Effect of Tofogliflozin on UACR Compared to Metformin Hydrochloride in Diabetic Kidney Disease (TRUTH-DKD)

Study Overview
=================
Brief Summary
-----------------
This multicenter, randomized, open-label, controlled study will assess the efficacy of the SGLT2 inhibitor tofogliflozin on Urine Albumin-to-Creatinine Ratio (UACR) compared to metformin in patients with type 2 diabetes with chronic kidney disease (CKD).

Detailed Description
-----------------
Eligible participants will be randomly assigned (1:1) to tofogliflozin or metformin with stratification based on UACR (<300 mg/gCr，≧300mg/gCr), an estimated glomerular filtration rate (eGFR) (<60mL/min/1.73m2, ≧60 mL/min/1.73m2), and age (<65 years old, ≧65 years old). The primary end point is change in urine albumin-to-creatinine ratio (UACR) from baseline after 52 weeks treatment. Changes in eGFR, HbA1c, body weight, systolic blood pressure, diastolic blood pressure, total serum proteins, serum albumin, uric acid, hematocrit, hemoglobin, red blood cell count, pulse rate, triglyceride, low-density lipoprotein, high-density lipoprotein and albuminuria class transition rate will also be evaluated.

Official Title
-----------------
Effect of Tofogliflozin on Urine Albumin-to-Creatinine Ratio Compared to Metformin Hydrochloride in Diabetic Kidney Disease

Conditions
-----------------
T2DM (Type 2 Diabetes Mellitus), Metformin, SGLT2-Inhibitors

Intervention / Treatment
-----------------
* Drug: Tofogliflozin
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetic patients Patients aged 20 years or older at the time of obtaining consent Patients with HbA1c 6.5 or more and 9.0% or less within 13 weeks before obtaining consent (evaluated by test values after 4 weeks or more without taking SGLT2 inhibitor / metformin) Patients who have been judged by their doctor to need a diabetic drug when they are first seen, or who have already taken a diabetic drug and have decided that it is necessary to add one diabetic drug. Patients who have been receiving RAS inhibitors (ARB, ARNI, ACE inhibitors, direct renin inhibitors) for 4 weeks or longer Patients with eGFR of 30 or more (mL / min / 1.73m2) within 13 weeks before obtaining consent (evaluated by test values after 4 weeks or more without taking SGLT2 inhibitor / metformin) Patients with urinary albumin / creatinine ratio (UACR) of 30 or more and less than 2000 (mg / gCr) (4 weeks or more without taking SGLT2 inhibitor / metformin) within 13 weeks before obtaining consent Evaluate by inspection value) Patients for whom written consent was obtained based on the patient's free will after receiving sufficient explanation for participation in this study Exclusion Criteria: Patients receiving treatment with SGLT2 inhibitor or metformin within 13 weeks before obtaining consent Dialysis patient Patients with a history of severe hypoglycemia Patients with hypersensitivity to SGLT2 inhibitor or metformin Pregnant women, lactating patients, and patients who wish to raise children Patients with BMI of 35 kg / m2 or more based on the latest measured values within 13 weeks before obtaining consent Patients who are contraindicated for the study drug Other patients who the attending physician deems inappropriate as a subject

Ages Eligible for Study
-----------------
Minimum Age: 20 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofogliflozin<br> | Drug: Tofogliflozin<br>* Tofogliflozin 20 mg is orally administered once daily for 104 weeks before or after breakfast.<br>|
| Active Comparator: Metformin<br> | Drug: Metformin<br>* Metformin is started at 500 mg daily and orally administered in 2 to 3 divided doses immediately before or after meals. The dose during the maintenance period is determined by observing the effect, but is usually 750 to 1,500 mg daily. Metformin is orally administered for 104 weeks throughout post-start period. The dose may be adjusted according to the patient's condition, but the maximum daily dose should be 2,250 mg.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine albumin-to-creatinine ratio (UACR) | Change from baseline in urine albumin-to-creatinine ratio (UACR) after 52 weeks treatment. | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine albumin-to-creatinine ratio (UACR) | Change from baseline in urine albumin-to-creatinine ratio (UACR) after 26 and 104 weeks treatment. | Up to 26 and 104 weeks | 
| Urine albumin-to-creatinine ratio (UACR) | Change rates from baseline in urine albumin-to-creatinine ratio (UACR) after 26, 52 and 104weeks treatment. | Up to 26, 52 and 104 weeks | 
| Change slope in eGFR | Change slope in eGFR | Up to 52 and 104 weeks | 
| HbA1c | Change in HbA1c | Up to 52 and 104 weeks | 
| Body weight | Changes in body weight | Up to 52 and 104 weeks | 
| Systolic / diastolic blood pressure | Changes in systolic / diastolic blood pressure | Up to 52 and 104 weeks | 
| Total serum proteins | Changes in total serum proteins | Up to 52 and 104 weeks | 
| Serum albumin | Changes in serum albumin | Up to 52 and 104 weeks | 
| Uric acid | Changes in uric acid | Up to 52 and 104 weeks | 
| Hematocrit | Changes in hematocrit | Up to 52 and 104 weeks | 
| Hemoglobin | Changes in hemoglobin | Up to 52 and 104 weeks | 
| Red blood cell count | Changes in red blood cell count | Up to 52 and 104 weeks | 
| Pulse rate | Changes in pulse rate | Up to 52 and 104 weeks | 
| Triglyceride | Changes in triglyceride | Up to 52 and 104 weeks | 
| Low-density lipoprotein | Changes in low-density lipoprotein | Up to 52 and 104 weeks | 
| High-density lipoprotein | Changes in high-density lipoprotein | Up to 52 and 104 weeks | 
| Albuminuria class | Transition of albuminuria class | Up to 104 weeks |