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)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-Week Multicenter Study to Evaluate the Efficacy and Safety of Ertugliflozin in Asian Subjects With Type 2 Diabetes Mellitus and Inadequate Glycemic Control on Metformin Monotherapy (VERTIS-ASIA)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin 5 mg
* Drug: Ertugliflozin 15 mg
* Drug: Placebo matching ertugliflozin
* Drug: Metformin
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin 5 mg<br>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. | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg oral tablet taken once daily<br>* Other names: PF-04971729;Drug: Placebo matching ertugliflozin<br>* Placebo matching ertugliflozin (5-mg and/or 10-mg tablet) oral taken once daily<br>Drug: Metformin<br>* Participants are to remain on their stable doses of metformin (oral, >=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period. Participants on metformin <1500 at screening are up-titrated to >= 1500 daily.<br>Drug: Glimepiride<br>* Glycemic rescue therapy with open-label glimepiride will be initiated in participants with glucose values exceeding protocol-specified values. Dosing and titration of open-label glimepiride rescue therapy will be at the Investigator's discretion.<br>|
| Experimental: Ertugliflozin 15 mg<br>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. | Drug: Ertugliflozin 15 mg<br>* Ertugliflozin 15 mg (5-mg and 10-mg tablets) oral taken once daily<br>* Other names: PF-04971729;Drug: Metformin<br>* Participants are to remain on their stable doses of metformin (oral, >=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period. Participants on metformin <1500 at screening are up-titrated to >= 1500 daily.<br>Drug: Glimepiride<br>* Glycemic rescue therapy with open-label glimepiride will be initiated in participants with glucose values exceeding protocol-specified values. Dosing and titration of open-label glimepiride rescue therapy will be at the Investigator's discretion.<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo matching ertugliflozin<br>* Placebo matching ertugliflozin (5-mg and/or 10-mg tablet) oral taken once daily<br>Drug: Metformin<br>* Participants are to remain on their stable doses of metformin (oral, >=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period. Participants on metformin <1500 at screening are up-titrated to >= 1500 daily.<br>Drug: Glimepiride<br>* Glycemic rescue therapy with open-label glimepiride will be initiated in participants with glucose values exceeding protocol-specified values. Dosing and titration of open-label glimepiride rescue therapy will be at the Investigator's discretion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) | 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. | Baseline and Week 26 | 
| Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation) | 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. | Baseline and Week 26 | 
| Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) | 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. | Up to 28 weeks | 
| Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation) | 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. | Up to 28 weeks | 
| Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) | 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. | Up to 26 weeks | 
| Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation) | 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. | Up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) | 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. | Baseline and Week 26 | 
| Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation) | 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. | Baseline and Week 26 | 
| Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) | 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. | Baseline and Week 26 | 
| Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation) | 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. | Baseline and Week 26 | 
| Percentage of Participants With HbA1c of <7.0% (53 mmol/Mol) (Logistic Regression Using Multiple Imputation Based on cLDA Model: Excluding Rescue Approach) | 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. | Week 26 | 
| 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) | 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. | Week 26 | 
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) | 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. | Baseline and Week 26 | 
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation) | 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. | Baseline and Week 26 | 
| Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) | 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. | Baseline and Week 26 | 
| Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation) | 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. | Baseline and Week 26 | 
| Percentage of Participants With HbA1c of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach) | 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. | Week 26 | 
| Percentage of Participants With HbA1c of <6.5% (48 mmol/Mol) at Week 26 (Logistic Regression Using Multiple Imputation: Excluding Rescue Approach) (China Subpopulation) | 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. | Week 26 | 
| Percentage of Participants Requiring Glycemic Rescue Therapy Through 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. | Week 26 | 
| Percentage of Participants Requiring Glycemic Rescue Therapy Through Week 26 (China Subpopulation) | Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. | Week 26 | 
| Time to Glycemic Rescue Therapy | Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. | Up to 183 days | 
| Time to Glycemic Rescue Therapy (China Subpopulation) | Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of open-label glimepiride and dosed according to Investigator judgment. | Up to 149 days | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 6: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 12: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 12: 60 min. Post-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 18: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 18: 60 min. Post-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 26: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 6: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 12: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 12: 60 min. Post-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 18: Pre-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 18: 60 min. Post-Dose | 
| Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation) | No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL. | Week 26: Pre-Dose |