Type 2 Diabetes Mellitus
Conditions
Brief summary
This trial will evaluate the efficacy and safety of ertugliflozin monotherapy in the treatment of participants with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on diet and exercise. This trial consists of a run-in period of 3 to 11 weeks, a 26-week placebo-controlled treatment period (Phase A), and a 26-week active treatment period (Phase B). The primary hypotheses of the trial are that at Week 26, the mean reduction from baseline in hemoglobin A1c (A1C) for 15 mg ertugliflozin is greater than that for placebo and the mean reduction from baseline in A1C for 5 mg ertugliflozin is greater than that for placebo.
Interventions
One tablet taken orally the same time in the morning from Day 1 through Week 52 (Phase A and Phase B).
One tablet taken orally the same time in the morning from Day 1 through Week 52 (Phase A and Phase B).
One placebo tablet matching the ertugliflozin 5 mg tablet and/or 1 placebo tablet matching the ertugliflozin 10 mg tablet per day taken orally the same time in the morning from Day 1 through Week 52 (Phase A and Phase B).
DRUGMetformin
500 mg (1 tablet) in the morning and 500 mg (1 tablet) in the evening for 2 weeks, 1000 mg (2 tablets 500 mg) in the morning and 500 mg (1 tablet) in the evening for 2 weeks and 1000 mg (2 tablets 500 mg) in the morning and 1000 mg (2 tablets 500 mg) in the evening, thereafter.
1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.
DRUGGlimepiride
Dosing and titration of glimepiride as rescue therapy was determined by the investigator.
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
* Diagnosis of T2DM in accordance to American Diabetes Association guidelines * Participants with no prior allowable oral anti-hyperglycemic agents (AHA) for at least 8 weeks prior to study participation or participants on a single allowable oral AHA at the start of study participation * Participants on a single allowable AHA must be willing to discontinue this medication at the Screening Visit (S2) and remain off this medication for the duration of the trial. Allowable oral AHAs for discontinuation are metformin, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides or alpha-glucosidase inhibitors.
Exclusion criteria
* 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 participation * A clinically significant electrocardiogram abnormality * A history of malignancy ≤5 years prior to study participation, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer * A known hypersensitivity or intolerance to any sodium-glucose co-transporter 2 (SGLT2) inhibitor or metformin * On a blood pressure or lipid altering medication that have not been on a stable dose for at least 4 weeks prior to study participation * A surgical procedure within 4 weeks prior to study participation or planned major surgery during the trial * Donation of blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial * Pregnant or breast-feeding, or is expecting to conceive during the trial, including 14 days following the last dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In A1C at Week 26 | Baseline and Week 26 | A1C is measured as percent. The change from baseline is the Week 26 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy. |
| Percentage of Participants Experiencing An Adverse Event (AE) | Up to 54 weeks (including 2 weeks following last dose) | An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy. |
| Percentage of Participants Discontinuing Study Treatment Due to an AE | Up to 52 weeks | An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline 2-hour Post-prandial Glucose (2-hr PPG) Level | Baseline | Laboratory measurements were performed 120 minutes following the start of the administration of the meal for the Mixed Meal Tolerance Test (MMTT). Change from baseline in 2-hr PPG level at Week 26 data are presented in the following outcome measure. |
| Change From Baseline in 2-hr PPG at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 2-hr PPG minus the Week 0 2-hr PPG. Laboratory measurements were performed 120 minutes following the start of the administration of the meal for the MMTT. Data presented exclude data following the initiation of rescue therapy. |
| Baseline Sitting Systolic Blood Pressure (SBP) | Baseline | Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Change from baseline in SBP at Week 26 data are presented in the following outcome measure. |
| Change From Baseline in FPG at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of glycemic rescue therapy. |
| Baseline Sitting Diastolic Blood Pressure (DBP) | Baseline | Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Change from baseline in DBP at Week 26 data are presented in the following outcome measure. |
| Change From Baseline in DBP at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 DBP minus the Week 0 DBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in SBP at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 SBP minus the Week 0 SBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in Body Weight at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy. |
| Percentage of Participants With A1C <7% (<53 mmol/Mol) at Week 26 | Week 26 | A1C is measured as percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 5 mg/Ertugliflozin 5 mg Phase A: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride. | 156 |
