Type 2 Diabetes Mellitus

This is a study to evaluate the efficacy and safety of the addition of ertugliflozin to metformin monotherapy in Asian participants with Type 2 diabetes mellitis (T2DM) who have inadequate glycemic control on metformin monotherapy. The primary hypothesis is that the mean reduction from baseline in HbA1C for 15 mg and 5 mg ertugliflozin (tested sequentially) is greater than for placebo.

Ertugliflozin

Ertugliflozin

film-coated tablet

5mg
10mg

Primary Endpoint:
• Change in HbA1c from Baseline to Week 26.
Secondary Endpoints:
• Change in FPG from Baseline to Week 26.
• Change in body weight from Baseline to Week 26.
• Proportion of subjects with HbA1c of <7.0% (53 mmol/mol) at Week 26.
• Change in systolic blood pressure from Baseline to Week 26.
• Change in diastolic blood pressure from Baseline to Week 26.
• Proportion of subjects with HbA1c <6.5% (48 mmol/mol) at Week 26.
• Proportion of subjects requiring glycemic rescue therapy by Week 26.
• Time to glycemic rescue therapy.
• Endpoints related to pharmacokinetics of ertugliflozin.

Inclusion Criteria:
• Asian participants ≥18 years of age at the time of initial Screening.
• Type 2 diabetes mellitus as per American Diabetes Association guidelines.
• Metformin monotherapy (≥1500 mg/day) with an initial Screening A1C of 7.0-10.5% (53-91 mmol/mol) OR metformin monotherapy (<1500 mg/day) with an initial Screening A1C of 7.5-11.0% (58-97 mmol/mol) OR dual combination therapy with metformin + sulfonylurea, dipeptidyl peptidase-4 (DDP-4) inhibitor, meglitinide, or alpha-glucosidase inhibitor with an initial Screening A1C of 6.5-9.5% (48-80 mmol/mol).
• Body mass index (BMI) ≥18.0 kg/m^2.
• Male or female not of reproductive potential.
• Female of reproductive potential who agrees to remain abstinent from heterosexual activity or to use 2 acceptable combinations of contraception.

Exclusion Criteria:
• History of type 1 diabetes mellitus or a history of ketoacidosis.
• History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant.)
• History of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional class III-IV heart failure within 3 months of study start.
• Mean value for triplicate screening sitting systolic blood pressure >160 mm Hg and/or diastolic blood pressure >90 mm Hg after at least a 5-minute seated rest at screening
• Active, obstructive uropathy or indwelling urinary catheter.
• History of malignancy ≤5 years prior to study start, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
• Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking.
• Any clinically significant malabsorption condition.
• Is on a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable prior to study start.
• Has undergone bariatric surgery within the past 12 months or >12 months and is not weight stable prior to study start.
• A known hypersensitivity or intolerance to any sodium glucose co-transporter (SGLT2) inhibitor.
• On a previous clinical study with ertugliflozin.
• Is taking blood pressure or lipid altering medications that have not been on a stable dose for at least 4 weeks prior to study start.
• Current treatment for hyperthyroidism.
• Male participants with a serum creatinine >=1.3 mg/dL (>=115 mol/L) or female participants with a serum creatinine >=1.2 mg/dL (>=106 mol/L) or participants with an estimated glomerular filtration rate (eGFR) <55 mL/min/1.73m^2 according to the 4-variable Modification of Diet in Renal Disease (MDRD) equation at screening.
• An aspartate transaminase (AST) or alanine transaminase (ALT) >2X the upper limit of normal (ULN) range at screening, or a total bilirubin >1.5 X the ULN unless the participant has a history of Gilbert's.
• On thyroid replacement therapy and has not been on a stable dose for at least 6 weeks prior to study start.
• A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease.
• Has been treated with any of the following agents within 12 weeks of study start or during the pre-randomization period: Insulin of any type (except for short-term use during concomitant illness or other stress), other injectable anti-hyperglycemic agents (e.g., pramlintide, exenatide, liraglutide), another SGLT2 inhibitor, bromocriptine, colesevelam, rosiglitazone or pioglitazone, or any other AHA with the exception of the protocol-approved agents.
• Is on or likely to require treatment ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
• Has undergone a surgical procedure within 6 weeks prior to study start or has planned major surgery during the study.
• Pregnant or breast-feeding, or planning to conceive during the trial, including 14 days following the last dose of study medication.
• Planning to undergo hormonal therapy in preparation for egg donation during the trial, including 14 days following the last dose of study medication.
• Donated blood or blood products within 6 weeks of study start.
• Has Human Immunodeficiency Virus (HIV).
• Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells.
• Has clinically important hematological disorders (such as aplastic anemia, myeloproliferative or myelodyplastic syndromes, thrombocytopenia.)