Ertugliflozin and Sitagliptin Co-administration Factorial Study (VERTIS FACTORAL, MK-8835-005)

Study Overview
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Brief Summary
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This is a study of co-administration of ertugliflozin (MK-8835/PF-04971729) and sitagliptin given together or alone along with metformin in participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin monotherapy. The primary hypothesis of this study is that ertugliflozin 15 mg daily plus sitagliptin 100 mg daily provides greater hemoglobin A1C (A1C)-lowering compared with sitagliptin 100 mg daily alone.

Detailed Description
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This study will include a 1-week screening period; an up to 12-week metformin titration/dose stabilization period; a 2-week single-blind placebo run-in period; a 52-week (26-week Phase A and 26-week Phase B) double-blind treatment period and a post-treatment telephone contact 14 days after the last dose of study medication.

Official Title
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A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Ertugliflozin (MK-8835/PF-04971729) With Sitagliptin Compared With Ertugliflozin Alone and Sitagliptin Alone, in the Treatment of Subjects With T2DM With Inadequate Glycemic Control on Metformin Monotherapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Matching Placebo to Ertugliflozin 5 mg
* Drug: Matching Placebo to Ertugliflozin 10 mg
* Drug: Matching Placebo to sitagliptin 100 mg
* Drug: Ertugliflozin 5 mg
* Drug: Ertugliflozin 10 mg
* Drug: Sitagliptin 100 mg
* Drug: Metformin >= 1500 mg/day
* Biological: Insulin Glargine Rescue Medication
* Drug: Glimepiride Rescue Medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus as per American Diabetes Association guidelines On metformin monotherapy (>=1500 mg/day) for >=8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy (>=1500 mg/day) for <8 weeks with a Visit 1/Screening A1C >=7.5% and <=11.0% (>=58 mmol/mol and <=97 mmol/mol) OR On metformin monotherapy <1500 mg/day with a Visit 1/Screening A1C >=8.0% and <=11.5% (>=64 mmol/mol and <=102 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 remain abstinent from heterosexual activity or to use 2 acceptable combinations of contraception Exclusion Criteria: History of type 1 diabetes mellitus or 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 2 (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 SGLT2 inhibitors, alpha glucosidase inhibitors or meglitinides, dipeptidyl-peptidase 4 inhibitor (DPP-4 inhibitor), sulfonylureas (SUs), bromocriptine (Cycloset™), colesevelam (Welchol™), any other antihyperglycemic agents (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 Estimated glomerular filtration rate (eGFR) (using the 4-variable Modification of Diet in Renal Disease Study Equation (MDRD) equation) <60 mL/min/1.73 m^2 Serum creatinine >= 1.3 mg/dL (115 µmol/L) for males and >= 1.2 mg/dL (106 µmol/L) for females Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times upper limit of normal Hemoglobin <12 g/dL (120 g/L) for males and <11 g/dL (110 g/L) for females. 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 + sitagliptin 100 mg<br>Ertugliflozin 5 mg + sitagliptin 100 mg, oral, once daily for 52 weeks | Drug: Matching Placebo to Ertugliflozin 10 mg<br>* Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Sitagliptin 100 mg<br>* Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: JANUVIA®;Drug: Metformin >= 1500 mg/day<br>* Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period<br>* Other names: Glucophage XR;Biological: Insulin Glargine Rescue Medication<br>* Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion<br>* Other names: Lantus;Drug: Glimepiride Rescue Medication<br>* Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion<br>* Other names: AMARYL;|
| Experimental: Ertugliflozin 15 mg + sitagliptin 100 mg<br>Ertugliflozin 15 mg + sitagliptin 100 mg, oral, once daily for 52 weeks | Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Ertugliflozin 10 mg<br>* Ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Sitagliptin 100 mg<br>* Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: JANUVIA®;Drug: Metformin >= 1500 mg/day<br>* Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period<br>* Other names: Glucophage XR;Biological: Insulin Glargine Rescue Medication<br>* Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion<br>* Other names: Lantus;Drug: Glimepiride Rescue Medication<br>* Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion<br>* Other names: AMARYL;|
| Experimental: Ertugliflozin 5 mg<br>Ertugliflozin 5 mg, oral, once daily for 52 weeks | Drug: Matching Placebo to Ertugliflozin 10 mg<br>* Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Matching Placebo to sitagliptin 100 mg<br>* Placebo to sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Metformin >= 1500 mg/day<br>* Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period<br>* Other names: Glucophage XR;Biological: Insulin Glargine Rescue Medication<br>* Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion<br>* Other names: Lantus;Drug: Glimepiride Rescue Medication<br>* Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion<br>* Other names: AMARYL;|
