Type 2 Diabetes Mellitus
Conditions
Brief summary
This is a safety and efficacy study of ertugliflozin (MK-8835/PF-04971729) in the treatment of participants with type 2 diabetes mellitus who have inadequate glycemic control on metformin and sitagliptin. The primary objective of the trial is to assess the hemoglobin A1C (A1C)-lowering efficacy of the addition of ertugliflozin compared to the addition of placebo with an underlying hypothesis that addition of treatment with ertugliflozin provides greater reduction in A1C compared with the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.
Detailed description
The duration of the trial will be approximately 69 weeks. This will include a 1-week Screening Period, an up to 12-week wash-off/titration /dose-stabilization period, a 2-week single-blind, placebo run-in period, a 52-week double-blind, placebo-controlled treatment period (including a 26-week Phase A and 26-week Phase B), and a post-treatment telephone contact 14 days after the last dose of blinded investigational product.
Interventions
Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks
Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks
DRUGPlacebo for ertugliflozin 5 mg
Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks
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.
DRUGSitagliptin
Participants are to remain on their stable doses of sitagliptin (oral, 100 mg once daily) while receiving blinded investigational product during the double-blind treatment period.
DRUGGlimepiride
Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion
BIOLOGICALInsulin
Insulin glargine rescue medication, injectable, as required. In the event that an investigator considers use of glimepiride to not be appropriate for a participant meeting protocol specified glycemic rescue criteria, insulin glargine can be initiated as the rescue medication, and managed by the investigator according to clinical practice guidelines of the local country.
DRUGPlacebo for ertugliflozin 10 mg
Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks
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 type 2 diabetes mellitus (T2DM) * On stable diabetes therapy of metformin with either sitagliptin or another dipeptidyl peptidase-4 (DPP-4) inhibitor or a sulfonylurea (SU) prior to study participation and is willing to wash-off/switch from another DPP-4 inhibitor/SU to sitagliptin * Body Mass Index (BMI) greater than or equal to 18.0 kg/m\^2 * Male, postmenopausal female or surgically sterile female * If a female of reproductive potential, agrees to remain abstinent or to use (or have their partner use) 2 acceptable combinations of birth control while participating in the trial and for 14 days after the last use of study drug
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 endocrine disorders, drug- or chemical-induced, and post-organ transplant) * A known hypersensitivity or intolerance to any sodium-glucose co-transporter 2 (SGLT2) or DPP-4 inhibitor * On a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable * Has undergone bariatric surgery within the past 12 months or \>12 months and is not weight stable * Has been treated with insulin (except for short-term use \[\<= 7 days\]), injectable antihyperglycemic agents (AHAs) (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other sodium-glucose co-transporter 2 (SGLT2) inhibitors, alpha glucosidase inhibitors or meglitinides, bromocriptine (Cycloset™), colesevelam (Welchol™), or any other non-protocol approved AHAs within 12 weeks of study participation * Has active, obstructive uropathy or indwelling urinary catheter * 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 history of malignancy ≤5 years prior to study participation, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer * Known history of Human Immunodeficiency Virus (HIV) * Has blood dyscrasias or any disorders causing hemolysis or unstable red blood cells or any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) * A medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or active symptomatic gallbladder disease * Has any clinically significant malabsorption condition * If taking thyroid replacement therapy, has not been on a stable dose for at least 6 weeks prior to study participation * Has been previously randomized in a study with ertugliflozin * Has participated in other studies involving an investigational drug within 30 days prior or during study participation * Has undergone a surgical procedure within 6 weeks prior to or planned major surgery during study participation * Has a positive urine pregnancy test * Is pregnant or breast-feeding, or is planning to conceive during the trial, including 14 days following the last dose of study medication * Planning to undergo hormonal therapy in preparation to donate eggs during the trial, including 