Efficacy of Alogliptin and With Pioglitazone in Patients With Type 2 Diabetes.

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the efficacy of Alogliptin, once daily (QD), taken by itself and with pioglitazone on postprandial lipid measures in type 2 diabetes.

Detailed Description
-----------------
SYR-322 (alogliptin) is a selective, orally available inhibitor of dipeptidyl peptidase IV being developed as a treatment for type 2 diabetes mellitus. Dipeptidyl peptidase IV is the primary enzyme involved in the in vivo degradation of at least 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan). Pioglitazone HCl depends on the presence of insulin for its mechanism of action. This study will assess the effects of alogliptin and alogliptin coadministered with pioglitazone HCl on postprandial lipid and lipoprotein metabolism in participants with type 2 diabetes. Individuals who participate in this study will be required to commit to a screening visit and up to 6 additional visits at the study center. Study participation is anticipated to be about 20 weeks (or approximately 5 months). Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations and electrocardiograms. At 3 of the visits a meal will be served that must be eaten within 10 minutes.

Official Title
-----------------
Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing SYR-322 Alone and Combination SYR-322 With Pioglitazone Versus Placebo on Postprandial Lipids in Subjects With Type 2 Diabetes

Conditions
-----------------
Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Alogliptin and Pioglitazone
* Drug: Alogliptin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Diagnosis of type 2 diabetes Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. Either failed treatment with diet and exercise for 3 months prior to Screening or has been receiving a stable dose of metformin, sulfonylurea, nateglinide, or repaglinide for more than 3 months prior to Screening. Inadequate glycemic control as defined by glycosylated hemoglobin concentration between 6.5 and 9.0%, inclusive. Fasting plasma glucose less than 13.3 mmol per L. Fasting serum triglyceride level of 1.7 to 5.0 mmol per L, inclusive. Has not been receiving any lipid-lowering therapy within 3 months prior to Screening or on a stable statin and/or ezetimibe therapy (same drug and dose) for at least 3 months. Body mass index greater than 23 kg/m2 and less than 45 kg/m2. If has regular use of other, non-excluded medications, must be on a stable dose for at least 4 weeks prior to Screening. Use of as needed prescription medications and over-the-counter medications is allowed at the discretion of the investigator. Is to be Apolipoprotein E 3/3 or Apolipoprotein E 3/4 phenotype positive prior to baseline. Exclusion Criteria History of type 1 diabetes. History of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years. Diastolic blood pressure greater than 100 mm Hg or a systolic blood pressure of greater than 160 mm Hg. History of cancer, other than basal cell carcinoma, that has not been in remission for at least 5 years prior to the first dose of study medication. Hemoglobin less than 120 g per L for males and less than100 g per L for females. Alanine transaminase level greater than 2.5 times the upper limit of normal, active liver disease, or jaundice. Serum creatinine level greater than 133 μmol per L. Fasting total cholesterol greater than 6.5 mmol per L. New York Heart Association heart failure of any Class (I-IV) regardless of therapy. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening. History of acute metabolic diabetic complications. History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin. History of infection with human immunodeficiency virus. History of diabetic gastro paresis. History of gastric bypass surgery.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 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 QD<br> | Drug: Placebo<br>* Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 16 weeks.<br>* Other names: SYR-322;|
| Experimental: Alogliptin 25 mg QD<br> | Drug: Alogliptin<br>* Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 16 weeks.<br>* Other names: SYR-322;|
| Experimental: Alogliptin 25 mg QD + Pioglitazone 30 mg QD<br> | Drug: Alogliptin and Pioglitazone<br>* Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 16 weeks.<br>* Other names: SYR-322;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Postprandial Incremental Area Under the Curve for Total Triglycerides at Week 16. | The change in postprandial (after eating a meal) incremental area under the plasma concentration-time curve from 0 to 8 hours (AUC (0-8h)) postdose at week 16 relative to baseline. | Baseline and Week 16. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Postprandial Incremental Area Under the Curve for Total Triglycerides at Week 4. | The change in postprandial incremental area under the plasma concentration-time curve from 0 to 8 hours (AUC(0-8h)) postdose at week 4 relative to baseline. | Baseline and Week 4. | 
| Change From Baseline in Postprandial Incremental Area Under the Curve Changes for Lipid Parameters. | The change in postprandial incremental area under the plasma concentration-time curve for very-low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL2 cholesterol, VLDL2 triglycerides, chylomicron cholesterol, chylomicron triglycerides, intermediate-density lipoprotein (IDL) cholesterol, and IDL triglycerides from 0 to 8 hours postdose at week 4 and week 16 relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Postprandial Incremental Area Under the Curve for Lipoprotein Parameters. | Postprandial incremental area under the curve changes for very-low-density lipoprotein (VLDL) Apo B-48, VLDL Apo B 100, VLDL2 Apo B-48, VLDL2 Apo B 100, chylomicron Apo B-48, chylomicron Apo B 100, and intermediate density lipoprotein (IDL) Apo B-48, IDL Apo B 100, and triglyceride-rich remnant (TRR) lipoproteins from 0 to 8 hours postdose at week 4 and week 16 relative to baseline. | Baseline, Week 4 and Week 16. | 
| Postprandial Changes Over Time From Baseline for Glucagon-like Peptide-1 (GLP-1) | Postprandial changes over time at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Postprandial Changes Over Time From Baseline for Glucose | Postprandial changes over time at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Postprandial Changes Over Time From Baseline for Insulin | Postprandial changes over time at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Postprandial Changes Over Time From Baseline for Glucagon | Postprandial changes over time at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Glycosylated Hemoglobin | The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at each week indicated relative to baseline. | Baseline, Week 8 and Week 16. | 
| Change From Baseline in Fasting Plasma Glucose | The change in fasting plasma glucose collected at each week indicated relative to baseline. | Baseline, Week 4, Week 8 and Week 16. | 
| Change From Baseline in Postprandial C-Peptide | The change in postprandial C-peptide collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Postprandial Proinsulin | The change in postprandial proinsulin collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in High-sensitive C-reactive Protein (Hs-CRP) | The change in hs-CRP collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Adiponectin | The change in adiponectin collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Anti-Vascular Cell Adhesion Molecule (VCAM) | The change in VCAM collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Anti-Intercellular Adhesion Molecule (ICAM) | The change in ICAM collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in e-Selectin | The change in e-Selectin collected at each week indicated relative to baseline. | Baseline, Week 4 and Week 16. | 
| Change From Baseline in Endothelial Function Through Pulse Wave Tonometry | Pulse wave tonometry performed before the meal and 2 hours postmeal using one recording consisting of 15 to 20 sequentially recorded radial artery waveforms collected at each assessment. | Baseline and Week 16. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic; Dyslipidemia, Drug Therapy