Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will evaluate the efficacy and safety of ertugliflozin (MK-8835/PF-04971729) in participants with Type 2 diabetes mellitus with Stage 3 Chronic Kidney Disease (CKD) who have inadequate glycemic control on background antihyperglycemic therapy. The duration of this trial will be up to 67 weeks. This study will consist of a 1-week Screening Period, a 10-week wash-off period from metformin, if needed, and a 2-week placebo run-in period, a 52-week double-blind treatment period, and a 14-day post-treatment follow-up period. The primary objective of this 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 to the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.
Detailed description
Participants who meet protocol-defined glycemic rescue criteria will be permitted to have an adjustment in the dose(s) of background antihyperglycemic agent (AHA) therapy or addition of new AHA therapy as directed by their investigator until the participant no longer meets the rescue criteria.
Interventions
Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks
DRUGPlacebo 5 mg
Placebo to ertugliflozin, oral, tablet, 5 mg tablet once daily for 52 weeks
Ertugliflozin, oral, tablet, 10 mg tablet once daily for 52 weeks
DRUGPlacebo 10 mg
Placebo to ertugliflozin, oral, tablet, 10 mg tablet 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
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Type 2 diabetes mellitus in accordance with American Diabetes Association guidelines * Have Stage 3 chronic kidney disease * On stable diabetes therapy (diet/exercise therapy alone or anti-hyperglycemic agents \[AHA\] monotherapy or combination therapy) for at least 6 weeks prior to study participation OR on metformin (with or without diet/exercise therapy or other AHA therapy) and is willing to undergo a 10-week metformin wash-off period * Have an estimated glomerular filtration rate (eGFR) of ≥30 to \<60 mL/min/1.73m\^2 * 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) * History of nephrotic range proteinuria with hypoalbuminemia and edema * History of rapidly progressive glomerulonephritis, lupus nephritis, renal or systemic vasculitis, renal artery stenosis with renovascular hypertension, or ischemic nephropathy * History of familial renal glucosuria * History of renal dialysis or renal transplant or renal disease requiring treatment with any immunosuppressive agent * A known hypersensitivity or intolerance to any (sodium-glucose co-transporter 2) SGLT2 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 * Has been treated with rosiglitazone or other SGLT2 inhibitors 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 non-alcoholic 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 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 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 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. |
| Percentage of Participants Who Experienced an Adverse Event (AE) | 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. |
| Percentage of Participants Who Discontinued Study Treatment Due to an AE | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | Baseline and Week 26 | This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. 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 A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - 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 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. |
| Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | Week 26 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). 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 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | Baseline and Week 26 | This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. 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 Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | Baseline and Week 26 | This change from baseline reflects the Week 26 sitting systolic blood pressure minus the Week 0 sitting systolic blood pressure. 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. |
Participant flow
Recruitment details
The trial was conducted in 13 countries, including 171 trial centers; 1709 participants were screened and 468 were randomized.
Pre-assignment details
Eligible participants began a ≥10-week metformin wash-off during which participant's antihyperglycemic agents (AHAs) could be adjusted. All participants entered a 2-week placebo run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin 5 mg Ertugliflozin, oral, 5-mg tablet once daily for 52 weeks. Participants also received a 10-mg matching placebo tablet once daily for 52 weeks. | 158 |
| Ertugliflozin 15 mg Ertugliflozin, oral, 5-mg and 10-mg tablet once daily for 52 weeks | 155 |
| Placebo Placebo, oral, tablet, 5-mg or 5-mg and 10-mg tablet once daily for 52 weeks | 154 |
| Total | 467 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Death | 3 | 4 | 4 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 |
| Overall Study | Participant Moved | 0 | 0 | 2 |
| Overall Study | Screen Failure | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 8 | 5 |
Baseline characteristics
| Characteristic | Ertugliflozin 5 mg | Ertugliflozin 15 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 66.7 Years STANDARD_DEVIATION 8.3 | 67.5 Years STANDARD_DEVIATION 8.5 | 67.5 Years STANDARD_DEVIATION 8.9 | 67.3 Years STANDARD_DEVIATION 8.6 |
| Baseline Estimated glomerular filtration rate (eGFR) ≥30 to <45 | 52 Participants | 53 Participants | 54 Participants | 159 Participants |
| Baseline Estimated glomerular filtration rate (eGFR) ≥45 to <60 | 106 Participants | 102 Participants | 100 Participants | 308 Participants |
| Baseline Fasting Plasma Glucose (FPG) | 160.9 mg/dL STANDARD_DEVIATION 56.4 | 157.5 mg/dL STANDARD_DEVIATION 47.8 | 156.9 mg/dL STANDARD_DEVIATION 56.4 | 158.5 mg/dL STANDARD_DEVIATION 53.6 |
| Baseline Hemoglobin A1C (A1C) | 8.20 Percentage STANDARD_DEVIATION 1.02 | 8.17 Percentage STANDARD_DEVIATION 0.87 | 8.08 Percentage STANDARD_DEVIATION 0.89 | 8.15 Percentage STANDARD_DEVIATION 0.93 |
| Baseline Weight | 89.4 Kilograms STANDARD_DEVIATION 22.5 | 85.8 Kilograms STANDARD_DEVIATION 17.4 | 90.4 Kilograms STANDARD_DEVIATION 18.9 | 88.5 Kilograms STANDARD_DEVIATION 19.8 |
| Sex: Female, Male Female | 74 Participants | 80 Participants | 82 Participants | 236 Participants |
| Sex: Female, Male Male | 84 Participants | 75 Participants | 72 Participants | 231 Participants |