14 days following the last dose of study medication * Excessive consumption of alcoholic beverages or binge drinking * Has donated blood or blood products within 6 weeks of study participation or plans to donate blood or blood products at any time during the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C at Week 26 | Baseline and Week 26 | A1C is measured as percent. Thus this change from baseline reflects 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 Week 54 | An adverse event is defined as any untoward medical occurrence in a participant 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 Week 52 | An adverse event is defined as any untoward medical occurrence in a participant 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 |
|---|---|---|
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in Hemoglobin A1C at Week 52 | Baseline and Week 52 | A1C is measured as percent. Thus this change from baseline reflects the Week 52 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. |
| Change From Baseline in FPG at Week 52 | Baseline and Week 52 | The change from baseline is the Week 52 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 rescue therapy. |
| Change From Baseline in Body Weight at Week 52 | Baseline and Week 52 | The change from baseline is the Week 52 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy. |
| Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52 | Week 52 | 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. |
| Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Baseline and Week 52 | The change from baseline is the Week 52 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Baseline and Week 26 | The change from baseline is the Week 26 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Baseline and Week 52 | The change from baseline is the Week 52 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy. |
| Percentage of Participants Receiving Glycemic Rescue Medication by Week 26 | Week 26 | Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). |
| Change From Baseline in Fasting Plasma Glucose (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 rescue therapy. |
| Time to Initiation of Glycemic Rescue by Week 26 | Up to Week 26 (plus 30 days for 1 placebo participant) | Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days. Below data include data from 1 participant in the Placebo arm who continued Phase A treatment for an additional 30 days. |
| Time to Initiation of Glycemic Rescue by Week 52 | Up to week 52 | Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days. |
| Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value | Baseline | HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\] |
| Change From Baseline in HOMA-%β at Week 26 | Baseline and Week 26 | HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\]. Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in HOMA-%β at Week 52 | Baseline and Week 52 | HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\]. Data presented exclude data following the initiation of rescue therapy. |
| Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score | Baseline | The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 1-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ visual analogue score (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). |
| Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26 | Baseline and Week 26 | The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy. |
| Change From Baseline in EQ-5D-3L Score at Week 52 | Baseline and Week 52 | The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy. |
| Percentage of Participants Receiving Glycemic Rescue Medication by Week 52 | Week 52 | Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). |
| 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 an 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
Pre-assignment details
Two participants were randomized to Ertugliflozin 15 mg, but did not receive any treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 5 mg Ertugliflozin, 5 mg, oral, once daily for 52 weeks | 156 |
| Ertugliflozin 15 mg Ertugliflozin, 15 mg, oral, once daily for 52 weeks | 153 |
| Placebo Matching placebo to ertuglifozin, oral, once daily for 52 weeks | 153 |
| Total | 462 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 2 |
| Overall Study | Hyperglycemia | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 | 0 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 2 |
| Overall Study | Screen failure | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 7 | 9 |
Baseline characteristics
| Characteristic | Ertugliflozin 5 mg | Ertugliflozin 15 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 59.2 Years STANDARD_DEVIATION 9.3 | 59.7 Years STANDARD_DEVIATION 8.6 | 58.3 Years STANDARD_DEVIATION 9.2 | 59.1 Years STANDARD_DEVIATION 9 |