| Ertugliflozin 15 mg/Ertugliflozin 15 mg Phase A: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride. | 152 |
| Placebo/Metformin Phase A: Placebo to ertugliflozin administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Participants not rescued with open-label metformin in Phase A will also receive blinded metformin up to twice daily for 26 weeks in addition to placebo. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride. | 153 |
| Total | 461 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 5 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Excluded medication | 0 | 0 | 1 |
| Overall Study | Hyperglycemia | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 7 | 11 | 7 |
| Overall Study | Non-compliance with study drug | 1 | 1 | 1 |
| Overall Study | Participant moved | 0 | 0 | 1 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Study site terminated by sponsor | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 10 | 13 |
Baseline characteristics
| Characteristic | Ertugliflozin 5 mg/Ertugliflozin 5 mg | Ertugliflozin 15 mg/Ertugliflozin 15 mg | Placebo/Metformin | Total |
|---|---|---|---|---|
| Age, Continuous | 56.8 Years STANDARD_DEVIATION 11.4 | 56.2 Years STANDARD_DEVIATION 10.8 | 56.1 Years STANDARD_DEVIATION 10.9 | 56.4 Years STANDARD_DEVIATION 11 |
| Body weight | 94.0 Kilograms STANDARD_DEVIATION 25.4 | 90.6 Kilograms STANDARD_DEVIATION 18.3 | 94.2 Kilograms STANDARD_DEVIATION 25.2 | 92.9 Kilograms STANDARD_DEVIATION 23.2 |
| Estimated glomerular filtration rate (eGFR) | 88.5 mL/min/1.75m^2 STANDARD_DEVIATION 18.4 | 88.3 mL/min/1.75m^2 STANDARD_DEVIATION 18 | 86.2 mL/min/1.75m^2 STANDARD_DEVIATION 19.4 | 87.7 mL/min/1.75m^2 STANDARD_DEVIATION 18.6 |
| Fasting plasma glucose (FPG) | 180.9 mg/dL STANDARD_DEVIATION 48.5 | 179.1 mg/dL STANDARD_DEVIATION 48.2 | 180.2 mg/dL STANDARD_DEVIATION 45.8 | 180.1 mg/dL STANDARD_DEVIATION 47.4 |
| Hemoglobin A1c (A1C) | 8.16 Percent STANDARD_DEVIATION 0.88 | 8.35 Percent STANDARD_DEVIATION 1.12 | 8.11 Percent STANDARD_DEVIATION 0.92 | 8.21 Percent STANDARD_DEVIATION 0.98 |
| Sex: Female, Male Female | 67 Participants | 62 Participants | 71 Participants | 200 Participants |
| Sex: Female, Male Male | 89 Participants | 90 Participants | 82 Participants | 261 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 50 / 156 | 48 / 152 | 68 / 153 |
| serious Total, serious adverse events | 11 / 156 | 6 / 152 | 8 / 153 |
Outcome results
Primary
Change From Baseline In A1C at Week 26
A1C is measured as percent. The change from baseline is the Week 26 A1C percent minus the Week 0 A1C percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline A1C measurement or at least 1 post-randomization A1C measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline In A1C at Week 26 | -0.79 Percent |
| Ertugliflozin 15 mg | Change From Baseline In A1C at Week 26 | -0.96 Percent |
| Placebo | Change From Baseline In A1C at Week 26 | 0.20 Percent |
p-value: <0.00195% CI: [-1.22, -0.76]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-1.39, -0.93]Constrained longitudinal data analysis
Primary
Percentage of Participants Discontinuing Study Treatment Due to an AE
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.
Time frame: Up to 52 weeks
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were classified according to randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Discontinuing Study Treatment Due to an AE | 4.5 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Discontinuing Study Treatment Due to an AE | 3.9 Percentage of participants |
| Placebo | Percentage of Participants Discontinuing Study Treatment Due to an AE | 6.5 Percentage of participants |
95% CI: [-7.7, 3.3]
95% CI: [-8.2, 2.7]
Primary
Percentage of Participants Experiencing An Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy.
Time frame: Up to 54 weeks (including 2 weeks following last dose)
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were classified according to randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Experiencing An Adverse Event (AE) | 64.1 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Experiencing An Adverse Event (AE) | 62.5 Percentage of participants |
| Placebo | Percentage of Participants Experiencing An Adverse Event (AE) | 66.7 Percentage of participants |
95% CI: [-13.1, 8.1]
95% CI: [-14.8, 6.6]
Secondary
Baseline 2-hour Post-prandial Glucose (2-hr PPG) Level
Laboratory measurements were performed 120 minutes following the start of the administration of the meal for the Mixed Meal Tolerance Test (MMTT). Change from baseline in 2-hr PPG level at Week 26 data are presented in the following outcome measure.
Time frame: Baseline
Population: Analysis population consisted of all randomized participants who had a baseline 2-hr PPG measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Baseline 2-hour Post-prandial Glucose (2-hr PPG) Level | 260.32 mg/dL | Standard Deviation 76.11 |
| Ertugliflozin 15 mg | Baseline 2-hour Post-prandial Glucose (2-hr PPG) Level | 262.91 mg/dL | Standard Deviation 78.189 |
| Placebo | Baseline 2-hour Post-prandial Glucose (2-hr PPG) Level | 256.21 mg/dL | Standard Deviation 76.917 |
Secondary
Baseline Sitting Diastolic Blood Pressure (DBP)
Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Change from baseline in DBP at Week 26 data are presented in the following outcome measure.
