A Study of the Efficacy and Safety of MK-0431D (a Fixed-dose Combination of Sitagliptin and Simvastatin) for the Treatment of Participants With Type 2 Diabetes Mellitus (T2DM) With Inadequate Glycemic Control on Metformin Monotherapy (MK-0431D-266)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of sitagliptin/simvastatin fixed-dose combination (FDC) in participants with T2DM who have inadequate glycemic control while on metformin monotherapy. The primary hypothesis of this study is that after 16 weeks of therapy, the mean change from baseline in hemoglobin A1C (A1C) in participants treated with sitagliptin/simvastatin FDC is non-inferior compared to sitagliptin alone.

Official Title
-----------------
A Phase III, Randomized, Double-blind, Clinical Trial to Study the Efficacy and Safety of MK-0431D (a Fixed-dose Combination [FDC] of Sitagliptin and Simvastatin) for the Treatment of Patients With Type 2 Diabetes Mellitus (T2DM) With Inadequate Glycemic Control on Metformin Monotherapy

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

Intervention / Treatment
-----------------
* Drug: Sitagliptin/Simvastatin FDC
* Drug: Sitagliptin
* Drug: Simvastatin
* Drug: Placebo to sitagliptin
* Drug: Placebo to simvastatin
* Drug: Placebo to Sitagliptin/Simvastatin FDC
* Drug: Metformin
* Drug: Glimepiride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: has T2DM (1) Male; (2) female not of reproductive potential; or (3) female of reproductive potential who agrees to remain abstinent or use alone or in conjunction with their partner 2 methods of contraception to prevent pregnancy during the study and for 14 days after the last dose of study drug is currently on metformin monotherapy at a daily dose of at least 1500 mg for at least 10 weeks is not on a lipid-lowering agent for at least 6 weeks prior to entering the study Exclusion Criteria: has history of type 1 diabetes mellitus (T1DM), or a history of ketoacidosis or possibly has T1DM has been on a thiazolidinedione (TZD) within the previous 16 weeks has been treated with a statin or other lipid-lowering agent (including over-the-counter [OTC] supplements) within the previous 6 weeks currently participating in or has participated in another clinical study within the past 12 weeks intends to consume >1.2 liters of grapefruit juice daily during the study is on or likely to require treatment for at least 2 consecutive weeks or repeated courses of corticosteroids (inhaled, nasal and topical corticosteroids are permitted) intolerance or hypersensitivity to sitagliptin, simvastatin, metformin or glimepiride is on a weight loss program and not in the maintenance phase or has started a weight loss medication or has undergone bariatric surgery in the previous 12 months has undergone a surgical procedure in the past 4 weeks or planned major surgery during the study has symptomatic hyperglycemia that requires immediate initiation, adjustment, or addition of antihyperglycemic therapy has a history of myopathy or rhabdomyolysis with any statin has cardiovascular disease, a diagnosis of congestive heart failure, or uncontrolled high blood pressure has a history of active liver disease has chronic progressive neuromuscular disorder, human immunodeficiency virus (HIV), hematological disorder, or uncontrolled endocrine or metabolic disease is currently being treated for hyperthyroidism or is on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks has a history of malignancy in the previous 5 years (excluding adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer) is pregnant or breast feeding, or is expecting to conceive or donate eggs during the course of the study, including 14 days after the last dose of study drug is a user of recreational or illicit drugs or has had a recent history of drug abuse consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 79 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: Sitagliptin/Simvastatin FDC<br>Sitagliptin 100 mg/simvastatin 40 mg FDC plus placebo to sitagliptin plus placebo to simvastatin administered orally once daily in the evening for 16 weeks. Participants will continue on their stable pre-screening metformin dose and dosing regimen of >=1500 mg daily for the duration of the study. Participants may receive glimepiride 1 mg once daily or 2 mg once daily (may be up-titrated to 6 mg once daily) as rescue therapy. | Drug: Sitagliptin/Simvastatin FDC<br>* Sitagliptin 100 mg/Simvastatin 40 mg fixed-dose combination tablet<br>* Other names: Juvicor®;Drug: Placebo to sitagliptin<br>* Matching placebo to sitagliptin 100 mg tablet<br>Drug: Placebo to simvastatin<br>* Matching placebo to simvastatin 40 mg tablet<br>Drug: Metformin<br>* Participants will continue on their stable, pre-screening metformin daily dose of >= 1500 mg for at least 12 weeks prior to randomization and during the study<br>* Other names: Glycoran®;Drug: Glimepiride<br>* Following randomization, participants requiring glycemic rescue may receive open-label glimepiride initiated at a dose of 1 mg/day or 2 mg/day which may be up-titrated to 6 mg/day taken once daily with breakfast or the first main meal of the day.<br>* Other names: Glimy;|
