Efficacy of SYR-322 and Pioglitazone in Subjects With Type 2 Diabetes Mellitus - Full Text View

Sponsor:	Takeda Global Research & Development Center, Inc.
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00432276

Purpose

The purpose of the study is to compare the effect of adding SYR-322 to the ongoing treatment regimen of pioglitazone HCl and metformin in subjects with inadequate glycemic control.

Condition	Intervention	Phase
Diabetes Mellitus	Drug: SYR-322 and pioglitazone and metformin Drug: Pioglitazone and metformin	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Official Title:	A Multicenter, Randomized, Double-Blind Study to Determine the Efficacy and Safety of the Addition of SYR-322 25 mg Versus Dose Titration From 30 mg to 45 mg of Pioglitazone HCl (ACTOS®) in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Control on a Combination of Metformin and 30 mg of Pioglitazone HCl Therapy

Resource links provided by NLM:

MedlinePlus related topics: Diabetes

Drug Information available for: Pioglitazone Pioglitazone hydrochloride Alogliptin Metformin Metformin hydrochloride

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Change from Baseline in Glycosylated Hemoglobin. [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Glycosylated Hemoglobin [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
Fasting Plasma Glucose [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 26, 34, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Proinsulin [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
Insulin [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
Proinsulin/Insulin ratio [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
C-peptide [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
Serum Lipids [ Time Frame: Weeks 4, 8, 12, 16, 20, 34, and 42 or Final Visit. ] [ Designated as safety issue: No ]
Nuclear magnetic resonance Lipid Fractionation [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Free Fatty Acids [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Apolipoprotein A-I [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Apolipoprotein A-II [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Apolipoprotein B [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Apolipoprotein C-III [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Plasminogen activator inhibitor-1 [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
High-sensitivity C-reactive protein [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Adiponectin [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Body weight [ Time Frame: 4, 8, 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in calculated HOMA insulin resistance [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in calculated HOMA beta-cell function [ Time Frame: Weeks 12, 26, 42, and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Marked Hyperglycemia (fasting plasma glucose greater than or equal to 200 mg/dL) (11.10 mmol/L). [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Incidence of Rescue. [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin less than or equal to 6.5% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin less than or equal to 7.0% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin less than or equal to 7.5% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 0.5% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 1.0% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 1.5% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]
Incidence of Glycosylated Hemoglobin decrease from Baseline greater than or equal to 2.0% [ Time Frame: Weeks 26 and 52 or Final Visit. ] [ Designated as safety issue: No ]

Enrollment:	821
Study Start Date:	December 2006
Study Completion Date:	June 2009
Primary Completion Date:	May 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	Drug: SYR-322 and pioglitazone and metformin SYR-322 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, once daily for up to 52 weeks
2: Active Comparator	Drug: Pioglitazone and metformin SYR-322 placebo-matching tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, once daily for up to 52 weeks

Detailed Description:

Despite the introduction of new classes of medications for glycemic control, the percentage of adults with type 2 diabetes mellitus achieving a glycosylated hemoglobin level less than 7.0% ADA recommended glycosylated hemoglobin goal has remained around 37%. The rising incidence of type 2 diabetes mellitus along with limitations of the currently available treatments suggest the need for new therapies for glycemic control along with the increased requirement for combination therapy in type 2 diabetes mellitus.

One of the most recent drug classes to be introduced for the treatment of type 2 diabetes is the thiazolidinediones. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal through an incompletely understood mechanism but one associated with binding of the drug to nuclear receptors known as peroxisome proliferator-activated receptors. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis) with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan). Pioglitazone depends on the presence of insulin for its mechanism of action. Worldwide clinical investigation has shown that, as an adjunct to diet and exercise, pioglitazone improves glycemic control when used as monotherapy, and in combination with commonly used antidiabetic medications (ie, sulfonylureas, metformin, or insulin).

SYR-322 is a selective, orally available inhibitor of dipeptidyl peptidase IV currently in development by Takeda Global Research & Development Center, Inc. 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. Both peptides exert important effects on islet β-cells to stimulate glucose-dependent insulin secretion and regulate β-cell proliferation and cytoprotection. Glucagon-like peptide-1 also inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes.

This study is designed to determine if the addition of SYR-322 to a combination of pioglitazone with metformin can be effective at achieving glycemic control without increasing safety risks in patients with type 2 diabetes mellitus who are experiencing inadequate glycemic control on a current regimen of metformin.

