Type 2 Diabetes Mellitus
Conditions
Brief summary
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.
Detailed 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.
Interventions
DRUGMatching Placebo to Ertugliflozin 5 mg
Placebo to ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
DRUGMatching Placebo to Ertugliflozin 10 mg
Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
DRUGMatching Placebo to sitagliptin 100 mg
Placebo to sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period
DRUGMetformin >= 1500 mg/day
Metformin \>= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period
BIOLOGICALInsulin Glargine Rescue Medication
Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion
DRUGGlimepiride Rescue Medication
Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion
Sponsors
Pfizer
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
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 and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. |
| Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | Up to 54 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. Including rescue approach data analysis included data following the initiation of rescue therapy. |
| Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | Up to 52 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. Including rescue approach data analysis included data following the initiation of rescue therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 30 min. before and 0, 15, 30, 60, 90, 120, and 180 minutes following the start of the standard meal at Baseline and Week 26 | Static beta-cell sensitivity to glucose index (SBCSGI) estimates the ratio of insulin secretion (expressed in pmol/min) related to above-basal glucose concentration (expressed in mmol/L \* L) following a meal. Blood samples were collected before and after a standard meal and glucose, insulin, and C-peptide levels were analyzed. The C-peptides minimal model was used to estimate the insulin secretion rate (ISR). Analysis included both non-model-based \[including insulinogenic index with C-peptide, glucose area under the curve (AUC)/insulin AUC\] and model-based \[beta cell function and insulin secretion rate at 9 mM glucose\] testing. Analysis was performed with non-linear least squares using the Software Architecture Analysis Method (SAAM) II software. SBCSGI was expressed in units of 10\^-9 min\^-1. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. |
| Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | Baseline and Week 26 | This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the 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 systolic blood pressure minus the Week 0 systolic blood pressure. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | Baseline and Week 26 | Blood glucose was measured on a fasting basis after at least a 10-hour fast. This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. |
| Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | Week 26 | A1C is blood marker used to report average blood glucose levels over a prolonged periods of time and is reported as a percentage (%). Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. |
Participant flow
Recruitment details
The trial was conducted in 21 countries and included 242 trial centers.
Pre-assignment details
Participants on ≥1500 mg/day of metformin for ≥8 weeks with A1C ≥7.5 and ≤11% at screening could directly enter a 2-week, single-blind, placebo run-in period. Participants who did not meet these criteria, received diet/exercise counseling and metformin titration (as necessary) for \ 8 weeks before entering the 2-week, placebo run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 5 mg Ertugliflozin 5 mg, oral, once daily for 52 weeks | 250 |
| Ertugliflozin 15 mg Ertugliflozin, oral, once daily for 52 weeks | 248 |
| Sitagliptin 100 mg Sitagliptin 100 mg, oral, once daily for 52 weeks | 247 |
| Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 5 mg + sitagliptin 100 mg, oral, once daily for 52 weeks | 243 |
| Ertugliflozin 15 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + sitagliptin 100 mg, oral, once daily for 52 weeks | 244 |
| Total | 1,232 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 | 2 | 3 | 2 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 6 | 12 | 11 | 5 | 6 |
| Overall Study | Non-compliance with study drug | 2 | 0 | 0 | 0 | 1 |
| Overall Study | Participant moved | 1 | 1 | 1 | 0 | 2 |
| Overall Study | Physician Decision | 3 | 0 | 1 | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 1 | 0 | 3 | 1 |
| Overall Study | Screen failure | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 11 | 13 | 9 | 13 |
Baseline characteristics
