Safety and Efficacy of Ertugliflozin in the Treatment of Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin (MK-8835-006; VERTIS SITA2)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Clinical Trial to Evaluate the Safety and Efficacy of Ertugliflozin (MK-8835/PF-04971729) in the Treatment of Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin and Sitagliptin

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ertugliflozin 5 mg
* Drug: Ertugliflozin 15 mg
* Drug: Placebo for ertugliflozin 5 mg
* Drug: Metformin
* Drug: Sitagliptin
* Drug: Glimepiride
* Biological: Insulin
* Drug: Placebo for ertugliflozin 10 mg


Participation Criteria
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Eligibility Criteria
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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

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<br>Ertugliflozin, 5 mg, oral, once daily for 52 weeks | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin, oral, 5 mg tablet once daily for 52 weeks<br>* Other names: PF-04971729;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.<br>* Other names: Glucophage XR;Drug: Sitagliptin<br>* 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.<br>* Other names: JANUVIA®;Drug: Glimepiride<br>* Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion<br>* Other names: AMARYL;Biological: Insulin<br>* 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.<br>Drug: Placebo for ertugliflozin 10 mg<br>* Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks<br>|
| Experimental: Ertugliflozin 15 mg<br>Ertugliflozin, 15 mg, oral, once daily for 52 weeks | Drug: Ertugliflozin 15 mg<br>* Ertugliflozin, oral, 5 mg and 10 mg tablet once daily for 52 weeks<br>* Other names: PF-04971729;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.<br>* Other names: Glucophage XR;Drug: Sitagliptin<br>* 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.<br>* Other names: JANUVIA®;Drug: Glimepiride<br>* Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion<br>* Other names: AMARYL;Biological: Insulin<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Matching placebo to ertuglifozin, oral, once daily for 52 weeks | Drug: Placebo for ertugliflozin 5 mg<br>* Matching placebo for ertugliflozin 5 mg, oral, once daily for 52 weeks<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.<br>* Other names: Glucophage XR;Drug: Sitagliptin<br>* 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.<br>* Other names: JANUVIA®;Drug: Glimepiride<br>* Glimepiride rescue medication, oral, once daily, open-label glimepiride; dose determined per the investigator's discretion<br>* Other names: AMARYL;Biological: Insulin<br>* 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.<br>Drug: Placebo for ertugliflozin 10 mg<br>* Matching placebo for ertugliflozin 10 mg, oral, once daily for 52 weeks<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 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. | Baseline and Week 26 | 
| 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. | Up to Week 54 | 
| 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. | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Week 26 | 
| 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. | Baseline and Week 26 | 
| 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. | Week 26 | 
| 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. | Baseline and Week 26 | 
| 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. | Baseline and Week 52 | 
| 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. | Baseline and Week 52 | 
| 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. | Baseline and Week 52 | 
| 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. | Week 52 | 
| 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. | Baseline and Week 52 | 
| 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. | Baseline and Week 26 | 
| 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. | Baseline and Week 52 | 
| 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). | Week 26 | 
| 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). | Week 52 | 
| 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. | Up to Week 26 (plus 30 days for 1 placebo participant) | 
| 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. | Up to week 52 | 
| 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] | Baseline | 
| 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. | Baseline and Week 26 | 
| 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. | Baseline and Week 52 | 
| 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). | Baseline | 
| 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. | Baseline and Week 26 | 
| 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. | Baseline and Week 52 |