| Body weight | 87.6 Kilograms STANDARD_DEVIATION 18.6 | 86.6 Kilograms STANDARD_DEVIATION 19.5 | 86.4 Kilograms STANDARD_DEVIATION 20.8 | 86.9 Kilograms STANDARD_DEVIATION 19.6 |
| Estimated glomerular filtration rate (eGFR) | 87.0 mL/min/1.73m^2 STANDARD_DEVIATION 17.5 | 86.9 mL/min/1.73m^2 STANDARD_DEVIATION 15.6 | 89.9 mL/min/1.73m^2 STANDARD_DEVIATION 17.5 | 87.9 mL/min/1.73m^2 STANDARD_DEVIATION 16.9 |
| Fasting plasma glucose | 167.7 mg/dL STANDARD_DEVIATION 37.7 | 171.7 mg/dL STANDARD_DEVIATION 39.1 | 169.6 mg/dL STANDARD_DEVIATION 37.8 | 169.7 mg/dL STANDARD_DEVIATION 38.2 |
| Hemoglobin A1c (A1C) | 8.05 Percent STANDARD_DEVIATION 0.86 | 8.00 Percent STANDARD_DEVIATION 0.83 | 8.03 Percent STANDARD_DEVIATION 0.93 | 8.03 Percent STANDARD_DEVIATION 0.88 |
| Sex: Female, Male Female | 75 Participants | 71 Participants | 53 Participants | 199 Participants |
| Sex: Female, Male Male | 81 Participants | 82 Participants | 100 Participants | 263 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 | 24 / 156 | 18 / 153 | 29 / 153 |
| serious Total, serious adverse events | 13 / 156 | 3 / 153 | 8 / 153 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C at Week 26
A1C is measured as percent. Thus this change from baseline reflects 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 included all randomized participants who took at least one dose of study medication and had at least one A1C measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Hemoglobin A1C at Week 26 | -0.78 Percent |
| Ertugliflozin 15 mg | Change From Baseline in Hemoglobin A1C at Week 26 | -0.86 Percent |
| Placebo | Change From Baseline in Hemoglobin A1C at Week 26 | -0.09 Percent |
p-value: <0.00195% CI: [-0.87, -0.5]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-0.95, -0.58]cLDA
Primary
Percentage of Participants Discontinuing Study Treatment Due to an AE
An adverse event is defined as any untoward medical occurrence in a participant 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 Week 52
Population: Analysis population consisted of all randomized participants who took at least one dose of study medication.
| 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 | 3.9 Percentage of participants |
95% CI: [-4.4, 5.6]
95% CI: [-4.9, 4.9]
Primary
Percentage of Participants Experiencing An Adverse Event (AE)
An adverse event is defined as any untoward medical occurrence in a participant 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 Week 54
Population: Analysis population consisted of all randomized participants who took at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Experiencing An Adverse Event (AE) | 57.7 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Experiencing An Adverse Event (AE) | 60.1 Percentage of participants |
| Placebo | Percentage of Participants Experiencing An Adverse Event (AE) | 63.4 Percentage of participants |
95% CI: [-16.5, 5.2]
95% CI: [-14.1, 7.6]
Secondary
Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score
The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 1-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ visual analogue score (VAS) that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best).
Time frame: Baseline
Population: Analysis population included all randomized participants who took at least one dose of study medication and had a baseline EQ-5D-3L measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score | 0.88 Score on a scale | Standard Deviation 0.166 |
| Ertugliflozin 15 mg | Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score | 0.89 Score on a scale | Standard Deviation 0.182 |
| Placebo | Baseline EQ-5D 3-level Version (EQ-5D-3L) Questionnaire Score | 0.90 Score on a scale | Standard Deviation 0.144 |
Secondary
Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value
HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\]
Time frame: Baseline
Population: Analysis population included all randomized participants who took at least one dose of study medication and had HOMA-%β measurement at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value | 47.99 Percentage | Standard Deviation 23.89 |
| Ertugliflozin 15 mg | Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value | 48.54 Percentage | Standard Deviation 34.782 |
| Placebo | Baseline Homeostasis Model Assessment of β-cell Function (HOMA-%β) Value | 48.04 Percentage | Standard Deviation 30.733 |
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 included all randomized participants who took at least one dose of study medication and had at least one body weight measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 26 | -3.35 kg |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 26 | -3.04 kg |
| Placebo | Change From Baseline in Body Weight at Week 26 | -1.32 kg |
