Efficacy and Safety of Ertugliflozin (MK-8835/PF-04971729) With Sitagliptin in the Treatment of Participants With Type 2 Diabetes Mellitus (T2DM) With Inadequate Glycemic Control on Diet and Exercise (MK-8835-017)

Study Overview
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Brief Summary
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This is a study to evaluate the efficacy and safety of ertugliflozin (MK-8835/PF-04971729) in combination with sitagliptin in the treatment of participants with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control on diet and exercise. The primary hypothesis of the study is that ertugliflozin plus sitagliptin is more effective in lowering of hemoglobin A1C (HbA1C) than placebo.

Detailed Description
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Each participant will be in the study for approximately 39 weeks including: a 1-week screening period, an 8-week (or greater) antihyperglycemic agent (AHA) wash-off period, a 2-week single-blind placebo run-in period, a 26-week double-blind treatment period, and a post-treatment telephone contact 14 days after the last dose of study drug.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial to Evaluate the Efficacy and Safety of the Initial Combination of Ertugliflozin (MK-8835/PF-04971729) With Sitagliptin in the Treatment of Subjects With T2DM With Inadequate Glycemic Control on Diet and Exercise

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin
* Drug: Sitagliptin
* Drug: Placebo to Ertugliflozin
* Drug: Placebo to Sitagliptin
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus as per American Diabetes Association guidelines Not on antihyperglycemic agent (AHA) >=8 weeks with a Visit 1/Screening HbA1C >=8.0% and <=10.5% (>=64 mmol/mol and <=91 mmol/mol) OR on single allowable AHA (allowable AHAs prior to screening are: metformin, α-glucosidase inhibitors, sulfonylureas and glinides) with a Visit 1/Screening HbA1C >=7.5% and <=10.0% (>=58 mmol/mol and <=86 mmol/mol) OR on low-dose dual combination therapy (≤50% of maximum labeled dose of an AHA) with allowable AHAs with a Visit 1/Screening HbA1C >=7.5% and <=10.0% (>=58 mmol/mol and <=86 mmol/mol) Body mass index (BMI) >=18.0 kg/m^2 Male or female not of reproductive potential Female of reproductive potential who agrees to (or have their partner agree to) remain abstinent from heterosexual activity or to use 2 acceptable combinations of contraception. Exclusion Criteria: History of type 1 diabetes mellitus or diabetic ketoacidosis History of other specific types of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant A known hypersensitivity or intolerance to any sodium glucose co-transporter (SGLT2) inhibitor or sitagliptin Has been treated with any of the following agents within 12 weeks of study start or during the pre-randomization period: insulin of any type (except for short-term use [i.e., <=7 days] during concomitant illness or other stress), other injectable anti-hyperglycemic agents (e.g., pramlintide, exenatide, liraglutide), pioglitazone or rosiglitazone, other sodium glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl-peptidase 4 inhibitors (DPP-4 inhibitors), bromocriptine (Cycloset™), colesevelam (Welchol™), any other AHA with the exception of the protocol-approved agents Is on a weight-loss program or weight-loss medication or other medication associated with weight changes and is not weight stable prior to study start Has undergone bariatric surgery within the past 12 months or >12 months and is not weight stable prior to study start A history of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, or New York Heart Association (NYHA) functional Class III-IV heart failure within 3 months of study start Active, obstructive uropathy or indwelling urinary catheter History of malignancy <=5 years prior to study start, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer A known history of human immunodeficiency virus (HIV) A blood dyscrasia or any disorder causing hemolysis or unstable red blood cells, or a clinically important hematological disorder (e.g. aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) A medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease Any clinically significant malabsorption condition Current treatment for hyperthyroidism On thyroid replacement therapy and not on a stable dose for at least 6 weeks prior study start On a previous clinical study with ertugliflozin Participated in other studies involving investigational drug(s) 30 days prior to study start Surgical procedure within 6 weeks prior to study start or major surgery planned during the trial Positive urine pregnancy test Pregnant or breast-feeding, or planning to conceive during the trial, including 14 days following the last dose of study medication Planning to undergo hormonal therapy in preparation for egg donation during the trial, including 14 days following the last dose of study medication Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week or engages in binge drinking Donated blood or blood products within 6 weeks of study start.