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)

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: Ertugliflozin 5 mg
Drug: Ertugliflozin 15 mg
Drug: Placebo matching ertugliflozin
Drug: Metformin
Drug: Glimepiride

Registration Number: NCT02630706

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 506

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.)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ertugliflozin 5 mg	Placebo matching ertugliflozin	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.
Ertugliflozin 5 mg	Ertugliflozin 5 mg	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.
Ertugliflozin 15 mg	Ertugliflozin 15 mg	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.
Placebo	Placebo matching ertugliflozin	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.
Ertugliflozin 5 mg	Glimepiride	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.
Ertugliflozin 5 mg	Metformin	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.
Ertugliflozin 15 mg	Glimepiride	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.
Ertugliflozin 15 mg	Metformin	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.
Placebo	Metformin	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.
Placebo	Glimepiride	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach)	Baseline and Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 26 A1C minus the Week 0 A1C (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)	Up to 28 weeks	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)	Up to 28 weeks	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)	Up to 26 weeks	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)	Up to 26 weeks	An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)	Baseline and Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 26 A1C minus the Week 0 A1C (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)	Baseline and Week 26	Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 26 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 26 minus FPG at Week 0) which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)	Baseline and Week 26	Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 26 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 26 minus FPG at Week 0) which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)	Baseline and Week 26	The change in body weight from baseline reflects the Week 26 body weight minus the Week 0 body weight (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)	Baseline and Week 26	The change in body weight from baseline reflects the Week 26 body weight minus the Week 0 body weight (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)	Baseline and Week 26	This change from baseline reflects the Week 26 sitting systolic blood pressure (SBP) minus the Week 0 sitting SBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	Baseline and Week 26	This change from baseline reflects the Week 26 sitting systolic blood pressure (SBP) minus the Week 0 sitting SBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)	Baseline and Week 26	This change from baseline reflects the Week 26 sitting diastolic blood pressure (DBP) minus the Week 0 sitting DBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants With HbA1c of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach)	Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants With HbA1c of <7.0% (53 mmol/Mol) (Logistic Regression Using Multiple Imputation Based on cLDA Model: Excluding Rescue Approach)	Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants With HbA1c of <7.0% (53 mmol/Mol) (Logistic Regression Using Multiple Imputation Based on cLDA Model: Excluding Rescue Approach) (China Subpopulation)	Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation)	Week 26: Pre-Dose	No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL.
Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	Baseline and Week 26	This change from baseline reflects the Week 26 sitting diastolic blood pressure (DBP) minus the Week 0 sitting DBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.
Percentage of Participants Requiring Glycemic Rescue Therapy Through Week 26.	Week 26	Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment.
Percentage of Participants Requiring Glycemic Rescue Therapy Through Week 26 (China Subpopulation)	Week 26	Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment.
Time to Glycemic Rescue Therapy	Up to 183 days	Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment.
Time to Glycemic Rescue Therapy (China Subpopulation)	Up to 149 days	Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment.
Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach	Week 26: Pre-Dose	No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL.
Percentage of Participants With HbA1c of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach) (China Subpopulation)	Week 26	A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy.