Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will evaluate the efficacy and safety of the addition of ertugliflozin (MK-8835/PF-04971729) compared with the addition of glimepiride in participants with T2DM who have inadequate glycemic control on metformin. The primary hypothesis of this study is that after 52 weeks, the change from baseline in hemoglobin A1c (A1C) in participants treated with the addition of ertugliflozin 15 mg once daily is non-inferior compared with that in participants treated with the addition of glimepiride.
Detailed description
The duration of the trial will be up to approximately 122 weeks. This will include a 1-week screening period, an up to 13-week wash-off/titration/dose stabilization period, a 2-week placebo run-in period, a 104-week double-blind, active comparator-controlled treatment period, and a post-treatment telephone contact 14 days after the last dose of study drug.
Interventions
Ertugliflozin, 5 mg, oral, once daily, from Day 1 to Week 104
Ertugliflozin, 10 mg, oral, once daily from Day 1 to Week 104.
DRUGGlimerpiride
Glimepiride, oral tablets, initiated at 1 mg daily and titrated up to the maximum approved dose (8 mg daily based on the local country label) or maximum tolerated dose
Matching placebo to ertugliflozin, 5 mg and/or 10 mg, oral, once daily, from Day 1 to Week 104
Matching placebo to glimepiride, 1 mg or 2 mg, oral, once daily, from Day 1 to Week 104.
DRUGMetformin
Participants are to remain on their stable doses of metformin (oral, \>=1500 mg/day) while receiving blinded investigational product during the double-blind treatment period. Participants on metformin \<1500 at screening are up-titrated to \>= 1500 daily.
DRUGSitagliptin
Open label, oral, once daily, rescue medication as required.
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 * On metformin monotherapy or metformin in combination with a single allowable anti-hyperglycemic agent (AHA), DPP-4 inhibitors, meglitinides and AGIs are listed as allowable AHAs along with sulfonylureas prior to study participation. * Body Mass Index (BMI) ≥18.0 kg/m\^2 * Male or female not of reproductive potential * If a female of reproductive potential, agree 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 or presence of type 1 diabetes mellitus or a history of ketoacidosis * History of other specific types of diabetes (eg, 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 * Use of the following prohibited therapeutic agents within 12 weeks of study participation: insulin, injectable anti-hyperglycemic agents, pioglitazone or rosiglitazone, another SGLT2 inhibitor, bromocriptine (Cycloset®), colesevelam (Welchol®), and any other non-approved anti-hyperglycemic therapy * Known hypersensitivity or intolerance to metformin or glimepiride * On a weight-loss program or medication or medication associated with weight changes and is not weight-stable (\>=5% change in body weight in the last 6 months) * History of bariatric surgery less than 12 months prior to study participation * 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 * Active, obstructive uropathy or an indwelling urinary catheter * 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) * Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells * A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C (assessed by medical history), primary biliary cirrhosis, or symptomatic gallbladder disease * Any clinically significant malabsorption condition * Being treated for hyperthyroidism, or on thyroid replacement therapy that has not been at a stable dose for at least 6 weeks prior to study participation * Previous randomization in a study with ertugliflozin * Participation in other studies involving investigational drug(s) within 30 days of study participation and/or during the pre-randomization period * A surgical procedure within 6 weeks prior to study participation or planned major surgery during the trial * A positive urine pregnancy test * Pregnant or breast-feeding, or expecting to conceive during the trial, including 14 days following the last dose of study drug * Undergoing hormonal therapy in preparation to donate eggs during the period of the trial, including 14 days following the last dose of study drug * Consumption of more than 2 alcoholic drinks per day or engages in binge drinking * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach | Baseline and Week 52 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 52 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. The primary study objective was the MK-8835 15 mg vs. glimepiride comparison; the MK-8835 5mg vs glimerpiride comparison was a secondary study objective. |
| Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106 | Up to Week 106 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104 | Up to Week 104 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach | Up to Week 52 | Symptomatic hypoglycemia was an event with clinical symptoms reported by the investigator as hypoglycemia (biochemical documentation not required). Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. |
| Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach | Baseline and Week 52 | This change from baseline reflects the Week 52 body weight minus the Week 0 body weight. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. |
| Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach | Baseline and Week 52 | This change from baseline reflects the Week 52 SBP minus the Week 0 SBP. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. |
Participant flow
Recruitment details
The trial was conducted in 16 countries at 232 trial centers in Argentina, Canada, Czech Republic, Hungary, South Korea, Lithuania, Mexico, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Taiwan, Ukraine, and the United States.