| Experimental: Ertugliflozin 15 mg<br>Ertugliflozin, oral, once daily for 52 weeks | Drug: Matching Placebo to sitagliptin 100 mg<br>* Placebo to sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Ertugliflozin 5 mg<br>* Ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Ertugliflozin 10 mg<br>* Ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: PF-04971729;Drug: Metformin >= 1500 mg/day<br>* Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period<br>* Other names: Glucophage XR;Biological: Insulin Glargine Rescue Medication<br>* Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion<br>* Other names: Lantus;Drug: Glimepiride Rescue Medication<br>* Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion<br>* Other names: AMARYL;|
| Active Comparator: Sitagliptin 100 mg<br>Sitagliptin 100 mg, oral, once daily for 52 weeks | Drug: Matching Placebo to Ertugliflozin 5 mg<br>* Placebo to ertugliflozin 5 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Matching Placebo to Ertugliflozin 10 mg<br>* Placebo to ertugliflozin 10 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>Drug: Sitagliptin 100 mg<br>* Sitagliptin 100 mg tablet, oral, once daily for 52 weeks during the double-blind treatment period<br>* Other names: JANUVIA®;Drug: Metformin >= 1500 mg/day<br>* Metformin >= 1500 mg/day, tablets, oral, for 52 weeks while receiving blinded investigational product during the double-blind treatment period<br>* Other names: Glucophage XR;Biological: Insulin Glargine Rescue Medication<br>* Open-label insulin glargine, subcutaneous injection, as required as a rescue medication; dose determined per the investigator's discretion<br>* Other names: Lantus;Drug: Glimepiride Rescue Medication<br>* Open-label glimepiride tablets, oral, as required as a rescue medication, dose determined per the investigator's discretion<br>* Other names: AMARYL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 recue 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. | Baseline and Week 26 | 
| Percentage of Participants Who Experienced an Adverse Event (AE): Including 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. Including rescue approach data analysis included data following the initiation of rescue therapy. | Up to 54 weeks | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE: Including 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. Including rescue approach data analysis included data following the initiation of rescue therapy. | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Body Weight at Week 26: Excluding Rescue Approach | This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding recue 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. | Baseline and Week 26 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Excluding Rescue Approach | Blood glucose was measured on a fasting basis after at least a 10-hour fast. This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding recue 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. | Baseline and Week 26 | 
| Percentage of Participants Achieving a Hemoglobin A1C of <7% (<53 mmol/Mol) (Raw Proportions): Excluding Rescue Approach | A1C is blood marker used to report average blood glucose levels over a prolonged periods of time and is reported as a percentage (%). Excluding recue 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. | Week 26 | 
| Change From Baseline in Static Beta-Cell Sensitivity to Glucose Index at Week 26; Excluding Rescue Approach | Static beta-cell sensitivity to glucose index (SBCSGI) estimates the ratio of insulin secretion (expressed in pmol/min) related to above-basal glucose concentration (expressed in mmol/L * L) following a meal. Blood samples were collected before and after a standard meal and glucose, insulin, and C-peptide levels were analyzed. The C-peptides minimal model was used to estimate the insulin secretion rate (ISR). Analysis included both non-model-based [including insulinogenic index with C-peptide, glucose area under the curve (AUC)/insulin AUC] and model-based [beta cell function and insulin secretion rate at 9 mM glucose] testing. Analysis was performed with non-linear least squares using the Software Architecture Analysis Method (SAAM) II software. SBCSGI was expressed in units of 10^-9 min^-1. 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. | 30 min. before and 0, 15, 30, 60, 90, 120, and 180 minutes following the start of the standard meal at Baseline and Week 26 | 
| Change From Baseline in Sitting Systolic Blood Pressure at Week 26: Excluding Rescue Approach | This change from baseline reflects the Week 26 systolic blood pressure minus the Week 0 systolic blood pressure. Excluding recue 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. | Baseline and Week 26 |