Time frame: Baseline
Population: Analysis population consisted of all randomized participants who had a baseline DBP measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Baseline Sitting Diastolic Blood Pressure (DBP) | 78.46 mmHg | Standard Deviation 8.117 |
| Ertugliflozin 15 mg | Baseline Sitting Diastolic Blood Pressure (DBP) | 78.53 mmHg | Standard Deviation 7.714 |
| Placebo | Baseline Sitting Diastolic Blood Pressure (DBP) | 78.13 mmHg | Standard Deviation 7.458 |
Secondary
Baseline Sitting Systolic Blood Pressure (SBP)
Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Change from baseline in SBP at Week 26 data are presented in the following outcome measure.
Time frame: Baseline
Population: Analysis population consisted of all randomized participants who had a baseline SBP measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Baseline Sitting Systolic Blood Pressure (SBP) | 130.49 mmHg | Standard Deviation 13.511 |
| Ertugliflozin 15 mg | Baseline Sitting Systolic Blood Pressure (SBP) | 129.67 mmHg | Standard Deviation 14.208 |
| Placebo | Baseline Sitting Systolic Blood Pressure (SBP) | 129.80 mmHg | Standard Deviation 14.464 |
Secondary
Change From Baseline in 2-hr PPG at Week 26
The change from baseline is the Week 26 2-hr PPG minus the Week 0 2-hr PPG. Laboratory measurements were performed 120 minutes following the start of the administration of the meal for the MMTT. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline 2-hr PPG measurement or at least 1 post-randomization 2-hr PPG measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in 2-hr PPG at Week 26 | -64.15 mg/dL |
| Ertugliflozin 15 mg | Change From Baseline in 2-hr PPG at Week 26 | -62.45 mg/dL |
| Placebo | Change From Baseline in 2-hr PPG at Week 26 | 4.88 mg/dL |
p-value: <0.00195% CI: [-83.24, -54.83]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-81.73, -52.93]Constrained longitudinal data analysis
Secondary
Change From Baseline in Body Weight at Week 26
The change from baseline is the Week 26 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline body weight measurement or at least 1 post-randomization body weight measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 26 | -3.18 Kilograms |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 26 | -3.58 Kilograms |
| Placebo | Change From Baseline in Body Weight at Week 26 | -1.42 Kilograms |
p-value: <0.00195% CI: [-2.57, -0.95]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-2.98, -1.34]Constrained longitudinal data analysis
Secondary
Change From Baseline in DBP at Week 26
The change from baseline is the Week 26 DBP minus the Week 0 DBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline DBP measurement or at least 1 post-randomization DBP measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in DBP at Week 26 | -2.52 mmHg |
| Ertugliflozin 15 mg | Change From Baseline in DBP at Week 26 | -1.10 mmHg |
| Placebo | Change From Baseline in DBP at Week 26 | -0.72 mmHg |
p-value: 0.03995% CI: [-3.51, -0.09]Constrained longitudinal data analysis
p-value: 0.66995% CI: [-2.09, 1.35]Constrained longitudinal data analysis
Secondary
Change From Baseline in FPG at Week 26
The change from baseline is the Week 26 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of glycemic rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline FPG measurement or at least 1 post-randomization FPG measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in FPG at Week 26 | -33.96 mg/dL |
| Ertugliflozin 15 mg | Change From Baseline in FPG at Week 26 | -43.44 mg/dL |
| Placebo | Change From Baseline in FPG at Week 26 | 0.57 mg/dL |
p-value: <0.00195% CI: [-42.76, -26.29]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-52.28, -35.74]Constrained longitudinal data analysis
Secondary
Change From Baseline in SBP at Week 26
The change from baseline is the Week 26 SBP minus the Week 0 SBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline SBP measurement or at least 1 post-randomization SBP measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in SBP at Week 26 | -5.54 mmHg |
| Ertugliflozin 15 mg | Change From Baseline in SBP at Week 26 | -3.93 mmHg |
| Placebo | Change From Baseline in SBP at Week 26 | -2.22 mmHg |
p-value: 0.01595% CI: [-5.98, -0.65]Constrained longitudinal data analysis
p-value: 0.21395% CI: [-4.4, 0.98]Constrained longitudinal data analysis
Secondary
Percentage of Participants With A1C <7% (<53 mmol/Mol) at Week 26
A1C is measured as percent. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of rescue therapy.
Time frame: Week 26
Population: Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline A1C measurement or at least 1 post-randomization A1C measurement subsequent to at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants With A1C <7% (<53 mmol/Mol) at Week 26 | 28.2 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants With A1C <7% (<53 mmol/Mol) at Week 26 | 35.8 Percentage of participants |
| Placebo | Percentage of Participants With A1C <7% (<53 mmol/Mol) at Week 26 | 13.1 Percentage of participants |
p-value: <0.00195% CI: [1.85, 6.95]Regression, Logistic
p-value: <0.00195% CI: [3.46, 13.24]Regression, Logistic