| Characteristic | Total | Ertugliflozin 5 mg | Ertugliflozin 15 mg | Sitagliptin 100 mg | Ertugliflozin 5 mg + Sitagliptin 100 mg | Ertugliflozin 15 mg + Sitagliptin 100 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 55.1 Years STANDARD_DEVIATION 10.1 | 55.1 Years STANDARD_DEVIATION 10.1 | 55.3 Years STANDARD_DEVIATION 9.5 | 54.8 Years STANDARD_DEVIATION 10.7 | 55.2 Years STANDARD_DEVIATION 10.4 | 55.1 Years STANDARD_DEVIATION 9.8 |
| Baseline Body Weight | 88.7 Kilograms STANDARD_DEVIATION 21.5 | 88.6 Kilograms STANDARD_DEVIATION 22.2 | 88.0 Kilograms STANDARD_DEVIATION 20.3 | 89.8 Kilograms STANDARD_DEVIATION 23.4 | 89.5 Kilograms STANDARD_DEVIATION 20.8 | 87.5 Kilograms STANDARD_DEVIATION 20.5 |
| Baseline estimated glomerular filtration rate, eGFR | 92.4 mL/min/1.73m^2 STANDARD_DEVIATION 20 | 91.9 mL/min/1.73m^2 STANDARD_DEVIATION 20.6 | 92.8 mL/min/1.73m^2 STANDARD_DEVIATION 21.4 | 92.6 mL/min/1.73m^2 STANDARD_DEVIATION 18.2 | 91.9 mL/min/1.73m^2 STANDARD_DEVIATION 20.4 | 92.6 mL/min/1.73m^2 STANDARD_DEVIATION 19.2 |
| Baseline Fasting Plasma Glucose | 180.4 mg/dL STANDARD_DEVIATION 47.8 | 184.1 mg/dL STANDARD_DEVIATION 52.2 | 179.5 mg/dL STANDARD_DEVIATION 45.7 | 177.4 mg/dL STANDARD_DEVIATION 46.6 | 183.8 mg/dL STANDARD_DEVIATION 44.3 | 177.2 mg/dL STANDARD_DEVIATION 49.4 |
| Baseline Hemoglobin A1C (A1C) | 8.6 Percent STANDARD_DEVIATION 1 | 8.6 Percent STANDARD_DEVIATION 1 | 8.6 Percent STANDARD_DEVIATION 1 | 8.5 Percent STANDARD_DEVIATION 1 | 8.6 Percent STANDARD_DEVIATION 1 | 8.6 Percent STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 568 Participants | 123 Participants | 114 Participants | 93 Participants | 120 Participants | 118 Participants |
| Sex: Female, Male Male | 664 Participants | 127 Participants | 134 Participants | 154 Participants | 123 Participants | 126 Participants |
| Sitting Systolic Blood Pressure | 129.3 mm Hg STANDARD_DEVIATION 12.6 | 129.7 mm Hg STANDARD_DEVIATION 12.5 | 128.9 mm Hg STANDARD_DEVIATION 12.5 | 128.3 mm Hg STANDARD_DEVIATION 12.2 | 130.2 mm Hg STANDARD_DEVIATION 12.6 | 129.1 mm Hg STANDARD_DEVIATION 13.3 |
| Static Beta-Cell Sensitivity to Glucose Index | 19.7 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 20.5 | 20.9 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 26.1 | 18.0 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 16.3 | 20.2 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 21.2 | 20.0 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 16.6 | 19.3 SBCSGI (10^-9min^-1) STANDARD_DEVIATION 21 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 250 | 43 / 248 | 28 / 247 | 31 / 243 | 38 / 244 |
| serious Total, serious adverse events | 12 / 250 | 5 / 248 | 8 / 247 | 9 / 243 | 12 / 244 |
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 and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: Baseline and Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a baseline measurement or a post-randomization measurement for the A1C change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in A1C at Week 26: Excluding Rescue Approach | -1.02 Percentage |
| Ertugliflozin 15 mg | Change From Baseline in A1C at Week 26: Excluding Rescue Approach | -1.08 Percentage |
| Sitagliptin 100 mg | Change From Baseline in A1C at Week 26: Excluding Rescue Approach | -1.05 Percentage |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Change From Baseline in A1C at Week 26: Excluding Rescue Approach | -1.49 Percentage |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Change From Baseline in A1C at Week 26: Excluding Rescue Approach | -1.52 Percentage |
p-value: <0.00195% CI: [-0.63, -0.3]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-0.6, -0.27]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-0.61, -0.27]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-0.63, -0.3]Constrained longitudinal data analysis
Primary
Percentage of Participants Who Discontinued 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. Including rescue approach data analysis included data following the initiation of rescue therapy.
Time frame: Up to 52 weeks
Population: The analysis population consists of all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | 3.2 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | 3.2 Percentage of participants |
| Sitagliptin 100 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | 2.8 Percentage of participants |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | 3.3 Percentage of participants |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including Rescue Approach | 3.7 Percentage of participants |
95% CI: [-3.3, 3.6]
95% CI: [-3, 4]
95% CI: [-2.9, 3.9]
95% CI: [-2.5, 4.4]
Primary
Percentage of Participants Who Experienced 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. Including rescue approach data analysis included data following the initiation of rescue therapy.
