Efficacy of Alogliptin With Pioglitazone (Actos®) in Subjects With Type 2 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the combination of alogliptin, once daily (QD), and pioglitazone in patients with type 2 diabetes mellitus who are inadequately controlled with diet and exercise alone.

Detailed Description
-----------------
There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% is 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, placing an ever-increasing burden on families and the health care system. Current pharmacologic interventions for type 2 diabetes mellitus include a diverse range of antidiabetic medications with different mechanisms of action including insulin and insulin analogues, sulfonylureas, metformin, meglitinides, thiazolidinediones, inhibitors of alpha- glucosidase, analogs of glucagon-like peptide-1, and synthetic analogues of human amylin. Despite the variety of medications, many have clinically important or potentially life-threatening side effects, restricted use in many subpopulations, concerns with long-term tolerability, and challenges related to compliance due to side effects and route of administration. All of these reasons contribute to the difficulties patients have reaching the target glycosylated hemoglobin level less than 7%. SYR-322 (alogliptin) is a selective, orally available inhibitor of the dipeptidyl peptidase-4 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. Pioglitazone (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan) that is approved for the treatment of type 2 diabetes mellitus. Pioglitazone is a selective peroxisome proliferator-activated receptor-gamma agonist that decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. As the rate of newly diagnosed cases of type 2 diabetes mellitus continues to grow, so does the need for products that will provide better glycemic control and improved safety and tolerability. Alogliptin and pioglitazone have complementary actions. Alogliptin inhibits the degradation of glucagon-like peptide-1 by inhibiting the enzyme dipeptidyl peptidase IV, thus augmenting glucose-dependent insulin secretion while pioglitazone is a peripheral and hepatic insulin sensitizer. Given the complementary mechanisms of action of alogliptin (stimulates insulin secretion) and pioglitazone (enhances insulin sensitivity), the addition of combination therapy in treatment naïve type 2 diabetes patients may potentially allow the patients to reach and maintain their glycosylated hemoglobin goal more effectively. The aim of this study is to evaluate the effectiveness of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on diet and exercise alone. Study participation is anticipated to be approximately 8.5 months.

Official Title
-----------------
A Multicenter, Double-Blind Study to Determine the Efficacy and Safety of SYR-322 Plus Pioglitazone HCl (Actos®), SYR-322 Alone or Pioglitazone HCl Alone in Subjects With Type 2 Diabetes

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Historical diagnosis of type 2 diabetes. Failed treatment with diet and exercise for at least 2 months prior to Screening. Is experiencing inadequate glycemic control as defined as glycosylated hemoglobin concentration between 7.5-11%, inclusive. Has received any antidiabetic therapy for less than 7 days within 3 months prior to Screening. Has a body mass index greater than or equal to 23 kg/m2 and less than or equal to45 kg/m2. Fasting C-peptide greater than or equal to 0.8 ng per mL. Regular use of other, non-excluded medications is allowed if participant is on a stable dose for at least 4 weeks prior to Screening. 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. Must be willing and able to monitor their blood concentrations with a home glucose monitor. Exclusion Criteria Systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure greater than or equal to 100 mmHg. Hemoglobin less than or equal to 12 g per dL for males and less than or equal to 10 g per dL for females. Alanine aminotransferase greater than or equal to 2.5times the upper limit of normal. Serum creatinine greater than 2.0 mg per dL. Thyroid stimulating hormone level greater than the upper limit of normal range. Major illness or debility that in the investigator's opinion prohibits the subject from completing the study. Urine albumin to creatinine ratio of greater than 1000 ug per mg at Screening. If elevated, the subject may be rescreened within 1 week. 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 History of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening. History of gastroparesis. Has New York Heart Association Class I to IV heart failure regardless of therapy. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening. History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin. History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. History of a psychiatric disorder that will affect participant's ability to participate in the study. History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors. Any alteration in angiotensin-II receptor inhibitors within 2 months prior to Randomization, if applicable. History of alcohol (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within 2 years prior to Screening. Received any investigational drug within 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within 3 months prior to Screening. Previously participated in an investigational study of SYR-322. Glycosylated hemoglobin concentration between 7.5-11%, inclusive, and a fasting plasma glucose less than 310 mg per dL. At least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period.

