A Randomised Double-Blind Placebo-Controlled Multicenter Study with Extension to Evaluate the Efficacy Safety and Tolerability of Canagliflozin in the Treatment of Subjects with Type 2 Diabetes Mellitus Who Have Moderate Renal Impairment

Exclusion Criteria53

• History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta-cell transplantation, or
• diabetes secondary to pancreatitis or pancreatectomy
• Repeated (ie, 2 or more over a 1-week period) FPG and/or fasting SMBG glucose
• measurements >270 mg/dL (15 mmol/L) during the pretreatment phase, despite
• reinforcement of diet and exercise counseling
• Have proliferative diabetic retinopathy for which treatment is planned during the
• course of the study
• History of 1 or more severe hypoglycemic episode within 6 months before screening.
• History of hereditary glucose-galactose malabsorption or primary renal glucosuria
• Ongoing, inadequately controlled thyroid disorder (eg, subject has a known thyroid
• stimulating hormone [TSH] value that is either <0.2 or >10 mIU/L)
• Ongoing eating disorder or significant weight loss or weight gain within 12 weeks,
• defined as an increase or decrease of 5% in body weight based upon clinic-based
• measurement or, if not available, subject report
• Renal disease that required treatment with immunosuppressive therapy or a history of dialysis or renal transplant
• Presence of nephrotic syndrome (eg, severe proteinuria with hypoalbuminemia and/or edema), or inflammatory renal disease (eg, acute interstitial nephritis, acute or rapidly-progressive glomerulonephritis)
• Subject is likely to require dialysis or transplantation during participation in the study
• Myocardial infarction, unstable angina, revascularization procedure (eg, stent or
• bypass graft surgery), or cerebrovascular accident within 3 months before screening,
• or revascularization procedure is planned, or subject has a history of New York Heart
• Association (NYHA) Class III-IV cardiac disease (refer to Attachment 3, New York
• Heart Association Classification of Cardiac Disease, for a description of the classes)
• Findings on 12-lead ECG that would require urgent diagnostic evaluation or
• intervention (eg, new clinically important arrhythmia or conduction disturbance)
• Uncontrolled hypertension (ie, using an average of 3 seated blood pressure readings with a diastolic blood pressure =100 mmHg or systolic blood pressure =160 mmHg) at Week -2
• History of hepatitis B surface antigen or hepatitis C antibody positive (unless associated with documented persistently stable/normal range aspartate
• aminotransferase [AST] and Alanine Transaminase (ALT) levels, or other clinically active liver disease
• History of prior bariatric surgical procedure within 3 years before the screening visit
• Fasting serum triglycerides =600 mg/dL (6.74 mmol/L) at screening (or subsequent
• visit if not fasting at screening)
• Alanine aminotransferase level >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN at screening (for elevations in bilirubin: if, in the opinion of the investigator and agreed upon by the sponsor’s medical officer, the elevation in bilirubin is consistent with Gilbert’s disease, the subject may participate)
• Hemoglobin concentration <10 g/L at screening
• History of malignancy within 5 years before screening (exceptions: squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or a malignancy that in the opinion of the investigator, with concurrence with the sponsor’s medical monitor, is considered cured with minimal risk of recurrence)
• Clinically important hematologic disorder (eg, symptomatic anemia, proliferative bone marrow disorder, thrombocytopenia)
• History of human immunodeficiency virus (HIV) antibody positive
• Investigator’s assessment that the subject’s life expectancy is less than 1 year
• Any condition that in the opinion of the investigator would make participation not in
• the best interest of the subject, or could prevent, limit, or confound the protocol-specified assessments
• Major surgery (ie, requiring general anesthesia) within 12 weeks before screening, or subject has not fully recovered from surgery, or planned surgery during time the subject is expected to participate in the study
• Any other sodium glucose transporter 2 (SGLT2) inhibitor
• Colesevelam and bromocriptine
• Subjects receiving anti-hypertensive or anti-hyperlipidemic therapy not on a stable
• regimen (same medication and dose[s]) for at least 4 weeks before Day 1
• Known allergies, hypersensitivity, or intolerance to canagliflozin or its excipients
• Current use of a corticosteroid medication or immunosuppressive agent, or likely to require treatment with a corticosteroid medication (for longer than 2 weeks in duration) or an immunosuppressive agent
• Subject currently treated with or who are likely to require treatment with a
• non-steroidal anti-inflammatory drug (NSAID) in higher doses during their expected participation in the study
• Received an investigational drug (including vaccines), other than a placebo agent, or used an investigational medical device within 3 months before the planned start of reatment or received at least 1 dose of canagliflozin in a prior study
• History of drug or alcohol abuse within 3 years before screening
• Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study
• Employees of the investigator or study site, with direct involvement in the proposed
• study or other studies under the direction of that investigator or study site, as well as
• family members of the employees or the investigator