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)

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)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02630706

Enrollment

506

Registered

2015-12-15

Start date

2015-12-16

Completion date

2017-12-27

Last updated

2018-12-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes Mellitus

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.

Interventions

DRUGErtugliflozin 5 mg

Ertugliflozin 5 mg oral tablet taken once daily

DRUGErtugliflozin 15 mg

Ertugliflozin 15 mg (5-mg and 10-mg tablets) oral taken once daily

DRUGPlacebo matching ertugliflozin

Placebo matching ertugliflozin (5-mg and/or 10-mg tablet) oral taken once daily

DRUGMetformin

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.

DRUGGlimepiride

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

Sponsor was masked.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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.)

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
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.

Secondary

Measure	Time frame	Description
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.
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 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 <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.
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.
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 6: Pre-Dose	No ertugliflozin plasma concentrations were determined for participants receiving placebo. Lower limit of quantification for ertugliflozin was 0.500 ng/mL.
Ertugliflozin Plasma Concentrations Summary Statistics Over Time: Including Rescue Approach (China Subpopulation)	Week 6: 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 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.
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.
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.

Participant flow

Recruitment details

In total, 1078 participants were screened, and 506 participants were randomized at 50 sites in China, Hong Kong, Republic of Korea, the Philippines, and Taiwan.

Participants by arm

Arm	Count
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.	170
Ertugliflozin 15 mg Ertugliflozin 15 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.	169
Placebo 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.	167
Total	506

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	2	1	1
Overall Study	Lost to Follow-up	0	1	2
Overall Study	Physician Decision	1	1	0
Overall Study	Pregnancy	0	1	0
Overall Study	Withdrawal by Subject	4	5	7

