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

Study Overview
=================
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)

Official Title
-----------------
An Exploratory Phase II/III, Randomized, Double-blind, Placebo Controlled, Parallel Design Study to Evaluate the Efficacy, Safety and Pharmacodynamics of Dapagliflozin and Dapagliflozin in Combination With Saxagliptin in CKD Patients With Type 2 Diabetes Mellitus and Albuminuria Treated With ACEi or ARB

Conditions
-----------------
Type 2 Diabetes Mellitus, CKD and Albuminuria

Intervention / Treatment
-----------------
* Drug: Dapagliflozin 10 mg
* Drug: Saxagliptin 2.5 mg
* Drug: Matching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mg


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin 10mg<br>Tablets administered orally once daily for 24 weeks | Drug: Dapagliflozin 10 mg<br>* Tablets administered orally once daily for 24 weeks.<br>* Other names: Forxiga™;|
| Experimental: Dapagliflozin 10mg + Saxagliptin 2.5mg<br>Tablets administered orally once daily for 24 weeks | Drug: Saxagliptin 2.5 mg<br>* Tablets administered orally once daily for 24 weeks.<br>* Other names: Onglyza™;|
| Placebo Comparator: Placebo<br>Tablets administered orally once daily for 24 weeks | Drug: Matching Placebo for Dapagliflozin 10 mg and Saxagliptin 2.5mg<br>* Tablets administered orally once daily for 24 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Glycosylated Haemoglobin (HbA1c): Comparison of Dapagliflozin 10 mg Plus Saxagliptin 2.5 mg and Placebo at 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. | Baseline and Week 24 | 
| Adjusted Mean Percent Change From Baseline in Urine Albumin-to-Creatinine Ratio (UACR) at 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. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Percent Change From Baseline in Total Body Weight at 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. | Baseline and Week 24 | 
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at 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. | Baseline and Week 24 | 
| Percentage of Patients Achieving at Least 30% Reduction in UACR at 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]). | From baseline up to Week 24 | 
| Percentage of Patients Achieving a Reduction in HbA1c of Less Than 7.0% at 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. | From baseline to Week 24 | 
| Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (SBP) at 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. | Baseline and Week 24 | 
| Adjusted Mean Change From Baseline in HbA1c: Comparison of Dapagliflozin 10 mg and Placebo at 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. | Baseline and Week 24 |