A Study to Evaluate the Renal Protective Effect (Urine Albumin-to-Creatinine Ratio (UACR)), Efficacy and Safety of Ipragliflozin in Type 2 Diabetes Mellitus Patients With Albuminuria

Study Overview
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Brief Summary
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The primary purpose of this study is to assess the renal protective effect of ipragliflozin in combination with metformin on the percent change of UACR from baseline to 24 weeks against glimepiride in combination with metformin in type 2 diabetes mellitus patients with albuminuria. The secondary purpose of this study is to assess the efficacy, safety and impact on quality of life (QoL) of ipragliflozin in combination with metformin against glimepiride in combination with metformin in type 2 diabetes mellitus patients with albuminuria.

Detailed Description
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This is a multicenter study that will compare ipragliflozin/metformin with glimepiride/metformin in the treatment of type 2 diabetes mellitus (T2DM) with albuminuria. The study will include screening and 24-week treatment period. Subjects entering the study have been on a stable dose of at least 1000 mg/day metformin monotherapy for at least 8 weeks (56 days) prior to Visit 1. For randomization, subject will be stratified by the site and the administration of renin-angiotensin system inhibitors (angiotensin receptor blockers and/or angiotensin-converting-enzyme inhibitors) at Visit 2. Subjects will be centrally randomized to either ipragliflozin/metformin group or glimepiride/metformin group and receive 24-week treatment by each group

Official Title
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A Phase 4, Randomized, Open-label, Active-controlled, Multicenter Study to Evaluate the Renal Protective Effect (UACR), Efficacy and Safety of Ipragliflozin in Type 2 Diabetes Mellitus Patients With Albuminuria

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: metformin
* Drug: ipragliflozin
* Drug: glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria assessed at Visit 1: Subject who is outpatient. Subject who has been diagnosed with type 2 diabetes mellitus. Subject who has been on a stable dose of at least 1000 mg/day metformin monotherapy for at least 8 weeks (56 days) prior to Visit 1. Subject who has an HbA1C value between 7.0% and 9.0% at Visit 1. Subject who has a urinary albumin/creatinine ratio greater than or equal to 30 mg/g at Visit 1. Subject who has eGFR greater than or equal to 45 mL/min/1.73 m^2. Subject is on stable diet and exercise program for at least 8 weeks (56 days) prior to Visit 1. Inclusion Criterion assessed at Visit 2: Subject who has a urinary albumin/creatinine ratio greater than or equal to 30 mg/g at Visit 2. Exclusion Criteria: Subject who has been diagnosed with type 1 diabetes mellitus. Subject who started or has changed the types and/or dosage of Renin Angiotensin System (RAS) inhibitors (Angiotensin II Receptor Blockers (ARBs), ACE inhibitors) within 12 weeks prior to Visit 1. Subject who has been treated with Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitors within 12 weeks prior to Visit 1. Subject who has a history of clinically significant renal disease(s) (other than diabetic nephropathy) such as renovascular occlusive disease, nephrectomy, or renal transplant. Subject who has a diabetic ketoacidosis, or history of diabetic ketoacidosis. Subject with diabetic coma or precoma. Subject with severe infection, serious trauma, or perioperative subject at Visit 1 Subject who has a history of hypersensitivity to ipragliflozin or glimepiride or other SGLT-2 inhibitors or sulfonylureas. Subject has Aspartate Aminotransferase (GOT) (AST) or Alanine Aminotransferase (GPT) (ALT) value exceeding 3 times of upper limit of the normal range, or total bilirubin value exceeding 3 times of upper limit of the normal range at Visit 1. Subject has progressive proliferative diabetic retinopathy. Subject has a symptomatic urinary tract infection or genital infection at Visit 1. Subject has uncontrollable psychiatric disorder(s) with medication. Subject abuses drug or alcohol at Visit 1. Subject has lactic acidosis or has history of lactic acidosis. Subject who has been known to have Hepatitis B, Hepatitis C or Positive Human immunodeficiency virus (HIV). Subject is unable or unwilling to adhere to any of the protocol requirements such as hospital visits and dose instruction specified in this study. Subject with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Subject has participated in another interventional study with study drugs within 12 weeks prior to obtaining written informed consent. Subject has a clinical condition which would not allow safe conduct of the study.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 74 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ipragliflozin and metformin<br>Subjects will receive daily dosage of ipragliflozin and metformin as single tablets | Drug: metformin<br>* oral<br>* Other names: Glucophage XR;Drug: ipragliflozin<br>* oral<br>* Other names: Suglat;|
| Experimental: glimepiride and metformin<br>Subjects will receive daily dosage of glimepiride and metformin as single tablets | Drug: metformin<br>* oral<br>* Other names: Glucophage XR;Drug: glimepiride<br>* oral<br>* Other names: Amaryl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of change of Urine Albumin-to-Creatinine Ratio (UACR) | Early morning urinary sample will be collected for the test | Baseline up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients whose UACR level is normalized or improved more than 50% | Early morning urinary sample will be collected for the test | Baseline up to 24 weeks | 
| Change from baseline in Estimated glomerular filtration rate (e-GFR) | Test parameter e-GFR shall be measured at the local laboratory | Baseline up to 24 weeks | 
| Change from baseline in Hemoglobin A1c (HbA1c) | Test parameter HbA1c shall be measured at the local laboratory | Baseline up to 24 weeks | 
| Change from baseline in Fasting Plasma Glucose (FPG) | Test parameter FPG shall be measured at the local laboratory | Baseline up to 24 weeks | 
| Change from baseline in body weight | Body Weight shall be measured by the same scale for the clinical trial period | Baseline up to 24 weeks | 
| Change from baseline in blood pressure | Blood pressure will be measured two times with 1-2 minutes interval by the same arm and procedure during the study | Baseline up to 24 weeks | 
| Change from baseline in Uric Acid | Test parameter Uric Acid shall be measured at the local laboratory | Baseline up to 24 weeks | 
| Change from baseline in health status as measured through EuroQol 5 Dimension 5 Level Health State Utility Index (EQ-5D-5L) questionnaire | The EQ-5D-5L Questionnaire consists of 5 domains: mobility, self-care, usual activities, pain/discomfort, anxiety/depression | Baseline up to 24 weeks | 
| Change from baseline in health status as measured through EuroQol-Visual Analogue Scale (EQ VAS) questionnaire | The EQ VAS measures the score (0 to 100) of change from baseline to 24 weeks | Baseline up to 24 weeks | 
| Change from baseline in Quality of Life as measured through Audit of Diabetes-Dependent Quality of Life-19 (ADDQoL-19) questionnaire | Quality of Life will be assessed through ADDQoL-19. Patients will be asked to complete the questionnaires at visit 2 and 5 | Baseline up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ipragliflozin, Metformin, Type 2 Diabetes Mellitus, ASP1941, Glimepiride