| Active Comparator: Sitagliptin<br>Sitagliptin 100 mg plus placebo to simvastatin plus placebo to sitagliptin/simvastatin FDC administered orally once daily in the evening for 16 weeks. Participants will continue on their stable pre-screening metformin dose and dosing regimen of >=1500 mg daily for the duration of the study. Participants may receive glimepiride 1 mg once daily or 2 mg once daily (may be up-titrated to 6 mg once daily) as rescue therapy. | Drug: Sitagliptin<br>* Sitagliptin 100 mg tablet<br>* Other names: Ristaben®;Drug: Placebo to simvastatin<br>* Matching placebo to simvastatin 40 mg tablet<br>Drug: Placebo to Sitagliptin/Simvastatin FDC<br>* Matching placebo to sitagliptin 100 mg/simvastatin 40 mg FDC tablet<br>Drug: Metformin<br>* Participants will continue on their stable, pre-screening metformin daily dose of >= 1500 mg for at least 12 weeks prior to randomization and during the study<br>* Other names: Glycoran®;Drug: Glimepiride<br>* Following randomization, participants requiring glycemic rescue may receive open-label glimepiride initiated at a dose of 1 mg/day or 2 mg/day which may be up-titrated to 6 mg/day taken once daily with breakfast or the first main meal of the day.<br>* Other names: Glimy;|
| Active Comparator: Simvastatin<br>Simvastatin 40 mg plus placebo to sitagliptin plus placebo to sitagliptin/simvastatin FDC administered orally once daily in the evening for 16 weeks. Participants will continue on their stable pre-screening metformin dose and dosing regimen of >=1500 mg daily for the duration of the study. Participants may receive glimepiride 1 mg once daily or 2 mg once daily (may be up-titrated to 6 mg once daily) as rescue therapy. | Drug: Simvastatin<br>* Simvastatin 40 mg tablet<br>* Other names: Zocor®;Drug: Placebo to sitagliptin<br>* Matching placebo to sitagliptin 100 mg tablet<br>Drug: Placebo to Sitagliptin/Simvastatin FDC<br>* Matching placebo to sitagliptin 100 mg/simvastatin 40 mg FDC tablet<br>Drug: Metformin<br>* Participants will continue on their stable, pre-screening metformin daily dose of >= 1500 mg for at least 12 weeks prior to randomization and during the study<br>* Other names: Glycoran®;Drug: Glimepiride<br>* Following randomization, participants requiring glycemic rescue may receive open-label glimepiride initiated at a dose of 1 mg/day or 2 mg/day which may be up-titrated to 6 mg/day taken once daily with breakfast or the first main meal of the day.<br>* Other names: Glimy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1C (A1C) at Week 16 (Sitagliptin/Simvastatin FDC vs. Sitagliptin) | A1C is measured as percent. Thus, this change from baseline reflects the Week 16 A1C percent minus the Week 0 A1C percent. This primary outcome measure only includes results for sitagliptin/simvastatin FDC vs. sitagliptin. Results for simvastatin are presented below under secondary outcome measures. | Baseline and Week 16 | 
| Number of Participants Who Experienced at Least One Adverse Event (AE) | Excludes data after rescue therapy. Adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. | Up to 16 weeks for non-serious AEs, up to 18 weeks for serious AEs | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Excludes data after rescue therapy. Adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in A1C at Week 16 (Sitagliptin/Simvastatin FDC vs. Simvastatin) | A1C is measured as percent. Thus, this change from baseline reflects the Week 16 A1C percent minus the Week 0 A1C percent. This primary outcome measure only includes results for sitagliptin/simvastatin FDC vs. simvastatin. Results for sitagliptin are presented above under primary outcome measures. | Baseline and Week 16 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 16 | Change from baseline reflects the Week 16 value minus the Week 0 value. | Baseline and Week 16 | 
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Total Cholesterol (TC) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Non-high Density Lipoprotein Cholesterol (Non-HDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Triglycerides (TG) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at Week 16 | Percent change from baseline was calculated as the Week 16 value minus the Week 0 value, divided by the Week 0 value ×100%. | Baseline and Week 16 | 
| Percentage of Participants With A1C Level <7% at Week 16 | Percentage of participants achieving glycemic goal (A1C <7%) after 16 weeks of treatment. Data as observed. | Week 16 |