| Stratification Factor: Insulin at randomization No | 69 Participants | 68 Participants | 66 Participants | 203 Participants |
| Stratification Factor: Insulin at randomization Yes | 89 Participants | 87 Participants | 88 Participants | 264 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 | 68 / 154 | 82 / 158 | 62 / 155 |
| serious Total, serious adverse events | 24 / 154 | 26 / 158 | 30 / 155 |
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 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: Baseline and Week 26
Population: The analysis population included all randomized participants who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 A1C endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in A1C at Week 26 - Excluding Rescue Approach | -0.29 Percentage |
| Ertugliflozin 15 mg | Change From Baseline in A1C at Week 26 - Excluding Rescue Approach | -0.41 Percentage |
| Placebo | Change From Baseline in A1C at Week 26 - Excluding Rescue Approach | -0.26 Percentage |
p-value: 0.80795% CI: [-0.23, 0.18]Constrained longitudinal data analysis
p-value: 0.15595% CI: [-0.35, 0.06]Constrained longitudinal data analysis
Primary
Percentage of Participants Who Discontinued Study Treatment Due to an AE
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 52 weeks
Population: The analysis population included 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 | 8.2 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Who Discontinued Study Treatment Due to an AE | 3.9 Percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Treatment Due to an AE | 5.2 Percentage of participants |
95% CI: [-2.7, 9]
95% CI: [-6.5, 3.7]
Primary
Percentage of Participants Who Experienced an Adverse Event (AE)
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 54 weeks
Population: The analysis population included 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) | 84.8 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants Who Experienced an Adverse Event (AE) | 74.2 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced an Adverse Event (AE) | 81.2 Percentage of participants |
95% CI: [-4.8, 12.1]
95% CI: [-16.3, 2.3]
Secondary
Change From Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - 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 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: Baseline and Week 26
Population: The analysis population included all randomized participants with a Baseline eGFR of ≥45 to \<60 mL/min/1.73m\^2 and who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 A1C endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -0.31 Percentage |
| Ertugliflozin 15 mg | Change From Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -0.37 Percentage |
| Placebo | Change From Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -0.28 Percentage |
p-value: 0.82895% CI: [-0.28, 0.23]Constrained longitudinal data analysis
p-value: 0.49695% CI: [-0.35, 0.17]Constrained longitudinal data analysis
Secondary
Change From Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach
This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. 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: Baseline and Week 26
Population: The analysis population included all randomized participants with a Baseline eGFR of ≥45 to \<60 mL/min/1.73m\^2 and who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 body weight endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -1.31 Kilograms |
| Ertugliflozin 15 mg | Change From Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -1.39 Kilograms |
| Placebo | Change From Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | 0.46 Kilograms |
p-value: <0.00195% CI: [-2.57, -0.96]Constrained longitudinal data analysis
p-value: <0.00195% CI: [-2.66, -1.02]Constrained longitudinal data analysis
Secondary
Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach
This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. 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: Baseline and Week 26
Population: The analysis population included all randomized participants with a Baseline eGFR ≥45 to \<60 mL/min/1.73m\^2 and who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 FPG endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -11.76 mg/dL |
| Ertugliflozin 15 mg | Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -20.47 mg/dL |
| Placebo | Change From Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -4.95 mg/dL |
p-value: 0.29196% CI: [-19.47, 5.85]Constrained longitudinal data analysis
p-value: 0.01995% CI: [-28.5, -2.53]Constrained longitudinal data analysis
Secondary
Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach
This change from baseline reflects the Week 26 sitting systolic blood pressure minus the Week 0 sitting systolic blood pressure. 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: Baseline and Week 26
Population: The analysis population included all randomized participants with a Baseline eGFR of ≥45 to \<60 mL/min/1.73m\^2 and who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 sitting systolic blood pressure endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ertugliflozin 5 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -2.33 mmHg |
| Ertugliflozin 15 mg | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -4.36 mmHg |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | -0.90 mmHg |
p-value: 0.45195% CI: [-5.13, 2.29]Constrained longitudinal data analysis
p-value: 0.07295% CI: [-7.24, 0.31]Constrained longitudinal data analysis
Secondary
Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - 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 (%). 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: Week 26
Population: The analysis population included all randomized participants with a Baseline eGFR ≥45 to \<60 mL/min/1.73m\^2 and who took at least 1 dose of study treatment and had at least 1 assessment at Week 26 for the percentage of participants with an A1C \<7% at Week 26 endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin 5 mg | Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | 16.2 Percentage of participants |
| Ertugliflozin 15 mg | Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | 11.3 Percentage of participants |
| Placebo | Percentage of Participants With A1C <7.0% (<53 mmol/Mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/Min/1.73m^2 Stratum - Excluding Rescue Approach | 12.1 Percentage of participants |
p-value: 0.71395% CI: [0.53, 2.56]Logistic regression model
p-value: 0.8995% CI: [0.44, 2.55]Logistic regression model