Efficacy and Safety of Alogliptin Plus Metformin in Patients With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and effectiveness of alogliptin combined with metformin, once daily (QD) or twice daily (BID), in participants with Type 2 Diabetes.

Detailed Description
-----------------
There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected. Metformin is the usual choice of first-line therapy for type 2 diabetes. Metformin targets insulin resistance in type 2 diabetes by inhibiting hepatic glucose production and stimulating glucose uptake in skeletal muscle and adipose tissue, which results in a long-term glucose-lowering effect. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes. Based on the potential, complimentary mechanisms of action of alogliptin and metformin, this study will compare the safety and efficacy of alogliptin and metformin (SYR-322MET) on improving glycemic control in patients with type 2 diabetes mellitus who are inadequately controlled by diet adjustment and exercise alone. Participants taking part in this study will receive dietary and exercise coaching, and will monitor their own blood glucose concentrations with a home glucose monitor. Participants will also be required to maintain a hypoglycemic diary throughout the course of the study. Participation in this study is expected to last up to 34 weeks.

Official Title
-----------------
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of Alogliptin Plus Metformin, Alogliptin Alone, or Metformin Alone in Subjects With Type 2 Diabetes

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

Intervention / Treatment
-----------------
* Drug: Alogliptin
* Drug: Metformin
* Drug: Alogliptin Placebo
* Drug: Metformin Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has historical diagnosis of Type 2 Diabetes Mellitus. Has been treated with diet and exercise for at least 2 months prior to Screening, and has a Glycosylated Hemoglobin concentration between 7.5% and 10.0%, inclusive at Screening. Has received less than 7 days of any antidiabetic medication within 2 months prior to Screening. Body mass index greater than or equal to 23 kg/m^2 and less than or equal to 45 kg/m^2 (except for Asian or Asian-descendant subjects for whom the range is between 20 and 35 kg/ m^2, inclusive). Fasting C-peptide concentration greater than or equal to 0.8 ng/mL. Regularly using other, non-excluded, medications must be on a stable dose for at least the 4 weeks prior to Screening. Females of childbearing potential and males who are sexually active agree to routinely use adequate contraception from Screening throughout the duration of the study. Able and willing to monitor their own blood glucose concentrations with a home glucose monitor and complete patient diaries. Exclusion Criteria: Hemoglobin less than 12 g/dL for males and less than 10 g/dL for females at Screening Visit. Has a history of any hemoglobinopathy that may affect determination of Glycosylated Hemoglobin. Has a history of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening. Has a history of treatment for diabetic gastric paresis, gastric banding, or gastric bypass surgery. Has a history of diabetic ketoacidosis or hyperosmolar non-ketotic coma. Has systolic blood pressure greater than or equal to 150 mmHg and /or diastolic pressure greater than or equal to 90 mmHg at Screening visit. Has New York Heart Association Class III to IV heart failure. Has a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 90 days prior to Screening. Has Alanine aminotransferase greater than 3 times the upper limit of normal at Screening. Has a history of alcohol or substance abuse with the 2 years prior to Screening. Serum creatinine greater than or equal to 1.5 mg/dL for males and greater than or equal to 1.4 mg/dL for females. Has history of cancer, other than squamous cell or basal cell carcinoma of the skin that has not been in full remission for at least 5 years prior to Screening. Has a history of infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus. Has any major illness or debility that in the investigator's opinion prohibits the subject from completing the study. Has received any investigational drug within the 90 days prior to Screening. Has a history of hypersensitivity or allergy to alogliptin, other DPP-4 inhibitors, metformin or related compounds. Has used oral or systematically injected glucocorticoids or weight loss drugs prior to 2 months to screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Alogliptin placebo-matching tablets, orally, twice daily and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks. | Drug: Alogliptin Placebo<br>* Alogliptin placebo-matching tablets.<br>Drug: Metformin Placebo<br>* Metformin placebo-matching capsules.<br>|
| Experimental: Alogliptin 25 QD<br>Alogliptin 25 mg, tablets, orally, once daily (QD) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Metformin Placebo<br>* Metformin placebo-matching capsules.<br>|
| Experimental: Alogliptin 12.5 BID<br>Alogliptin 12.5 mg, tablets, orally, twice daily (BID) and Metformin placebo-matching capsules, orally, twice daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Metformin Placebo<br>* Metformin placebo-matching capsules.<br>|
| Active Comparator: Metformin 500 BID<br>Alogliptin placebo-matching tablets, orally, twice daily and Metformin 500 mg capsules, orally, twice daily for up to 26 weeks. | Drug: Metformin<br>* Metformin capsules<br>* Other names: Diaformin;Drug: Alogliptin Placebo<br>* Alogliptin placebo-matching tablets.<br>|
| Active Comparator: Metformin 1000 BID<br>Alogliptin placebo-matching tablets, orally, twice daily and Metformin 1000 mg capsules, orally, twice daily for up to 26 weeks. | Drug: Metformin<br>* Metformin capsules<br>* Other names: Diaformin;Drug: Alogliptin Placebo<br>* Alogliptin placebo-matching tablets.<br>|
| Experimental: Alogliptin 12.5 BID + Metformin 500 BID<br>Alogliptin 12.5mg, tablets, orally, twice daily and Metformin 500 mg, capsules, orally, twice daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Metformin<br>* Metformin capsules<br>* Other names: Diaformin;|
| Experimental: Alogliptin 12.5 BID + Metformin 1000 BID<br>Alogliptin 12.5 mg, tablets, orally, twice daily and Metformin 1000 mg, capsules, orally, twice daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Metformin<br>* Metformin capsules<br>* Other names: Diaformin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26 | The change from Baseline to Week 26 in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound). | Baseline and Week 26. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c Over Time | The change from Baseline in HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) was assessed at Weeks 4, 8, 12, 16 and 20. Least squares means are from an analysis of covariance (ANCOVA) model with treatment and geographic region as fixed effects, and baseline HbA1c as a covariate. | Baseline and Weeks 4, 8, 12, 16, and 20. | 
| Change From Baseline in Fasting Plasma Glucose Over Time | The change from Baseline in fasting plasma glucose was assessed at Weeks 1, 2, 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as fixed effects, and baseline fasting plasma glucose as a covariate. | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 Diabetes mellitus, Non-insulin dependent diabetes mellitus, Drug Therapy, Hypoglycemia,, Hyperglycemia