Baseline characteristics

Characteristic	Placebo	Total	Ertugliflozin 5 mg	Ertugliflozin 15 mg
Age, Continuous	56.9 Years STANDARD_DEVIATION 9	56.5 Years STANDARD_DEVIATION 9.1	56.1 Years STANDARD_DEVIATION 9	56.3 Years STANDARD_DEVIATION 9.3
Age Continuous (China Substudy)	56.8 Years STANDARD_DEVIATION 8.6	56.3 Years STANDARD_DEVIATION 9	56.0 Years STANDARD_DEVIATION 9	56.2 Years STANDARD_DEVIATION 9.4
Anti-AHA status at Screening (Metformin Alone OR Metformin + Another AHA) (China Substudy) Metformin Alone	93 Participants	270 Participants	85 Participants	92 Participants
Anti-AHA status at Screening (Metformin Alone OR Metformin + Another AHA) (China Substudy) Metformin + Another AHA	42 Participants	136 Participants	51 Participants	43 Participants
Anti-hyperglycemic Agent (AHA) Status at Screening (Metformin Alone OR Metformin + Another AHA) Metformin alone	121 Participants	353 Participants	111 Participants	121 Participants
Anti-hyperglycemic Agent (AHA) Status at Screening (Metformin Alone OR Metformin + Another AHA) Metformin + Another AHA	46 Participants	153 Participants	59 Participants	48 Participants
Baseline A1C (China Substudy)	8.09 Percentage A1C STANDARD_DEVIATION 0.98	8.14 Percentage A1C STANDARD_DEVIATION 0.96	8.22 Percentage A1C STANDARD_DEVIATION 0.94	8.13 Percentage A1C STANDARD_DEVIATION 0.96
Baseline eGFR (China Substudy)	100.8 mL/min/1.73 m^2 STANDARD_DEVIATION 21.1	101.1 mL/min/1.73 m^2 STANDARD_DEVIATION 19.9	99.8 mL/min/1.73 m^2 STANDARD_DEVIATION 19	102.7 mL/min/1.73 m^2 STANDARD_DEVIATION 19.8
Baseline estimated glomerular filtration rate (eGFR)	99.9 mL/min/1.73 m^2 STANDARD_DEVIATION 20.2	99.3 mL/min/1.73 m^2 STANDARD_DEVIATION 19.7	97.9 mL/min/1.73 m^2 STANDARD_DEVIATION 19.2	100.2 mL/min/1.73 m^2 STANDARD_DEVIATION 19.8
Baseline Fasting Plasma Glucose (FPG)	165.8 mg/dL STANDARD_DEVIATION 37.6	167.8 mg/dL STANDARD_DEVIATION 38.3	170.1 mg/dL STANDARD_DEVIATION 36	167.3 mg/dL STANDARD_DEVIATION 41.1
Baseline FPG (China Substudy)	165.5 mg/dL STANDARD_DEVIATION 37.9	170.6 mg/dL STANDARD_DEVIATION 39.3	175.7 mg/dL STANDARD_DEVIATION 36.2	170.5 mg/dL STANDARD_DEVIATION 43
Baseline Hemoglobin A1C (A1C)	8.13 Percentage A1C STANDARD_DEVIATION 0.96	8.12 Percentage A1C STANDARD_DEVIATION 0.92	8.14 Percentage A1C STANDARD_DEVIATION 0.89	8.09 Percentage A1C STANDARD_DEVIATION 0.91
Body Weight	70.1 Kilograms STANDARD_DEVIATION 12.4	70.3 Kilograms STANDARD_DEVIATION 11.5	71.4 Kilograms STANDARD_DEVIATION 11.1	69.5 Kilograms STANDARD_DEVIATION 10.9
Body Weight (China Substudy)	70.6 Kilograms STANDARD_DEVIATION 12.2	70.7 Kilograms STANDARD_DEVIATION 11.2	71.4 Kilograms STANDARD_DEVIATION 11.1	70.2 Kilograms STANDARD_DEVIATION 10.2
Country China	135 Participants	406 Participants	136 Participants	135 Participants
Country Hong Kong	7 Participants	27 Participants	10 Participants	10 Participants
Country Korea, Republic of	9 Participants	32 Participants	13 Participants	10 Participants
Country Philippines	8 Participants	23 Participants	7 Participants	8 Participants
Country Taiwan	8 Participants	18 Participants	4 Participants	6 Participants
Gender (China Substudy) Female	66 Participants	182 Participants	65 Participants	51 Participants
Gender (China Substudy) Male	69 Participants	224 Participants	71 Participants	84 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	167 Participants	506 Participants	170 Participants	169 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Female	79 Participants	225 Participants	75 Participants	71 Participants
Sex: Female, Male Male	88 Participants	281 Participants	95 Participants	98 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 170	0 / 169	0 / 167
other Total, other adverse events	22 / 170	31 / 169	44 / 167
serious Total, serious adverse events	9 / 170	10 / 169	2 / 167

Outcome results

Primary

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.

Time frame: Baseline and Week 26

Population: The analysis population included all randomized participants who received at least one dose of investigational product and who had at least one assessment of the respective endpoint at baseline or post baseline up to Week 26.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach)	-1.00 Percentage A1C
Ertugliflozin 15 mg	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach)	-0.89 Percentage A1C
Placebo	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach)	-0.20 Percentage A1C

Comparison: The primary hypothesis of the study was the mean change from baseline in HbA1c for 15 mg ertugliflozin is greater than that for placebo.p-value: <0.00195% CI: [-0.85, -0.52]cLDA

Comparison: The primary hypothesis of the study was the mean change from baseline in HbA1c for 5 mg ertugliflozin is greater than that for placebo.p-value: <0.00195% CI: [-0.97, -0.63]cLDA

Primary

Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)

Time frame: Baseline and Week 26

Population: The analysis population included all randomized participants in China who received at least one dose of investigational product and who had at least one assessment of the respective endpoint at baseline or post baseline up to Week 26.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-1.01 Percentage A1C
Ertugliflozin 15 mg	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-0.92 Percentage A1C
Placebo	Change From Baseline in A1C (%) at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-0.24 Percentage A1C

p-value: <0.00195% CI: [-0.86, -0.5]cLDA

p-value: <0.00195% CI: [-0.95, -0.58]cLDA

Primary

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.

Time frame: Up to 26 weeks

Population: The analysis population included all randomized participants who received at least one dose of investigational product.

