A Phase 1 Study to Investigate the Mechanism of Action of Ipragliflozin

This study will consist of 2 parts. In Part A the effect of ipragliflozin on the glucose homeostasis will be investigated and in Part B we will investigate the effect of exposure of ipragliflozin on UGE and plasma glucose levels.

Part A

This part will be a randomized, double-blind, placebo-controlled, 2-

period, 2 treatment crossover design in healthy subjects and in T2DM

subjects who are drug naïve or washed out for metformin prior to

admission to the clinical site.

Part B

This part will be an open-label, randomized, 2-period, 2 treatment

crossover design in T2DM subjects stratified by baseline HbA1c

levels (6.0-6.9%, 7.0-7.9%, 8.0-8.9% or 9.0-9.9%).

Inclusion criteria

Inclusion Part A: Healthy subjects

• Subject is healthy without diabetes mellitus
• Subject has a fasted plasma glucose (FPG) of less than 5.6 mmol/l at screening
• Subject has a Body Mass Index (BMI) more than or equal to 18.5 and less than 28.0 kg/m2
• Subject's serum creatinine is within the normal range

Inclusion Part A: T2DM subjects

• Subject has been diagnosed with T2DM for at least 6 months
• Subject's body mass index (BMI) is equal to or more than 20.0 and less than 35.0 kg/m2 at screening
• Subject has a HbA1c level above 7.0% and less than 9.0% at screening
• Subject has a (FPG) of less than 10.0 mmol/l
• Subject is treatment naïve to glucose-lowering medication or uses metformin that will be washed out at least 3 weeks prior to the first dosing at Day 1
• Subject's serum creatinine is within the normal range

Inclusion Part B: T2DM subjects

• Subject has a body mass index (BMI) of more than or equal to 20.0 and less than 35.0 kg/m2 at screening.
• Subject has been diagnosed with T2DM for at least 6 months
• Subject has HbA1c level of equal to or more than 6.0% and less than 10% at screening
• Subject has a FPG of less than 10.0 mmol/l
• Subject is drug naïve or on a stable glucose lowering therapy (metformin, TZD, DPP-4 inhibitor or SUD therapy

Exclusion criteria

Exclusion Part A: Healthy subjects

• Any of the liver function tests above the upper limit of normal
• A QTc interval of >430 ms (males) and >450 ms (females), a history of unexplained syncope, cardiac arrest, unexplained significant cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS)
• Abnormal pulse and/or blood pressure measurements at screening as follows: Pulse <40 or >90 bpm; mean systolic blood pressure >140 mmHg; mean diastolic blood pressure >90 mmHg
• eGFR (based on Modification of Diet in Renal Disease (MDRD) method) less than 60 ml/min/1.73m2 on Day -2

Exclusion Part A & Part B: T2DM subjects

• Subject has type 1 diabetes mellitus
• A QTc interval of >450 ms (males) and >470 ms (females), a history of unexplained syncope, cardiac arrest, unexplained significant cardiac arrhythmias or torsades de pointes, structural heart disease, or a family history of Long QT Syndrome (LQTS)
• Subject is on an insulin therapy or has received insulin within 3 months prior to screening, with the exception of acute use of <7 days prior to screening
• Subject has a urinary microalbumin/creatinine ratio above or equal to 300 mg/g at screening
• Subject has an ALT and/or AST higher than 3 times the upper limit of normal or has a total bilirubin more than 2 times the upper limit of normal at screening
• Subject has a symptomatic urinary tract infection or symptomatic genito-urinary infection at screening
• Subject has persistent, uncontrolled severe hypertension as indicated by a mean systolic blood pressure > 160 mmHg or a mean diastolic blood pressure of > 100 mmHg
• Subject has significant cardiovascular disease
• eGFR (based on MDRD method) less than 60 ml/min/1.73m2 on Day -2