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

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

The main purpose of this study is to evaluate the efficacy in reducing glycated hemoglobin of ipragliflozin in combination with metformin compared with metformin plus placebo 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:

  1. Be of non-childbearing potential:

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

  2. 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.