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ertugliflozin 5 mg and Sitagliptin 100 mg<br>Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. Placebo to ertugliflozin, 10 mg, administered orally, once daily for 26 weeks. | Drug: Ertugliflozin<br>* Ertugliflozin, 5 mg or 15 mg, administered orally, once daily for 26 weeks.<br>Drug: Sitagliptin<br>* Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.<br>Drug: Placebo to Ertugliflozin<br>* Matching placebo to ertugliflozin administered orally, once daily for 26 weeks.<br>Drug: Glimepiride<br>* Open-label glimepiride rescue therapy will be initiated at 1 or 2 mg/day and may be titrated to the maximum labeled dose or maximum tolerated dose (if lower than labeled dose), as considered appropriate by the investigator, based on blood glucose measurements and in accordance with the local, approved label.<br>|
| Experimental: Ertugliflozin 15 mg and Sitagliptin 100 mg<br>Ertugliflozin, 15 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. | Drug: Ertugliflozin<br>* Ertugliflozin, 5 mg or 15 mg, administered orally, once daily for 26 weeks.<br>Drug: Sitagliptin<br>* Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.<br>Drug: Glimepiride<br>* Open-label glimepiride rescue therapy will be initiated at 1 or 2 mg/day and may be titrated to the maximum labeled dose or maximum tolerated dose (if lower than labeled dose), as considered appropriate by the investigator, based on blood glucose measurements and in accordance with the local, approved label.<br>|
| Placebo Comparator: Placebo to Ertugliflozin and Placebo to Sitagliptin<br>Placebo to ertugliflozin, 5 mg and 10 mg, administered orally, once daily for 26 weeks. Placebo to sitagliptin, 100 mg, administered orally, once daily for 26 weeks. | Drug: Placebo to Ertugliflozin<br>* Matching placebo to ertugliflozin administered orally, once daily for 26 weeks.<br>Drug: Placebo to Sitagliptin<br>* Matching placebo to sitagliptin administered orally, once daily for 26 weeks.<br>Drug: Glimepiride<br>* Open-label glimepiride rescue therapy will be initiated at 1 or 2 mg/day and may be titrated to the maximum labeled dose or maximum tolerated dose (if lower than labeled dose), as considered appropriate by the investigator, based on blood glucose measurements and in accordance with the local, approved label.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1C (HbA1C) at Week 26 - Full Analysis Set (FAS Population Excluding Rescue Approach | HbA1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). HbA1C represents the percentage of glycated hemoglobin. A negative number indicates a reduction in HbA1C level. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 | 
| Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants as Treated Excluding Rescue Approach | An adverse event (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. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Up to Week 28 | 
| Percentage of Participants Who Discontinued Study Medication Due to an AE - All Participants as Treated Excluding Rescue Approach | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Up to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Full Analysis Set Excluding Rescue Approach | Blood glucose was measured after a ≥10 hour fast. Blood was drawn at predose on Day 1 and after 26 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 26 minus FPG at baseline). Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 | 
| Change From Baseline in 2-hour Post-Meal Glucose (PMG) at Week 26 - Full Analysis Set Excluding Rescue Approach | Change from baseline at Week 26 is defined as 2-hour PMG at Week 26 minus 2-hour PMG at Week 0. Two-hour post-meal glucose was measured following a standard meal. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 | 
| Percentage of Participants With HbA1C <7% (<53 mmol/Mol) at Week 26 | HbA1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). HbA1c represents the percentage of glycated hemoglobin. | Week 26 | 
| Change From Baseline in Body Weight at Week 26 - Full Analysis Set Excluding Rescue Approach | Body weight was measured using a standardized, digital scale at each of the pre-defined nominal time points. Weight was taken in duplicate throughout the trial at approximately the same time of day, after voiding (i.e., forced void) and while wearing only a gown and underwear. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 | 
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach | Blood pressure measurements were taken after at least 5 minutes of rest. Three measurements were taken approximately 2 minutes apart with the triplicate set recorded. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 | 
| Change From Baseline in Sitting Diastolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach | Blood pressure measurements were taken after at least 5 minutes of rest. Three measurements were taken approximately 2 minutes apart with the triplicate set recorded. Excluding rescue approach excludes all data following the initiation of rescue, in order to avoid the confounding influence of the rescue therapy with open-label glimepiride. | Baseline and Week 26 |