A Study to Assess the Efficacy and Safety of Ipragliflozin in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin

This is a phase 3, double-blind, randomized study to assess the efficacy and safety of ipragliflozin in combination with metformin compared to metformin plus placebo in subjects in Russia with type 2 diabetes mellitus who have inadequate glycemic control on metformin. Subjects will enter a 10-day (± 3 days) screening period, followed by a 2-week single-blind placebo run-in period, followed by a 24-week randomized double-blind treatment period and a 4-week follow-up period

Inclusion criteria

• Subject has been diagnosed with type 2 diabetes mellitus at least 12 weeks before visit 1.
• Subject has been on a stable dose and a daily dose regimen of metformin ≥ 1500 mg for at least 12 weeks prior to visit 1.
• Subject has HbA1c ≥ 7.5% and ≤ 11.0% at visit 1.
• Subject has been on a stable diet and exercise program for at least 12 weeks prior to visit 1 and is willing to maintain this program for the duration of the treatment period.
• Subject has a body mass index (BMI) of 20 to 45 kg/m2, inclusive, at visit 1.
• Subjects are allowed to continue taking their medication for concomitant diseases (including over-the-counter products), provided they have been on a stable dose for a minimum of 30 days prior to visit 1.
• Female subjects must either:

• Be of non-childbearing potential:

• postmenopausal (defined as at least 1 year without any menses) prior to screening, or
• documented as surgically sterile
• Or, if of childbearing potential,

• Agree not to try to become pregnant during the study and for 28 days after the final study drug administration
• And have a negative serum pregnancy test at visit 1
• And, if heterosexually active, agree to consistently use 2 forms of highly effective birth control (at least 1 of which must be a barrier method) starting at screening, throughout the study period and for 28 days after the final study drug administration.
• Female subjects must agree not to breastfeed starting at screening, throughout the study period and for 28 days after the final study drug administration.
• Female subjects must not donate ova starting at screening, throughout the study period and for 28 days after the final study drug administration.
• Male subjects and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting at screening and continue throughout the study period.
• Male subjects must not donate sperm starting at screening and throughout the study period.

Exclusion criteria

• Subject has type 1 diabetes mellitus.
• Subject has received any medication for glycemic control, with the exception of metformin, (e.g., oral antidiabetic drugs, insulin, etc.) within 12 weeks prior to visit 1.
• Subject is currently receiving an excluded medication or has received insulin within 12 weeks prior to visit 1 or during the screening period.
• Subject has a history of stroke, unstable angina, myocardial infarction, any vascular intervention or heart failure (New York Heart Association Class III-IV;) within 12 weeks prior to visit 1.
• Subject has had a malignancy in the last 5 years, except for adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
• Subject has a history of diabetic coma or precoma.
• Subject has a history of ketoacidosis or lactic acidosis.
• History of drinking more than 21 units of alcohol per week (1 unit = 10 g pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine [12%]) (> 14 units of alcohol for female subjects) or history of drugs abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) within 3 months prior to visit 1.
• Subject is known to have hepatitis or be a carrier of hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or is known to be positive for human immunodeficiency virus (HIV)-1 and/or HIV-2.
• Subject has a severe infection, has serious trauma, or is a perioperative subject.
• Subject has symptomatic urinary tract infection or genital infection at visit 1 and/or just prior to randomization at visit 3.
• Subject has uncontrolled severe hypertension (or subject whose systolic blood pressure is > 180 mmHg or diastolic blood pressure of > 110 mmHg measured in a sitting position after 5 minutes of rest at visit 1).
• Subject has an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x the upper limit of normal (ULN) range or has a total bilirubin > 1.5 x ULN at visit 1.
• Subject has a urinary microalbumin/creatinine ratio ≥ 300 mg/g at visit 1.
• Subject has estimated glomerular filtration rate (GFR) value of < 60 mL/min/1.73 m2 at visit 1 (using the Modification of Diet in Renal Disease [MDRD] calculation).
• Subject has known or suspected hypersensitivity to ipragliflozin or any components of the formulations used or a history of allergy for Sodium-glucose cotransporter (SGLT)2 inhibitors.
• Subject has previously received ipragliflozin or other SGLT2 inhibitors.
• Subject is concurrently participating in another drug study or has received an investigational drug within 30 days or the limit set by national law, whichever is longer, prior to visit 1 or plans to receive another investigational drug during the study.
• Female subject who is currently pregnant or lactating
• Male or female subject who does not use appropriate contraception during the study.
• The subject is unable to adhere to the treatment regimen, protocol procedures or study requirements (including discontinuation criteria during the run-in period), in the investigator's judgment.
• Subject has an unstable medical or psychiatric illness.