p-value: <0.00195% CI: [-2.65, -1.4]cLDA
p-value: <0.00195% CI: [-2.35, -1.09]cLDA
Secondary
Change From Baseline in Body Weight at Week 52
The change from baseline is the Week 52 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one body weight measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 52 | -3.46 kg |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 52 | -2.83 kg |
| Placebo | Change From Baseline in Body Weight at Week 52 | -0.95 kg |
95% CI: [-3.43, -1.59]
95% CI: [-2.81, -0.95]
Secondary
Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26
The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one EQ-5D-3L measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26 | 0.00 Score on a scale |
| Ertugliflozin 15 mg | Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26 | 0.02 Score on a scale |
| Placebo | Change From Baseline in EQ-5D-3L Questionnaire Score at Week 26 | 0.01 Score on a scale |
95% CI: [-0.04, 0.02]
95% CI: [-0.02, 0.04]
Secondary
Change From Baseline in EQ-5D-3L Score at Week 52
The EQ-5D-3L is a health profile questionnaire that assesses quality of life along 5 dimensions. Participants rate 5 aspects of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). The summed score ranges from 3-15 with 3 corresponding to no problems and 15 corresponding to severe problems in the 5 dimensions. EQ-5D-3L also includes an EQ VAS that ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease from baseline in EQ-5D-3L signifies improvement. Total index EQ-5D-3L summary score is weighted with a range of -0.594 (worst) to 1.0 (best). Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one EQ-5D-3L measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in EQ-5D-3L Score at Week 52 | 0.03 Score on a scale |
| Ertugliflozin 15 mg | Change From Baseline in EQ-5D-3L Score at Week 52 | -0.00 Score on a scale |
| Placebo | Change From Baseline in EQ-5D-3L Score at Week 52 | 0.02 Score on a scale |
95% CI: [-0.04, 0.04]
95% CI: [-0.07, 0.02]
Secondary
Change From Baseline in Fasting Plasma Glucose (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 rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one FPG measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -26.91 mg/dL | 95% Confidence Interval -32.58 |
| Ertugliflozin 15 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -33.04 mg/dL | — |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -1.76 mg/dL | — |
p-value: <0.00195% CI: [-32.76, -17.54]cLDA
p-value: <0.00195% CI: [-38.9, -23.66]cLDA
Secondary
Change From Baseline in FPG at Week 52
The change from baseline is the Week 52 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 rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one FPG measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in FPG at Week 52 | -25.57 mg/dL |
| Ertugliflozin 15 mg | Change From Baseline in FPG at Week 52 | -26.38 mg/dL |
| Placebo | Change From Baseline in FPG at Week 52 | 3.19 mg/dL |
95% CI: [-36.44, -21.09]
95% CI: [-37.3, -21.85]
Secondary
Change From Baseline in Hemoglobin A1C at Week 52
A1C is measured as percent. Thus this change from baseline reflects the Week 52 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 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one A1C measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Hemoglobin A1C at Week 52 | -0.75 Percent |
| Ertugliflozin 15 mg | Change From Baseline in Hemoglobin A1C at Week 52 | -0.81 Percent |
| Placebo | Change From Baseline in Hemoglobin A1C at Week 52 | 0.02 Percent |
95% CI: [-0.98, -0.54]
95% CI: [-1.05, -0.61]
Secondary
Change From Baseline in HOMA-%β at Week 26
HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\]. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one HOMA-%β measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in HOMA-%β at Week 26 | 13.28 Percentage |
| Ertugliflozin 15 mg | Change From Baseline in HOMA-%β at Week 26 | 12.43 Percentage |
| Placebo | Change From Baseline in HOMA-%β at Week 26 | 0.52 Percentage |
95% CI: [6.83, 18.68]
95% CI: [5.94, 17.88]
Secondary
Change From Baseline in HOMA-%β at Week 52
HOMA-%β is a well-accepted means of assessing fasting β-cell function, and is calculated using measured C-peptide and glucose levels and is measured as a percentage of a normal reference population. HOMA-%β = \[20 x fasting insulin (μU/mL)\] / \[fasting plasma glucose (mmol/L) - 3.5\]. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one HOMA-%β measurement (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in HOMA-%β at Week 52 | 10.85 Percentage |
| Ertugliflozin 15 mg | Change From Baseline in HOMA-%β at Week 52 | 10.93 Percentage |
| Placebo | Change From Baseline in HOMA-%β at Week 52 | -1.93 Percentage |
95% CI: [6.54, 19.03]
95% CI: [6.54, 19.18]
Secondary
Change From Baseline in Sitting Diastolic Blood Pressure at Week 26