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 |
| --- | --- |
| Experimental: Alogliptin 25 mg QD<br>Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Placebo<br>* Matching placebo tablets.<br>|
| Active Comparator: Pioglitazone 30 mg QD<br>Pioglitazone 30 mg, tablets, orally, once daily and alogliptin placebo-matching tablets, orally, once daily for up to 26 weeks. | Drug: Pioglitazone<br>* Pioglitazone tablets.<br>* Other names: AD4833;Drug: Placebo<br>* Matching placebo tablets.<br>|
| Experimental: Alogliptin 25 mg QD+ Pioglitazone 30 mg QD<br>Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Pioglitazone<br>* Pioglitazone tablets.<br>* Other names: AD4833;|
| Active Comparator: Alogliptin 12.5 mg QD + Pioglitazone 30 mg QD<br>Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks. | Drug: Alogliptin<br>* Alogliptin tablets.<br>* Other names: SYR-322;Drug: Pioglitazone<br>* Pioglitazone tablets.<br>* Other names: AD4833;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in Glycosylated Hemoglobin (HbA1c) | 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) at 4 week intervals during the study. Least Squares Means were from an Analysis of Covariance (ANCOVA) model with treatment and geographic region as class variables 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 class variables and baseline plasma glucose as a covariate. | Baseline and Weeks 1, 2, 4, 8, 12, 16, 20 and 26. | 
| Percentage of Participants With Marked Hyperglycemia | Marked Hyperglycemia is defined as fasting plasma glucose greater than or equal to 200 mg/dL. Study week windows are defined to place hyperglycemia into visit categories. | Weeks 1, 2, 4, 8, 12, 16, 20 and 26. | 
| Percentage of Participants Meeting Rescue Criteria | Rescue was defined as meeting 1 of the following criteria, confirmed by a 2nd sample drawn within 5 days after the first sample and analyzed by the central laboratory: After more than 4 weeks of treatment but prior to the Week 8 Visit: a single fasting plasma glucose ≥310 mg/dL (≥17.5 mmol/L); From the Week 8 Visit but prior to the Week 12 Visit: a single fasting plasma glucose ≥275 mg/dL (≥15.27 mmol/L); From the Week 12 Visit through the End-of-Treatment Visit: HbA1c ≥8.5% and ≤0.5% reduction in HbA1c as compared with the Baseline HbA1c. | Weeks 4, 8, 12, 16, 20 and 26. | 
| Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 6.5% | Clinical response at Week 26 was assessed by the percentage of participants with HbA1c ≤6.5%. | Week 26 | 
| Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.0% | Clinical response at Week 26 was assessed by the percentage of participants with HbA1c ≤ 7%. | Week 26 | 
| Percentage of Participants With Glycosylated Hemoglobin Less Than or Equal to 7.5% | Clinical response at Week 26 was assessed by the percentage of participants with HbA1c ≤ 7.5%. | Week 26 | 
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 0.5% | Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of ≥ 0.5%. | Baseline and Week 26 | 
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 1.0% | Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of ≥ 1%. | Baseline and Week 26 | 
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 1.5%. | Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of ≥ 1.5%. | Baseline and Week 26 | 
| Percentage of Participants With a Decrease in Glycosylated Hemoglobin Greater Than or Equal to 2.0% | Clinical response at Week 26 was assessed by the percentage of participants with a decrease from Baseline in HbA1c of ≥ 2.0%. | Baseline and Week 26 | 
| Change From Baseline in Fasting Proinsulin | Proinsulin is a precursor to insulin, and was measured as an indicator of pancreatic function. The change from Baseline in fasting proinsulin was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as class variables and baseline proinsulin as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Insulin | The change from Baseline in fasting insulin was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least Squares Means were from an ANCOVA model with treatment and geographic region as class variables and baseline insulin as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Proinsulin/Insulin Ratio | The ratio of proinsulin to insulin was calculated as proinsulin (pmol/L) / insulin (μIU/mL) at weeks 4, 8, 12, 16, 20 and 26 relative to the Baseline value. Least squares means were from an ANCOVA model with treatment and geographic region as class variables and Baseline proinsulin/insulin ratio as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in C-peptide Levels | C-peptide is a byproduct created when the hormone insulin is produced and is measured by a blood test. Change from Baseline was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline C-peptide as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Calculated Homeostatic Model Assessment Insulin Resistance | The Homeostasis Model Assessment of insulin resistance (HOMA IR) measures insulin resistance based on fasting glucose and insulin measurements: HOMA IR = fasting plasma insulin (µIU/mL) * fasting plasma glucose (mmol/L) / 22.5 A higher number indicates a greater degree of insulin resistance. The change from Baseline in HOMA IR was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline HOMA IR as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Homeostatic Model Assessment Beta Cell Function | The Homeostasis Model Assessment (HOMA) estimates steady state beta cell function (%B) as a percentage of a normal reference population. HOMA %B = 20 * insulin (µIU/mL) / fasting plasma glucose (mmol/L) - 3.5 The change from Baseline in the homeostasis model assessment of beta cell function was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline HOMA beta cell function as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Body Weight | Change from Baseline in body weight was assessed at Weeks 8, 12, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and Baseline weight as a covariate. | Baseline and Weeks 8, 12, 20 and 26. | 