Pre-assignment details
A total of 1326 participants were randomized. Ten randomized participants from one trial site were excluded from all final analyses (Week 104 and beyond), and one randomized participant did not receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 5 mg Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104 | 448 |
| Ertugliflozin 15 mg Ertugliflozin 15 mg QD from Day 1 to Week 104 | 441 |
| Glimepiride Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104 | 437 |
| Total | 1,326 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 7 | 7 |
| Overall Study | Creatinine/eGFR | 0 | 0 | 1 |
| Overall Study | Death | 7 | 1 | 2 |
| Overall Study | Excluded Medication | 1 | 1 | 2 |
| Overall Study | Hyperglycemia | 18 | 17 | 17 |
| Overall Study | Lack of Efficacy | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 22 | 17 | 18 |
| Overall Study | Non-Compliance With Study Drug | 6 | 4 | 1 |
| Overall Study | Participant moves | 2 | 5 | 3 |
| Overall Study | Physician Decision | 1 | 4 | 6 |
| Overall Study | Protocol Violation | 4 | 5 | 4 |
| Overall Study | Screen failure | 0 | 1 | 0 |
| Overall Study | Study Terminated By Sponsor | 7 | 5 | 12 |
| Overall Study | Treated but excluded at 1 trial site | 3 | 5 | 2 |
| Overall Study | Withdrawal by Subject | 28 | 29 | 34 |
Baseline characteristics
| Characteristic | Total | Glimepiride | Ertugliflozin 15 mg | Ertugliflozin 5 mg |
|---|---|---|---|---|
| Age, Continuous | 58.2 Years STANDARD_DEVIATION 9.6 | 57.8 Years STANDARD_DEVIATION 9.2 | 58.0 Years STANDARD_DEVIATION 9.9 | 58.8 Years STANDARD_DEVIATION 9.7 |
| Body Weight | 86.8 Kilograms STANDARD_DEVIATION 19.6 | 86.8 Kilograms STANDARD_DEVIATION 20.7 | 85.6 Kilograms STANDARD_DEVIATION 19.1 | 87.9 Kilograms STANDARD_DEVIATION 18.9 |
| Estimated Glomerular Filtration Rate (eGFR) | 87.2 milliliters/minute/1.73 meters^2 STANDARD_DEVIATION 18.5 | 86.6 milliliters/minute/1.73 meters^2 STANDARD_DEVIATION 18.5 | 86.7 milliliters/minute/1.73 meters^2 STANDARD_DEVIATION 18.3 | 88.3 milliliters/minute/1.73 meters^2 STANDARD_DEVIATION 18.7 |
| Hemoglobin A1C | 7.79 Percentage STANDARD_DEVIATION 0.6 | 7.76 Percentage STANDARD_DEVIATION 0.6 | 7.80 Percentage STANDARD_DEVIATION 0.6 | 7.81 Percentage STANDARD_DEVIATION 0.6 |
| Prior Antihyperglycemic (AHA) Medication (Monotherapy or Dual Therapy) Data not available | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Prior Antihyperglycemic (AHA) Medication (Monotherapy or Dual Therapy) No Prior Use & Not on Antihyperglycemic Medication | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Prior Antihyperglycemic (AHA) Medication (Monotherapy or Dual Therapy) Prior Antihyperglycemic Medication | 1324 Participants | 437 Participants | 439 Participants | 448 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 13 Participants | 5 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 240 Participants | 73 Participants | 86 Participants | 81 Participants |
| Race (NIH/OMB) Black or African American | 61 Participants | 25 Participants | 19 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 46 Participants | 16 Participants | 17 Participants | 13 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 966 Participants | 318 Participants | 316 Participants | 332 Participants |
| Sex: Female, Male Female | 684 Participants | 213 Participants | 250 Participants | 221 Participants |
| Sex: Female, Male Male | 642 Participants | 224 Participants | 191 Participants | 227 Participants |
| Sitting Systolic Blood Pressure | 130.3 Millimeters of mercury STANDARD_DEVIATION 12.4 | 129.9 Millimeters of mercury STANDARD_DEVIATION 12 | 130.8 Millimeters of mercury STANDARD_DEVIATION 12.4 | 130.2 Millimeters of mercury STANDARD_DEVIATION 12.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 445 | 2 / 435 | 1 / 435 |
| other Total, other adverse events | 110 / 445 | 104 / 435 | 165 / 435 |
| serious Total, serious adverse events | 41 / 445 | 32 / 435 | 30 / 435 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C (A1C) at Week 52: 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 (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 52 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. The primary study objective was the MK-8835 15 mg vs. glimepiride comparison; the MK-8835 5mg vs glimerpiride comparison was a secondary study objective.
