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

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”

The purpose of this study is to compare the efficacy of Alogliptin, once daily (QD), taken by itself and with pioglitazone on lipid measures in type 2 diabetes subjects after eating.

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 healthcare system. A recent review of results from 2 National Health and Nutritional Examination surveys conducted in the United States found that, despite the introduction of new classes of medications for glycemic control, the percentage of adults with diabetes mellitus achieving a glycosylated hemoglobin level of less than 7% (a goal set by the American Diabetes Association) has remained relatively unchanged when data from 1999 to 2000 were compared from data from 1988 to 1994. This percentage has remained high, despite compelling evidence from a United Kingdom Prospective Diabetes Study showing that a dramatic reduction in microvascular complications and cardiovascular complications occurred when the glycosylated hemoglobin target level was indeed achieved. The rising incidence of type 2 diabetes mellitus and the limitations of the currently available treatments suggest the need for new therapies for glycemic control.

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 subjects 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.

Intervention(s) in this Clinical Trial

• Drug: Alogliptin and Pioglitazone
  • Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 16 weeks.
• Drug: Alogliptin
  • Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 16 weeks.
• Drug: Pioglitazone
  • Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 16 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Alogliptin 25 mg QD + Pioglitazone 30 mg QD
• Experimental: Alogliptin 25 mg QD
• Active Comparator: Pioglitazone 30 mg QD

Primary Measures

• Change in postprandial incremental area under the curve for triglycerides.
  • Time Frame: Week 16 or Final Visit
    Safety Issue?: No

Secondary Measures

• Postprandial incremental area under the curve changes for triglycerides.
  • Time Frame: Week 4
    Safety Issue?: No
• Postprandial incremental area under the curve changes for lipid parameters.
  • Time Frame: Weeks: 4, 8 and 16 or Final Visit
    Safety Issue?: No
• Postprandial incremental area under the curve changes for lipoprotein parameters.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Postprandial changes over time in glucagon-like peptide-1, glucose, insulin, and glucagon.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Fasting plasma glucose.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• C-peptide.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• High-sensitive C-reactive protein.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Adiponectin.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Glycosylated hemoglobin.
  • Time Frame: Weeks: 8 and 16 or Final Visit
    Safety Issue?: No
• Insulin.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Proinsulin.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Anti-Vascular Cell Adhesion Molecule.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Anti-Intercellular Adhesion Molecule.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• e-Selectin.
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No
• Endothelial function (pulse wave tonometry).
  • Time Frame: Weeks: 4 and 16 or Final Visit
    Safety Issue?: No

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.
• Excluded Medications:
• Treatment with any antidiabetic agent other than metformin, sulfonylurea, nateglinide, or repaglinide is not allowed within 3 months prior to Screening through the completion of the end-of-treatment/early termination procedures.
• Treatment with a statin and/or ezetimibe therapy will be allowed during the course of the study provided the subject has been on a stable dose for at least three months and remains on a stable dose and the therapy is not changed during the study.
• Treatment with any weight loss drugs, any investigational antidiabetic, lipid-lowering agents (other than statins and/or ezetimibe), or oral or systemically injected glucocorticoids is not allowed for 3 months prior to randomization through the completion of the end-of-treatment/early termination procedures.
• Subjects must not take any medications, even over-the-counter medications, without first consulting with the investigator.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Takeda Global Research & Development Centre (Europe) Ltd. Industry

Overall Clinical Trial Officials and Contacts

Medical Director Study Director Takeda Global Research & Development Centre (Europe) Ltd.  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00655863

Study ID Number: SYR-322_301

ClinicalTrials.gov Identifier: NCT00655863

Health Authority: United States: Food and Drug Administration

ACTOS Package Insert.

FDA Safety Alerts and Recalls