| Change From Baseline in Total Cholesterol Level | Change from Baseline in total cholesterol level was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline total cholesterol as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Low-Density Lipoprotein Cholesterol | Change from Baseline in low-density lipoprotein cholesterol (LDL-C) was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline LDL cholesterol as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in High-Density Lipoprotein Cholesterol | Change from Baseline in high-density lipoprotein cholesterol (HDL-C) was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline HDL cholesterol as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Triglyceride Levels | Change from Baseline in triglycerides was assessed at Weeks 4, 8, 12, 16, 20 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline triglycerides as a covariate. | Baseline and Weeks 4, 8, 12, 16, 20 and 26. | 
| Change From Baseline in Free Fatty Acids | Change from Baseline in free fatty acids (FFA) was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline free fatty acid as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Plasminogen Activator Inhibitor-1 | Change from Baseline in plasminogen activator inhibitor-1 was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline plasminogen activator inhibitor-1 as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in High-sensitivity C-Reactive Protein | Change from Baseline in high-sensitivity C-Reactive Protein (hsCRP) was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline hsCRP as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Adiponectin | Change from Baseline in adiponectin was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline adiponectin as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Apolipoprotein A1 | Change from Baseline in Apolipoprotein A1 was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and Baseline apolipoprotein A1 as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Apolipoprotein A2 | Change from Baseline in apolipoprotein A2 was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline apolipoprotein A2 as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Apolipoprotein B | Change from Baseline in apolipoprotein B was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline apolipoprotein B as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Apolipoprotein C-III | Change from Baseline in apolipoprotein C-III was assessed at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline apolipoprotein C-III as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Nuclear Magnetic Resonance Lipid Fractionation Total Triglycerides | Nuclear Magnetic Resonance (NMR) lipid fractionation was used to assess the change from Baseline in total triglyceride levels at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline NMR total triglycerides as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Very Low Density Lipoprotein (VLDL) / Chylomicron Particles | The change from Baseline in levels of total VLDL/chylomicron particles and large VLDL/chylomicron particles was assessed by NMR lipid fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline VLDL/chylomicron particles as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in VLDL / Chylomicron Triglycerides | The change from Baseline in levels of VLDL/chylomicron triglycerides was assessed by NMR lipid fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline VLDL/chylomicron triglycerides as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in VLDL Particles | The change from Baseline in levels of medium VLDL particles and small VLDL particles was assessed by NMR fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline VLDL particles as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Mean VLDL Particle Size | Change from Baseline in mean VLDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline mean VLDL particle size as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Intermediate Density Lipoprotein (IDL) Particles | The change from Baseline in levels of IDL particles was assessed by NMR fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline IDL particles as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Low Density Lipoprotein (LDL) Particles | The change from Baseline in levels of total, large, medium-small, total small and very small LDL particles was assessed by NMR fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline LDL particles as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Mean LDL Particle Size | Change from Baseline in mean LDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline mean LDL particle size as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in High Density Lipoprotein (HDL) Particles | The change from Baseline in levels of total, large, medium and small HDL particles was assessed by NMR fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline HDL particles as a covariate. | Baseline and Weeks 12 and 26. | 
| Change From Baseline in Mean HDL Particle Size | Change from Baseline in mean HDL particle size was assessed by NMR lipid fractionation at Weeks 12 and 26. Least squares means are from an ANCOVA model with treatment and geographic region as class variables and baseline mean HDL particle size as a covariate. | Baseline and Weeks 12 and 26. | 

 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