A Study to Evaluate the Efficacy and Safety of Ertugliflozin in Asian Participants With Type 2 Diabetes and Inadequate Glycemic Control on Metformin Monotherapy (MK-8835-012)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: Metformin; Drug: Ertugliflozin 15 mg; Drug: Ertugliflozin 5 mg; Drug: Placebo matching ertugliflozin; Drug: Glimepiride

Study type: Interventional

Funder types: Industry

Identifiers

NCT02630706

8835-012

MK-8835-012 (Other Identifier)

B1521045 (Other Identifier)

Details and patient eligibility

About

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.

Full description

This study includes a 1-week screening period, an 8-week (or greater) antihyperglycemic agent (AHA) wash-off and/or metformin dose stable period (as necessary), a 2-week single-blind placebo run-in period, a 26-week double-blind treatment period, and a post-treatment telephone contact 14 days after the last dose of study drug.

Enrollment: 506 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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506 participants in 3 patient groups, including a placebo group

Ertugliflozin 5 mg

Experimental group

Description:

Ertugliflozin 5 mg oral and matching placebo for ertugliflozin 10 mg, oral, once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Treatment:

Drug: Metformin

Drug: Ertugliflozin 5 mg

Drug: Glimepiride

Drug: Placebo matching ertugliflozin

Ertugliflozin 15 mg

Experimental group

Description:

Ertugliflozin 15 mg (ertugliflozin 5 mg + ertugliflozin 10 mg) administered orally once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Treatment:

Drug: Metformin

Drug: Ertugliflozin 15 mg

Drug: Glimepiride

Placebo

Placebo Comparator group

Description:

Placebo matching ertugliflozin administered orally once daily for 26 weeks, while maintaining metformin at a stable dose (\>=1500 mg/day). Glycemic rescue therapy with open-label glimepiride was initiated in participants with glucose values exceeding protocol-specified values.

Treatment:

Drug: Metformin

Drug: Glimepiride

Drug: Placebo matching ertugliflozin