Ertugliflozin vs. Glimepiride in Type 2 Diabetes Mellitus (T2DM) Participants on Metformin (MK-8835-002)

Study Overview
=================
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.

Official Title
-----------------
A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Ertugliflozin (MK-8835/PF-04971729) Compared With the Addition of Glimepiride in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Ertugliflozin 5 mg
* Drug: Ertugliflozin 10 mg
* Drug: Glimerpiride
* Drug: Placebo to Ertugliflozin
* Drug: Placebo to Glimepiride
* Drug: Metformin
* Drug: Sitagliptin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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<br>Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104 | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin, 5 mg, oral, once daily, from Day 1 to Week 104<br>* Other names: MK-8835;Drug: Placebo to Ertugliflozin<br>* Matching placebo to ertugliflozin, 5 mg and/or 10 mg, oral, once daily, from Day 1 to Week 104<br>Drug: Placebo to Glimepiride<br>* Matching placebo to glimepiride, 1 mg or 2 mg, oral, once daily, from Day 1 to Week 104.<br>Drug: Metformin<br>* 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.<br>Drug: Sitagliptin<br>* Open label, oral, once daily, rescue medication as required.<br>|
| Experimental: Ertugliflozin 15 mg<br>Ertugliflozin 15 mg QD from Day 1 to Week 104 | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin, 5 mg, oral, once daily, from Day 1 to Week 104<br>* Other names: MK-8835;Drug: Ertugliflozin 10 mg<br>* Ertugliflozin, 10 mg, oral, once daily from Day 1 to Week 104.<br>* Other names: MK-8355;Drug: Placebo to Glimepiride<br>* Matching placebo to glimepiride, 1 mg or 2 mg, oral, once daily, from Day 1 to Week 104.<br>Drug: Metformin<br>* 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.<br>Drug: Sitagliptin<br>* Open label, oral, once daily, rescue medication as required.<br>|
| Active Comparator: Glimepiride up to 8 mg<br>Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104 | Drug: Glimerpiride<br>* 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<br>Drug: Placebo to Ertugliflozin<br>* Matching placebo to ertugliflozin, 5 mg and/or 10 mg, oral, once daily, from Day 1 to Week 104<br>Drug: Metformin<br>* 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.<br>Drug: Sitagliptin<br>* Open label, oral, once daily, rescue medication as required.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 52 | 
| 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. | Up to Week 106 | 
| 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. | Up to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to Week 52 | 
| 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. | Baseline and Week 52 | 
| 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. | Baseline and Week 52 |