Time frame: Baseline and Week 52
Population: All randomized, treated participants with at least one A1C measurement (baseline or a post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach | -0.56 Percent |
| Ertugliflozin 15 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach | -0.64 Percent |
| Glimepiride | Change From Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach | -0.74 Percent |
95% CI: [-0.02, 0.22]
95% CI: [0.06, 0.3]
Primary
Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to Week 104
Population: All randomized participants who took at least one dose of trial treatment, 10 randomized participants from one trial site were excluded from these analyzes, and one randomized participant did not receive treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104 | 6.5 Percentage of Participants |
| Ertugliflozin 15 mg | Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104 | 8.0 Percentage of Participants |
| Glimepiride | Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104 | 5.1 Percentage of Participants |
95% CI: [-0.3, 6.4]
95% CI: [-1.7, 4.7]
Primary
Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to Week 106
Population: All randomized participants who took at least one dose of trial treatment, 10 randomized participants from one trial site were excluded from these analyzes, and one randomized participant did not receive treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106 | 70.1 Percentage of Participants |
| Ertugliflozin 15 mg | Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106 | 71.3 Percentage of Participants |
| Glimepiride | Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106 | 69.7 Percentage of Participants |
95% CI: [-4.5, 7.7]
95% CI: [-5.6, 6.5]
Secondary
Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach
This change from baseline reflects the Week 52 body weight minus the Week 0 body weight. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication.
Time frame: Baseline and Week 52
Population: All randomized, treated participants with at least one body weight measurement (baseline or a post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach | -2.96 Kilograms |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach | -3.38 Kilograms |
| Glimepiride | Change From Baseline in Body Weight at Week 52 Excluding Rescue Approach | 0.91 Kilograms |
p-value: <0.00195% CI: [-4.77, -3.8]Constrained Longitudinal Data analysis
p-value: <0.00195% CI: [-4.36, -3.38]Constrained Longitudinal Data Analysis
Secondary
Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach
This change from baseline reflects the Week 52 SBP minus the Week 0 SBP. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication.
Time frame: Baseline and Week 52
Population: All randomized, treated participants with at least one SBP measurement (baseline or a post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach | -2.25 mmHg |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach | -3.81 mmHg |
| Glimepiride | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach | 0.95 mmHg |
p-value: <0.00195% CI: [-6.29, -3.25]Constrained Logitudinal Data Analysis
p-value: <0.0010.001% CI: [-4.73, -1.67]Constrained Logitudinal Data Analysis
Secondary
Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach
Symptomatic hypoglycemia was an event with clinical symptoms reported by the investigator as hypoglycemia (biochemical documentation not required). Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication.
Time frame: Up to Week 52
Population: All randomized participants who took at least one dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach | 3.1 Percentage of Participants |
| Ertugliflozin 15 mg | Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach | 5.2 Percentage of Participants |
| Glimepiride | Percentage of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach | 19.2 Percentage of Participants |
p-value: <0.00195% CI: [-18.4, -9.8]Based on Miettinen & Nurminen method
p-value: <0.00195% CI: [-20.3, -12.2]Based on Miettinen & Nurminen method