Efficacy and Safety of Alogliptin in Subjects With Type 2 Diabetes

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), in adults with type 2 diabetes.

Detailed Description
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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. 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. The aim of the current study is to evaluate the efficacy of alogliptin in subjects with type 2 diabetes mellitus who are inadequately controlled and who have failed treatment with diet and exercise. Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) Compared With Placebo in Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Type 2 diabetes mellitus, experiencing inadequate glycemic control, and are receiving no current antidiabetic therapy. Subjects will qualify if both of the following conditions apply: Subject has failed treatment with diet and exercise for at least one month prior to Screening Subject has received less than 7 days of any antidiabetic therapy within the 3 months prior to Screening Diagnosis of type 2 diabetes must be based on current American Diabetes Association criteria. Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2 Fasting C-peptide concentration greater than or equal to 0.8 ng per mL (greater than or equal to 0.26 nmol per L). (If this screening criterion is not met, the subject still qualifies if C-peptide greater than or equal to1.5 ng per mL (greater than or equal to 0.50 nmol per L) after a challenge test. Glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive If regular use of other, non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, as needed use of prescription or over-the-counter medications is allowed at the discretion of the investigator. Systolic blood pressure less than or equal to 180 mm Hg and diastolic pressure less than or equal to 110 mm Hg Hemoglobin greater than or equal to 12 g per dL (greater than or equal to 120 gm per L) for males and greater than or equal to 10 g per dL (greater than or equal to 100 gm per L) for females Alanine aminotransferase less than or equal to 3 times the upper limit of normal Serum creatinine less than or equal to 2.0 mg per dL (less than or equal to 17 micromol per L) Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the subject is clinically euthyroid Neither pregnant (confirmed by laboratory testing in females of childbearing potential) nor lactating. Female subjects of childbearing potential must be practicing adequate contraception. Adequate contraception must be practiced for the duration of participation in 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 subject from completing the study. Able and willing to provide written informed consent. Exclusion Criteria Urine albumin to creatinine ratio of greater than1000 μg per mg (greater than 113 mg per mol) 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. (A history of treated cervical intraepithelial neoplasia 1 or cervical intraepithelial neoplasia 2 is allowed). History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening. History of treated diabetic gastric paresis. New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated subjects who are stable at Class I or II are candidates for the study. 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 hepatitis B, hepatitis C, or human immunodeficiency virus. History of a psychiatric disorder that will affect the subject'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. Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening. Prior treatment in an investigational study of alogliptin. Excluded Medications Treatment with antidiabetic agents (other than study drug following enrollment in the study) is not allowed within the 3 months prior to Screening and through the completion of the end-of-treatment/early termination procedures. (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.) Treatment with weight-loss drugs, any investigational antidiabetics, or oral or systemically injected glucocorticoids is not allowed from 3 months prior to randomization through the completion of the end-of-treatment/early termination procedures. Inhaled corticosteroids are allowed. Subjects are not to take any medications, including over-the-counter products, without first consulting with the Study Doctor.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 12.5 mg QD<br> | Drug: Alogliptin<br>* Alogliptin 12.5 mg, tablets, orally, once daily for up to 26 weeks.<br>* Other names: SYR-322;|
| Experimental: Alogliptin 25 mg QD<br> | Drug: Alogliptin<br>* Alogliptin 25 mg, tablets, orally, once daily for up to 26 weeks.<br>* Other names: SYR-322;|
| Placebo Comparator: Placebo QD<br> | Drug: Placebo<br>* Alogliptin placebo-matching tablets, orally, once daily for up to 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26. | 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 week 26 or final visit and glycosylated hemoglobin collected at baseline. | Baseline and Week 26. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (Week 4). | 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 week 4 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Glycosylated Hemoglobin (Week 8). | 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 week 8 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Glycosylated Hemoglobin (Week 12). | 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 week 12 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Glycosylated Hemoglobin (Week 16). | 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 week 16 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Glycosylated Hemoglobin (Week 20). | 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 week 20 and Glycosylated Hemoglobin collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Fasting Plasma Glucose (Week 1). | The change between the value of fasting plasma glucose collected at final visit or week 1 and fasting plasma glucose collected at baseline. | Baseline and Week 1. | 
| Change From Baseline in Fasting Plasma Glucose (Week 2). | The change between the value of fasting plasma glucose collected at week 2 and fasting plasma glucose collected at baseline. | Baseline and Week 2. | 
| Change From Baseline in Fasting Plasma Glucose (Week 4). | The change between the value of fasting plasma glucose collected at week 4 and fasting plasma glucose collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Fasting Plasma Glucose (Week 8). | The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Fasting Plasma Glucose (Week 12). | The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Fasting Plasma Glucose (Week 16). | The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Fasting Plasma Glucose (Week 20). | The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Fasting Plasma Glucose (Week 26). | The change between the value of fasting plasma glucose collected at week 26 or final visit and fasting plasma glucose collected at baseline. | Baseline and Week 26. | 
| Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL). | The number of participants with a fasting plasma glucose value greater than or equal to 200 mg per dL at any measurement time point during the 26 week study. | 26 Weeks. | 
| Number of Participants Requiring Rescue. | The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 26 week study. | 26 Weeks. | 
| Change From Baseline in Fasting Proinsulin (Week 4). | The change between the value of fasting proinsulin collected at week 4 and fasting proinsulin collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Fasting Proinsulin (Week 8). | The change between the value of fasting proinsulin collected at week 8 and fasting proinsulin collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Fasting Proinsulin (Week 12). | The change between the value of fasting proinsulin collected at week 12 and fasting proinsulin collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Fasting Proinsulin (Week 16). | The change between the value of fasting proinsulin collected at week 16 and fasting proinsulin collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Fasting Proinsulin (Week 20). | The change between the value of fasting proinsulin collected at week 20 and fasting proinsulin collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Fasting Proinsulin (Week 26). | The change between the value of fasting proinsulin collected at week 26 or final visit and fasting proinsulin collected at baseline. | Baseline and Week 26. | 
| Change From Baseline in Insulin (Week 4). | The change between the value of insulin collected at week 4 and insulin collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Insulin (Week 8). | The change between the value of insulin collected at week 8 and insulin collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Insulin (Week 12). | The change between the value of insulin collected at week 12 and insulin collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Insulin (Week 16). | The change between the value of insulin collected at week 16 and insulin collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Insulin (Week 20). | The change between the value of insulin collected at week 20 and insulin collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Insulin (Week 26). | The change between the value of insulin collected at week 26 and insulin collected at baseline. | Baseline and Week 26. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 4). | The change between the ratio value of proinsulin and insulin collected at week 4 and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 8). | The change between the ratio value of proinsulin and insulin collected at week 8 and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 12). | The change between the ratio value of proinsulin and insulin collected at week 12 and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 16). | The change between the ratio value of proinsulin and insulin collected at week 16 and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 20). | The change between the ratio value of proinsulin and insulin collected at week 20 and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Proinsulin/Insulin Ratio (Week 26). | The change between the ratio value of proinsulin and insulin collected at week 26 or final visit and the ratio value of proinsulin and insulin collected at baseline. | Baseline and Week 26. | 
| Change From Baseline in C-peptide (Week 4). | The change between the value of C-peptide collected at week 4 and C-peptide collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in C-peptide (Week 8). | The change between the value of C-peptide collected at week 8 and C-peptide collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in C-peptide (Week 12). | The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in C-peptide (Week 16). | The change between the value of C-peptide collected at week 16 and C-peptide collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in C-peptide (Week 20). | The change between the value of C-peptide collected at week 20 and C-peptide collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in C-peptide (Week 26). | The change between the value of C-peptide collected at week 26 or final visit and C-peptide collected at baseline. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin ≤ 6.5%. | The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin ≤ 7.0%. | The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.0% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin ≤ 7.5%. | The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.5% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%. | The number 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% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%. | The number 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 1.0% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%. | The number 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 1.5% during the 26 week study. | Baseline and Week 26. | 
| Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%. | The number 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 2.0% during the 26 week study. | Baseline and Week 26. | 
| Change From Baseline in Body Weight (Week 8). | The change between Body Weight measured at week 8 and Body Weight measured at baseline. | Baseline and Week 8. | 
| Change From Baseline in Body Weight (Week 12). | The change between Body Weight measured at week 12 and Body Weight measured at baseline. | Baseline and Week 12. | 
| Change From Baseline in Body Weight (Week 20). | The change between Body Weight measured at week 20 and Body Weight measured at baseline. | Baseline and Week 20. | 
| Change From Baseline in Body Weight (Week 26). | The change between Body Weight measured at week 26 or final visit and Body Weight measured at baseline. | Baseline and Week 26. | 
| Change From Baseline in Glucagon (Week 4). | The change between the value of glucagon collected at week 4 and glucagon collected at baseline. | Baseline and Week 4. | 
| Change From Baseline in Glucagon (Week 8). | The change between the value of glucagon collected at week 8 and glucagon collected at baseline. | Baseline and Week 8. | 
| Change From Baseline in Glucagon (Week 12). | The change between the value of glucagon collected at week 12 and glucagon collected at baseline. | Baseline and Week 12. | 
| Change From Baseline in Glucagon (Week 16). | The change between the value of glucagon collected at week 16 and glucagon collected at baseline. | Baseline and Week 16. | 
| Change From Baseline in Glucagon (Week 20). | The change between the value of glucagon collected at week 20 and glucagon collected at baseline. | Baseline and Week 20. | 
| Change From Baseline in Glucagon (Week 26). | The change between the value of glucagon collected at week 26 or final visit and glucagon collected at baseline. | Baseline and Week 26. | 

 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