Efficacy and Safety of Alogliptin Compared to Glipizide in Elderly Diabetics

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of alogliptin, once daily (QD), compared to glipizide in elderly diabetic patients who have not received treatment or are on a single oral medication.

Detailed Description
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Type 2 diabetes is among the most common chronic condition in adults 65 years of age or older. A recent National Health and Nutrition Examination Survey reported that more than 20% of adults aged 65 years or older have diabetes. These individuals are often under-treated with respect to glucose-lowering medications, and their care is complicated by the extent of their clinical and functional status. Age-related changes in physiology, diabetes-associated illnesses and other illnesses (such as renal, cardiac, and hepatic insufficiency), as well as use of multiple medications make standard oral anti-hyperglycemic therapy and insulin use problematic. In addition, hypoglycemia is more common and severe in older rather than younger patients taking oral antidiabetic drugs which can precipitate serious events such as falls and hip fractures. While avoidance of hypoglycemia is paramount in elderly diabetic patients, many commonly used medications are associated with a substantial risk for hypoglycemia. New classes of drug which avoid such complications in the elderly population are of increasing interest as this population continues to expand. Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes. This study will compare the effectiveness and safety of alogliptin with that of glipizide (a commonly used diabetes medication) in adults who are 65 to 90 years of age with Type 2 diabetes. Individuals who participate in this study will either have failed diet and exercise therapy alone during the 2 months before Screening, or will have been receiving a single oral antidiabetic medication without obtaining good blood glucose (sugar) control. Each participant will be required to commit to screening visits. Study participation is anticipated to be up to 59 weeks.

Official Title
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A Multicenter, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Alogliptin Compared to Glipizide in Elderly Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Alogliptin
* Drug: Glipizide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of type 2 diabetes mellitus with either: Failed diet and exercise therapy alone as demonstrated by inadequate glycemic control while receiving no antidiabetic treatment within the two months prior to Screening, or Failed treatment with oral monotherapy alone (may include treatment with two or more antidiabetic agents if for less than 7 days) as demonstrated by inadequate glycemic control within the two months prior to Screening. Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2. If 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 who are sexually active must agree to use a medically accepted means of contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. Able and willing to monitor their own blood glucose concentrations with a home glucose monitor. No major illness or debility that in the investigator's opinion prohibits the participant from completing the study. Exclusion Criteria: Systolic blood pressure greater than or equal to 160 mm Hg and/or diastolic pressure greater than or equal to 100 mm Hg. Hemoglobin less than or equal to 12 g/dL for males or less than or equal to 10 g/dL for females. Alanine aminotransferase greater than or equal to 3 times the upper limit of normal. Calculated creatinine clearance less than or equal to 50 mL/min. Thyroid-stimulating hormone level outside of the normal range. 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 the 6 months prior to Screening. History of treated diabetic gastroparesis, gastric banding, or gastric bypass surgery. New York Heart Association Class III or IV heart failure regardless of therapy. History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening. History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin. History of infection with Human Immunodeficiency Virus. History of a psychiatric disorder that will affect the 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. History of alcohol or substance abuse within the 2 years prior to Screening. History of treatment with any weight-loss drugs or oral or systemically injected glucocorticoids within the 3 months prior to Screening. Receipt of any investigational drug within the 30 days prior to Screening. Prior treatment in an investigational study of alogliptin. Clinically significant medical abnormality or disease or clinically significant abnormal findings at Screening (other than type 2 diabetes) that, in the opinion of the investigator, should exclude the participant from the study. Has donated more than 400 mL of blood within the 90 days preceding their participation in the study. Has hypersensitivity or has had an anaphylactic reaction(s) to any DPP-4 inhibitor drug.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 90 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alogliptin 25 mg QD<br> | Drug: Alogliptin<br>* Alogliptin 25 mg, tablets, orally, once daily and glipizide placebo matching tablets, orally, once daily for up to 52 weeks.<br>* Other names: SYR-322;|
| Active Comparator: Glipizide 5 mg QD<br> | Drug: Glipizide<br>* Alogliptin placebo-matching tablets, orally, once daily and glipizide 5 mg to 10 mg, tablets, orally, once daily up to 52 weeks.<br>* Other names: Glucotrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin at Week 52. | The change in the percentage of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 52 or final visit and glycosylated hemoglobin collected at baseline. | Baseline and Week 52. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 including final visit relative to baseline. | Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 26, Week 34 and Week 42. | 
| Incidence of Hypoglycemia | Percentage of participants with at least one hypoglycemic episode during 52 week study. | On occurrence (up to 52 weeks). | 
| Incidence of Marked Hyperglycemia (Fasting Plasma Glucose ≥200 mg Per dL). | The number of participants with a fasting plasma glucose value ≥ to 200 mg per dL during the 52 week study. | On Occurrence (up to 52 weeks). | 
| Incidence of Hyperglycemic Rescue | The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 52 week study. | On Occurrence (up to 52 weeks). | 
| Change From Baseline in Fasting Plasma Glucose | The change in the value of fasting plasma glucose collected at each week indicated including final visit relative to baseline. | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 26, Week 34, Week 42 and Week 52. | 
| Change From Baseline in 2-hour Postprandial Glucose | The change in postprandial (after eating a meal) glucose levels at week 52 relative to baseline. Standard 2-hour postprandial glucose (PPG) tests performed following an overnight fast and evaluated right before and after a 120-minute (2-hour) timeframe relative to ingestion of a standard oral glucose drink. | Baseline and Week 52. | 
| Change From Baseline in Fasting Proinsulin | The change between the value of fasting proinsulin collected at each week indicated including final visit relative to baseline. | Baseline, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Insulin | The change between the value of insulin collected at each week indicated including final visit relative to baseline. | Baseline, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Proinsulin/Insulin Ratio | The change between the ratio value of proinsulin and insulin collected at each week indicated including final visit relative to baseline. | Baseline, Week 12, Week 26, Week 42 and Week 52. | 
| Homeostasis Model Assessment of Beta Cell Function | The change between homeostasis model assessment of beta cell function collected at each week indicated including final visit relative to baseline. Homeostasis model assessment of beta cell function measures beta cell function, calculated by a constant (20) times insulin, divided by fasting plasma glucose minus a constant (3.5). | Baseline, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Body Weight | The change in body weight measured at each week indicated including final visit from baseline. | Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Serum Lipids (Total Cholesterol) | The change in total cholesterol measured at each week indicated including final visit from baseline. | Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Serum Lipids (High-Density Lipoprotein Cholesterol) | The change in high-density lipoprotein cholesterol measured at each week indicated including final visit from baseline. | Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Serum Lipids (Low-Density Lipoprotein Cholesterol) | The change in low-density lipoprotein cholesterol measured at each week indicated including final visit from baseline. | Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in Serum Lipids (Triglycerides) | The change in triglycerides measured at each week indicated including final visit from baseline. | Baseline, Week 8, Week 12, Week 26, Week 42 and Week 52. | 
| Change From Baseline in High Sensitivity C-reactive Protein | The change between the high sensitivity C-reactive protein value collected at each week indicated including final visit from baseline. | Baseline, Week 12, Week 26, Week 42 and Week 52. | 
| Incidence of Subjects Achieving Glycosylated Hemoglobin <=7% | The percentage of participants with a value for the percentage of glycosylated hemoglobin (HbA1c; the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5 and 7.0% during the 52 week study. | Baseline and Week 52. | 
| Incidence of Glycosylated Hemoglobin Decrease From Baseline. | The percentage of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 0.5, 1.0, 1.5 and 2.0% during the 52 week study. | Baseline and Week 52. | 

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