Time frame: Up to 54 weeks
Population: The analysis population consists of all randomized participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | 62.0 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | 57.7 Percentage of participants |
| Sitagliptin 100 mg | Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | 57.5 Percentage of participants |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | 58.8 Percentage of participants |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Percentage of Participants Who Experienced an Adverse Event (AE): Including Rescue Approach | 55.7 Percentage of participants |
95% CI: [-11.7, 5.5]
95% CI: [-10.6, 6.8]
95% CI: [-7.4, 10.1]
95% CI: [-10.5, 7]
Secondary
Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach
This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: Baseline and Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a baseline measurement or a post-randomization measurement for the body weight change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | -2.69 Kilograms |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | -3.74 Kilograms |
| Sitagliptin 100 mg | Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | -0.67 Kilograms |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | -2.52 Kilograms |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | -2.94 Kilograms |
p-value: <0.00195% CI: [-2.48, -1.22]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-2.9, -1.64]Constrained logitudinal data analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach
Blood glucose was measured on a fasting basis after at least a 10-hour fast. This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: Baseline and Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a baseline measurement or a post-randomization measurement for the FPG change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | -35.73 mg/dL |
| Ertugliflozin 15 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | -36.91 mg/dL |
| Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | -25.56 mg/dL |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | -43.96 mg/dL |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | -48.70 mg/dL |
p-value: 0.00495% CI: [-13.82, -2.65]cLDA
p-value: <0.00195% CI: [-17.35, -6.23]cLDA
p-value: <0.00195% CI: [-24.03, -12.77]cLDA
p-value: <0.00195% CI: [-28.76, -17.53]cLDA
Secondary
Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach
This change from baseline reflects the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: Baseline and Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a baseline measurement or a post-randomization measurement for the systolic blood pressure change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | -3.89 mm Hg |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | -3.69 mm Hg |
| Sitagliptin 100 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | -0.66 mm Hg |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | -3.42 mm Hg |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | -3.67 mm Hg |
p-value: 0.00595% CI: [-4.69, -0.83]Constrained longitudinal data analysis
p-value: 0.00295% CI: [-4.94, -1.09]Constrained longitudinal data analysis
Secondary
Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach
Static beta-cell sensitivity to glucose index (SBCSGI) estimates the ratio of insulin secretion (expressed in pmol/min) related to above-basal glucose concentration (expressed in mmol/L \* L) following a meal. Blood samples were collected before and after a standard meal and glucose, insulin, and C-peptide levels were analyzed. The C-peptides minimal model was used to estimate the insulin secretion rate (ISR). Analysis included both non-model-based \[including insulinogenic index with C-peptide, glucose area under the curve (AUC)/insulin AUC\] and model-based \[beta cell function and insulin secretion rate at 9 mM glucose\] testing. Analysis was performed with non-linear least squares using the Software Architecture Analysis Method (SAAM) II software. SBCSGI was expressed in units of 10\^-9 min\^-1. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: 30 min. before and 0, 15, 30, 60, 90, 120, and 180 minutes following the start of the standard meal at Baseline and Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a baseline measurement or a post-randomization measurement for the beta-cell responsivity static component change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 8.62 SBCSGI (10^-9min^-1) |
| Ertugliflozin 15 mg | Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 9.71 SBCSGI (10^-9min^-1) |
| Sitagliptin 100 mg | Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 21.11 SBCSGI (10^-9min^-1) |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 16.24 SBCSGI (10^-9min^-1) |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | 11.51 SBCSGI (10^-9min^-1) |
p-value: 0.15595% CI: [-2.9, 18.13]Constrained longitudinal data analysis
p-value: 0.36995% CI: [-15.54, 5.8]Constrained longitudinal data analysis
p-value: 0.73495% CI: [-8.66, 12.27]Constrained longitudinal data analysis
p-value: 0.07595% CI: [-20.17, 0.98]Difference in the least squares means
Secondary
Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach
A1C is blood marker used to report average blood glucose levels over a prolonged periods of time and is reported as a percentage (%). Excluding recue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy.
Time frame: Week 26
Population: The analysis population consisted of all randomized participants who received at least one dose of study treatment, had a post-randomization measurement for the A1C change from baseline at Week 26 analysis endpoint subsequent to at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | 26.4 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | 31.9 Percentage of participants |
| Sitagliptin 100 mg | Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | 32.8 Percentage of participants |
| Ertugliflozin 5 mg + Sitagliptin 100 mg | Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | 52.3 Percentage of participants |
| Ertugliflozin 15 mg + Sitagliptin 100 mg | Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | 49.2 Percentage of participants |
p-value: <0.00195% CI: [2.68, 6.4]Regression, Logistic
p-value: <0.00195% CI: [1.68, 3.83]Regression, Logistic
p-value: <0.00195% CI: [1.92, 4.54]Regression, Logistic
p-value: <0.00195% CI: [1.69, 3.89]Regression, Logistic