The change from baseline is the Week 26 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one diastolic blood pressure measurement (baseline or post-baseline).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Baseline | 78.42 mmHg | Standard Error 0.36 |
| Ertugliflozin 5 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Change from baseline | -1.68 mmHg | Standard Error 0.61 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Baseline | 78.42 mmHg | Standard Error 0.36 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Change from baseline | -1.81 mmHg | Standard Error 0.62 |
| Placebo | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Baseline | 78.42 mmHg | Standard Error 0.36 |
| Placebo | Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 | Change from baseline | -0.43 mmHg | Standard Error 0.65 |
95% CI: [-2.97, 0.48]
95% CI: [-3.11, 0.36]
Secondary
Change From Baseline in Sitting Diastolic Blood Pressure at Week 52
The change from baseline is the Week 52 diastolic blood pressure minus the Week 0 diastolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one diastolic blood pressure measurement (baseline or post-baseline).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Baseline | 78.44 mmHg | Standard Error 0.36 |
| Ertugliflozin 5 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Change from baseline | -1.52 mmHg | Standard Error 0.61 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Baseline | 78.44 mmHg | Standard Error 0.36 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Change from baseline | -1.38 mmHg | Standard Error 0.62 |
| Placebo | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Baseline | 78.44 mmHg | Standard Error 0.36 |
| Placebo | Change From Baseline in Sitting Diastolic Blood Pressure at Week 52 | Change from baseline | -0.53 mmHg | Standard Error 0.73 |
95% CI: [-2.82, 0.84]
95% CI: [-2.69, 0.99]
Secondary
Change From Baseline in Sitting Systolic Blood Pressure at Week 26
The change from baseline is the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 26
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one systolic blood pressure measurement (baseline or post-baseline).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Baseline | 130.87 mmHg | Standard Error 0.62 |
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Change from baseline | -3.81 mmHg | Standard Error 0.87 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Baseline | 130.87 mmHg | Standard Error 0.62 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Change from baseline | -4.82 mmHg | Standard Error 0.88 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Baseline | 130.87 mmHg | Standard Error 0.62 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 | Change from baseline | -0.88 mmHg | Standard Error 0.93 |
p-value: 0.01995% CI: [-5.36, -0.49]cLDA
p-value: 0.00295% CI: [-6.39, -1.5]cLDA
Secondary
Change From Baseline in Sitting Systolic Blood Pressure at Week 52
The change from baseline is the Week 52 systolic blood pressure minus the Week 0 systolic blood pressure. Sitting blood pressure was measured in triplicate. Data presented exclude data following the initiation of rescue therapy.
Time frame: Baseline and Week 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one systolic blood pressure measurement (baseline or post-baseline).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Baseline | 130.92 mmHg | Standard Error 0.62 |
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Change from baseline | -4.16 mmHg | Standard Error 0.95 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Baseline | 130.92 mmHg | Standard Error 0.62 |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Change from baseline | -4.09 mmHg | Standard Error 0.96 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Baseline | 130.92 mmHg | Standard Error 0.62 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure at Week 52 | Change from baseline | 0.83 mmHg | Standard Error 1.14 |
95% CI: [-7.82, -2.15]
95% CI: [-7.76, -2.07]
Secondary
Percentage of Participants Receiving Glycemic Rescue Medication by Week 26
Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).
Time frame: Week 26
Population: Analysis population included all randomized participants who took at least one dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Receiving Glycemic Rescue Medication by Week 26 | 1.3 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Receiving Glycemic Rescue Medication by Week 26 | 2.0 Percentage of participants |
| Placebo | Percentage of Participants Receiving Glycemic Rescue Medication by Week 26 | 16.3 Percentage of participants |
95% CI: [-21.9, -9.4]
95% CI: [-21.3, -8.5]
Secondary
Percentage of Participants Receiving Glycemic Rescue Medication by Week 52
Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant).