Arm	Measure	Value (NUMBER)
Ertugliflozin 5 mg	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)	1.2 Percentage of Participants
Ertugliflozin 15 mg	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)	0.6 Percentage of Participants
Placebo	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)	1.8 Percentage of Participants

Primary

Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)

Time frame: Up to 26 weeks

Population: The analysis population included all randomized participants in China who received at least one dose of investigational product.

Arm	Measure	Value (NUMBER)
Ertugliflozin 5 mg	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)	0.7 Percentage of Participants
Ertugliflozin 15 mg	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)	0.7 Percentage of Participants
Placebo	Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach) (China Subpopulation)	2.2 Percentage of Participants

Primary

Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)

Time frame: Up to 28 weeks

Population: The analysis population included all randomized participants who received at least one dose of investigational product.

Arm	Measure	Value (NUMBER)
Ertugliflozin 5 mg	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)	56.5 Percentage of participants
Ertugliflozin 15 mg	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)	53.3 Percentage of participants
Placebo	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)	59.3 Percentage of participants

95% CI: [-16.5, 4.6]

95% CI: [-13.3, 7.7]

Primary

Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)

Time frame: Up to 28 weeks

Population: The analysis population included all randomized participants in China who received at least one dose of investigational product .

Arm	Measure	Value (NUMBER)
Ertugliflozin 5 mg	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)	54.4 Percentage of participants
Ertugliflozin 15 mg	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)	50.4 Percentage of participants
Placebo	Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach) (China Subpopulation)	59.3 Percentage of participants

95% CI: [-20.5, 3]

95% CI: [-16.5, 6.9]

Secondary

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.

Time frame: Baseline and Week 26

Population: The analysis population included all randomized participants and who received at least one dose of investigational product and who had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)	-2.95 Kilograms
Ertugliflozin 15 mg	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)	-3.18 Kilograms
Placebo	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach)	-1.17 Kilograms

p-value: <0.00195% CI: [-2.51, -1.5]cLDA

p-value: <0.00195% CI: [-2.28, -1.28]cLDA

Secondary

Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-3.11 Kilograms
Ertugliflozin 15 mg	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-3.38 Kilograms
Placebo	Change From Baseline in Body Weight at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-1.33 Kilograms

p-value: <0.00195% CI: [-2.63, -1.21]cLDA

p-value: <0.00195% CI: [-2.36, -1.21]cLDA

Secondary

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.

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)	-37.09 mg/dL
Ertugliflozin 15 mg	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)	-34.47 mg/dL
Placebo	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)	-6.69 mg/dL

p-value: <0.00195% CI: [-33.85, -21.7]cLDA

p-value: <0.00195% CI: [-36.45, -24.35]cLDA

Secondary

Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-39.01 mg/dL
Ertugliflozin 15 mg	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-36.67 mg/dL
Placebo	Change From Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-10.46 mg/dL

p-value: <0.00195% CI: [-32.41, -20.01]cLDA

p-value: <0.00195% CI: [-34.67, -22.43]cLDA

Secondary

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.

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)	-2.38 mmHg
Ertugliflozin 15 mg	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)	-2.36 mmHg
Placebo	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)	-0.96 mmHg

p-value: 0.08695% CI: [-3, 0.2]cLDA

p-value: 0.08195% CI: [-3.01, 0.17]cLDA

Secondary

Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-2.82 mmHg
Ertugliflozin 15 mg	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-2.77 mmHg
Placebo	Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-1.82 mmHg

p-value: 0.31595% CI: [-2.8, 0.9]cLDA

p-value: 0.28295% CI: [-2.83, 0.83]cLDA

Secondary

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.

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)	-5.09 mmHg
Ertugliflozin 15 mg	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)	-3.87 mmHg
Placebo	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)	0.22 mmHg

p-value: <0.00195% CI: [-6.48, -1.69]cLDA

p-value: <0.00195% CI: [-7.68, -2.92]cLDA

Secondary

Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)

Time frame: Baseline and Week 26

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Ertugliflozin 5 mg	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-5.64 mmHg
Ertugliflozin 15 mg	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-4.19 mmHg
Placebo	Change From Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach) (China Subpopulation)	-1.56 mmHg

p-value: 0.05895% CI: [-5.36, 0.09]cLDA

p-value: 0.00395% CI: [-6.78, -1.39]cLDA

Secondary