Ertugliflozin and Sitagliptin Co-administration Factorial Study (VERTIS FACTORAL, MK-8835-005)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 3

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: Ertugliflozin 10 mg; Biological: Insulin Glargine Rescue Medication; Drug: Ertugliflozin 5 mg; Drug: Matching Placebo to Ertugliflozin 10 mg; Drug: Matching Placebo to sitagliptin 100 mg; Drug: Sitagliptin 100 mg; Drug: Metformin >= 1500 mg/day; Drug: Matching Placebo to Ertugliflozin 5 mg; Drug: Glimepiride Rescue Medication

Study type: Interventional

Funder types: Industry

Identifiers

NCT02099110

B1521019 (Other Identifier)

2013-003698-82 (EudraCT Number)

MK-8835-005 (Other Identifier)

8835-005

Details and patient eligibility

About

This is a study of co-administration of ertugliflozin (MK-8835/PF-04971729) and sitagliptin given together or alone along with metformin in participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin monotherapy. The primary hypothesis of this study is that ertugliflozin 15 mg daily plus sitagliptin 100 mg daily provides greater hemoglobin A1C (A1C)-lowering compared with sitagliptin 100 mg daily alone.

Full description

This study will include a 1-week screening period; an up to 12-week metformin titration/dose stabilization period; a 2-week single-blind placebo run-in period; a 52-week (26-week Phase A and 26-week Phase B) double-blind treatment period and a post-treatment telephone contact 14 days after the last dose of study medication.

Enrollment: 1,233 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Type 2 diabetes mellitus as per American Diabetes Association guidelines
• On metformin monotherapy (>=1500 mg/day) for >=8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy (>=1500 mg/day) for <8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy <1500 mg/day with a Visit 1/Screening A1C >=8.0% and <=11.5% (>=64 mmol/mol and <=102 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 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
• A known hypersensitivity or intolerance to any sodium glucose co-transporter 2 (SGLT2) inhibitor or sitagliptin
• 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 [i.e., <=7 days] during concomitant illness or other stress), other injectable anti-hyperglycemic agents (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other SGLT2 inhibitors, alpha glucosidase inhibitors or meglitinides, dipeptidyl-peptidase 4 inhibitor (DPP-4 inhibitor), sulfonylureas (SUs), bromocriptine (Cycloset™), colesevelam (Welchol™), any other antihyperglycemic agents (AHA) with the exception of the protocol-approved agents
• 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 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
• 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
• A known history of human immunodeficiency virus (HIV)
• A blood dyscrasia or any disorder causing hemolysis or unstable red blood cells, or a clinically important hematological disorder (e.g. aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
• 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
• Any clinically significant malabsorption condition
• Current treatment for hyperthyroidism
• On thyroid replacement therapy and not on a stable dose for at least 6 weeks prior study start
• On a previous clinical study with ertugliflozin
• Estimated glomerular filtration rate (eGFR) (using the 4-variable Modification of Diet in Renal Disease Study Equation (MDRD) equation) <60 mL/min/1.73 m^2
• Serum creatinine >= 1.3 mg/dL (115 µmol/L) for males and >= 1.2 mg/dL (106 µmol/L) for females
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times upper limit of normal
• Hemoglobin <12 g/dL (120 g/L) for males and <11 g/dL (110 g/L) for females.
• Participated in other studies involving investigational drug(s) 30 days prior to study start
• Surgical procedure within 6 weeks prior to study start or major surgery planned during the trial
• Positive urine pregnancy test
• 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
• Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking
• Donated blood or blood products within 6 weeks of study start

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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1,233 participants in 5 patient groups

Ertugliflozin 5 mg + sitagliptin 100 mg

Experimental group

Description:

Ertugliflozin 5 mg + sitagliptin 100 mg, oral, once daily for 52 weeks

Treatment:

Drug: Glimepiride Rescue Medication

Drug: Metformin >= 1500 mg/day

Drug: Matching Placebo to Ertugliflozin 10 mg

Drug: Sitagliptin 100 mg

Biological: Insulin Glargine Rescue Medication

Drug: Ertugliflozin 5 mg

Ertugliflozin 15 mg + sitagliptin 100 mg

Experimental group

Description:

Ertugliflozin 15 mg + sitagliptin 100 mg, oral, once daily for 52 weeks

Treatment:

Drug: Glimepiride Rescue Medication

Drug: Metformin >= 1500 mg/day

Drug: Sitagliptin 100 mg

Biological: Insulin Glargine Rescue Medication

Drug: Ertugliflozin 5 mg

Drug: Ertugliflozin 10 mg

Ertugliflozin 5 mg

Experimental group

Description:

Ertugliflozin 5 mg, oral, once daily for 52 weeks

Treatment:

Drug: Glimepiride Rescue Medication

Drug: Matching Placebo to sitagliptin 100 mg

Drug: Metformin >= 1500 mg/day

Drug: Matching Placebo to Ertugliflozin 10 mg

Biological: Insulin Glargine Rescue Medication

Drug: Ertugliflozin 5 mg

Ertugliflozin 15 mg

Experimental group

Description:

Ertugliflozin, oral, once daily for 52 weeks

Treatment:

Drug: Glimepiride Rescue Medication

Drug: Matching Placebo to sitagliptin 100 mg

Drug: Metformin >= 1500 mg/day

Biological: Insulin Glargine Rescue Medication

Drug: Ertugliflozin 5 mg

Drug: Ertugliflozin 10 mg

Sitagliptin 100 mg

Active Comparator group

Description:

Sitagliptin 100 mg, oral, once daily for 52 weeks

Treatment:

Drug: Glimepiride Rescue Medication

Drug: Metformin >= 1500 mg/day

Drug: Matching Placebo to Ertugliflozin 10 mg

Drug: Sitagliptin 100 mg

Biological: Insulin Glargine Rescue Medication

Drug: Matching Placebo to Ertugliflozin 5 mg