Time frame: Week 52
Population: Analysis population included all randomized participants who took at least one dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Receiving Glycemic Rescue Medication by Week 52 | 12.8 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Receiving Glycemic Rescue Medication by Week 52 | 13.7 Percentage of participants |
| Placebo | Percentage of Participants Receiving Glycemic Rescue Medication by Week 52 | 41.8 Percentage of participants |
95% CI: [-38.3, -19.4]
95% CI: [-37.5, -18.4]
Secondary
Percentage of Participants With an 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 included all randomized participants who took at least one dose of study medication and had at least one A1C measurement (baseline or post-baseline).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26 | 32.1 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26 | 39.9 Percentage of participants |
| Placebo | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 26 | 17.0 Percentage of participants |
p-value: <0.00195% CI: [1.74, 5.72]Regression, Logistic
p-value: <0.00195% CI: [2.44, 8.02]Regression, Logistic
Secondary
Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52
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 52
Population: Analysis population included all randomized participants who took at least one dose of study medication and had at least one A1C measurement (baseline or post-baseline).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52 | 33.3 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52 | 32.7 Percentage of participants |
| Placebo | Percentage of Participants With an A1C <7% (53 mmol/Mol) at Week 52 | 13.7 Percentage of participants |
95% CI: [1.98, 6.64]
95% CI: [2.22, 7.28]
Secondary
Time to Initiation of Glycemic Rescue by Week 26
Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days. Below data include data from 1 participant in the Placebo arm who continued Phase A treatment for an additional 30 days.
Time frame: Up to Week 26 (plus 30 days for 1 placebo participant)
Population: Analysis population included all randomized participants who took at least one dose of trial treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ertugliflozin 5 mg | Time to Initiation of Glycemic Rescue by Week 26 | Minimum time to initiation of glycemic rescue | 135 Days |
| Ertugliflozin 5 mg | Time to Initiation of Glycemic Rescue by Week 26 | Maximum time to initiation of glycemic rescue | 141 Days |
| Ertugliflozin 15 mg | Time to Initiation of Glycemic Rescue by Week 26 | Minimum time to initiation of glycemic rescue | 43 Days |
| Ertugliflozin 15 mg | Time to Initiation of Glycemic Rescue by Week 26 | Maximum time to initiation of glycemic rescue | 147 Days |
| Placebo | Time to Initiation of Glycemic Rescue by Week 26 | Minimum time to initiation of glycemic rescue | 26 Days |
| Placebo | Time to Initiation of Glycemic Rescue by Week 26 | Maximum time to initiation of glycemic rescue | 212 Days |
Secondary
Time to Initiation of Glycemic Rescue by Week 52
Glycemic rescue medication was initiated for participants who met progressively more stringent glycemic rescue criteria. Rescue medication included glimepiride (or insulin glargine if glimepiride was not considered appropriate for the participant). Data presented are the minimum and maximum times to the initiation of rescue therapy in days.
Time frame: Up to week 52
Population: Analysis population included all randomized participants who took at least one dose of trial treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ertugliflozin 5 mg | Time to Initiation of Glycemic Rescue by Week 52 | Minimum time to initiation of glycemic rescue | 135 Days |
| Ertugliflozin 5 mg | Time to Initiation of Glycemic Rescue by Week 52 | Maximum time to initiation of glycemic rescue | 295 Days |
| Ertugliflozin 15 mg | Time to Initiation of Glycemic Rescue by Week 52 | Minimum time to initiation of glycemic rescue | 43 Days |
| Ertugliflozin 15 mg | Time to Initiation of Glycemic Rescue by Week 52 | Maximum time to initiation of glycemic rescue | 299 Days |
| Placebo | Time to Initiation of Glycemic Rescue by Week 52 | Minimum time to initiation of glycemic rescue | 26 Days |
| Placebo | Time to Initiation of Glycemic Rescue by Week 52 | Maximum time to initiation of glycemic rescue | 327 Days |