 mg
Drug: Saxagliptin 2.5 mg
Drug: Matching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mg

Registration Number: NCT02547935

Lead Sponsor: AstraZeneca

Brief Summary: The purpose of this clinical research study is to determine whether dapagliflozin alone or in combination with saxagliptin can decrease albuminuria and improve glycemic control in patients with Type 2 diabetes, albuminuria and renal impairment (CKD). The study is planned to randomize a total of 450 patients (150 patients per treatment arm)

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 459

Inclusion Criteria

Provision of informed consent prior to any study specific procedures
Female or male aged ≥18 years
History of type 2 diabetes mellitus for more than 12 months
HbA1c≥7.0% and ≤11.0%
Stable antidiabetic treatment during the last 12 weeks up to randomization
eGFR 25-75 mL/minute/1.73m2, inclusive
Micro or macroalbuminuria (UACR 30 - 3500 mg/g)
Treatment with ACE inhibitor or an ARB for at least 3 months prior to screening
Body mass index between 20 and 45 kg/m2

Exclusion Criteria

Any of the following CV/Vascular Diseases within 3 month prior to signing the consent at Visit 1:
- Myocardial infarction
- cardiac surgery or revascularization (CABG/PTCA)
- unstable angina
- unstable HF
- New York Heart Association (NYHA) Class III-IV
- transient ischemic attack (TIA) or significant cerebrovascular disease
- unstable or previously undiagnosed arrhythmia
Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3X ULN
Total Bilirubin (TB) >2 mg/dL (34.2 μmol/L)
History of acute kidney injury requiring renal replacement therapy (dialysis or ultrafiltration) or any biopsy or imaging verifying intercurrent kidney disease other than diabetic nephropathy or diabetic nephropathy with nephrosclerosis
Ongoing treatment with a SGLT2 inhibitor, GLP-1 agonist or DPP4 inhibitors
Any condition which, in the judgment of the Investigator, may render the patient unable to complete the study or which may pose a significant risk to the patient or patient suspected or with confirmed poor protocol or medication compliance

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin 10mg	Dapagliflozin 10 mg	Tablets administered orally once daily for 24 weeks
Dapagliflozin 10mg + Saxagliptin 2.5mg	Saxagliptin 2.5 mg	Tablets administered orally once daily for 24 weeks
Placebo	Matching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mg	Tablets administered orally once daily for 24 weeks

Primary Outcome Measures

Name	Time	Method
Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at Week 24	Baseline and Week 24	UACR was analysed at baseline and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. UACR values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24.
Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at Week 24	Baseline and Week 24	HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a mixed model repeated measures (MMRM) model.

Secondary Outcome Measures

Name	Time	Method
Adjusted Mean Percent Change From Baseline in Total Body Weight at Week 24	Baseline and Week 24	Total body weight was measured in kilograms (kg) at baseline and at Week 1 then every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. Total body weight values were first transformed to logarithms and the results were based on exponentiation of model estimates and expressed as adjusted mean percent change from baseline at Week 24.
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	Baseline and Week 24	FPG was analysed at baseline and Week 1 then every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.
Percentage of Patients Achieving at Least 30% Reduction in UACR at Week 24	From baseline up to Week 24	The percentage of patients meeting the criteria of at least a 30% reduction in UACR, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (Last Observation Carried Forward \[LOCF\]).
Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at Week 24	From baseline to Week 24	The percentage of patients meeting the criteria of a less than 7% reduction in HbA1c, was analysed using a logistic regression model. If no measurement was available at Week 24 the last available post-baseline measurement was carried forward (LOCF). Only measurements prior to rescue or treatment discontinuation were analysed.
Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at Week 24	Baseline and Week 24	Seated SBP was analysed at baseline, Week 1 and every 4 weeks during the 24-week treatment period. All measurements regardless of rescue medication or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.
Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at Week 24	Baseline and Week 24	HbA1c was analysed at baseline and every 4 weeks during the 24-week treatment period. Only measurements prior to rescue or treatment discontinuation were analysed. The adjusted mean change from baseline at Week 24 was analysed using a MMRM model.