Eligibility

Ages Eligible for Study:	18 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Has a historical diagnosis of type 2 diabetes mellitus.
Meets one of the following:
- Has been inadequately controlled on a stable dose of greater than or equal to 1500 mg (or maximum tolerated dose) of metformin and 30 mg of pioglitazone
- Has been inadequately controlled on a combination therapy including metformin and another oral antidiabetic agent.
No treatment with antidiabetic agents other than metformin and pioglitazone.
Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2.
Fasting plasma C-peptide concentration greater than or equal to 0.8 ng/mL.
Systolic blood pressure less than 160 mmHg and diastolic pressure less than 100 mmHg.
Hemoglobin greater than or equal to 12 g/dL for males and greater than or equal to 10 g/dL for females.
Alanine aminotransferase less than or equal to 2.5 x upper limit of normal.
Serum creatinine less than 1.5 mg/dL for males and less than 1.4 mg /dL for females.
Thyroid-stimulating hormone level less than or equal to the upper limit of normal range and the subject is clinically euthyroid.
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.
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.

Exclusion Criteria:

Urine albumin/creatinine ratio of greater than 1000 μg/mg.
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 bladder cancer.
History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
Subjects with unexplained microscopic hematuria of greater than +1, confirmed by repeat testing.
History of treated diabetic gastroparesis.
History of gastric bypass surgery.
New York Heart Association Class I-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 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 abuse 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 SYR-322.
Hypersensitive to pioglitazone HCl, metformin, SYR-322 or other excipients.
The subject has donated more than 400 mL of blood within the 90 days prior to Screening and Pre-Screening, if applicable.
Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
- antidiabetic agents other than pioglitazone and metformin
- weight-loss drugs
- investigational antidiabetics
- oral or systemically injected glucocorticoids

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00432276

Show 87 Study Locations

Sponsors and Collaborators

Takeda Global Research & Development Center, Inc.

Investigators

Study Director:

VP Biological Sciences

Takeda Global Research & Development Center, Inc.

More Information

Additional Information:

ACTOS® Package Insert This link exits the ClinicalTrials.gov site

FDA Safety Alerts and Recalls This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	01-06-TL-322OPI-004, 2006-006025-73, U1111-1112-3363
Study First Received:	February 5, 2007
Last Updated:	January 7, 2010
ClinicalTrials.gov Identifier:	NCT00432276 History of Changes
Health Authority:	United States: Food and Drug Administration; Australia: Department of Health and Ageing Therapeutic Goods Administration; Australia: Human Research Ethics Committee; Australia: National Health and Medical Research Council; Austria: Agency for Health and Food Safety; Austria: Ethikkommission; Austria: Federal Ministry for Health and Women; Austria: Federal Office for Safety in Health Care; Belgium: Directorate general for the protection of Public health: Medicines; Belgium: Federal Agency for Medicinal Products and Health Products; Belgium: Institutional Review Board; Belgium: Ministry of Social Affairs, Public Health and the Environment; Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment; Denmark: Danish Dataprotection Agency; Denmark: Danish Medicines Agency; Denmark: Ethics Committee; Denmark: National Board of Health; Denmark: The Danish National Committee on Biomedical Research Ethics; Denmark: The Ministry of the Interior and Health; Denmark: The Regional Committee on Biomedical Research Ethics; Finland: Ethics Committee; Finland: Ministry of Social Affairs and Health; Finland: Finnish Medicines Agency; France: Afssaps - French Health Products Safety Agency; France: Direction Générale de la Santé; France: French Data Protection Authority; France: Institutional Ethical Committee; France: Ministry of Health; France: National Consultative Ethics Committee for Health and Life Sciences; Germany: Ethics Commission; Germany: Federal Institute for Drugs and Medical Devices; Germany: Federal Ministry of Education and Research; Germany: Federal Ministry of Food, Agriculture and Consumer Protection; Germany: German Institute of Medical Documentation and Information; Germany: Ministry of Health; Germany: Paul-Ehrlich-Institut; Greece: Ethics Committee; Greece: Ministry of Health and Welfare; Greece: National Organization of Medicines; India: Central Drugs Standard Control Organization; India: Department of Atomic Energy; India: Drugs Controller General of India; India: Indian Council of Medical Research; India: Institutional Review Board; India: Ministry of Health; India: Ministry of Science and Technology; India: Science and Engineering Research Council; Italy: Ethics Committee; Italy: Ministry of Health; Italy: National Bioethics Committee; Italy: National Institute of Health; Italy: National Monitoring Centre for Clinical Trials - Ministry of Health; Italy: The Italian Medicines Agency; Netherlands: Independent Ethics Committee; Netherlands: Dutch Health Care Inspectorate; Netherlands: Medical Ethics Review Committee (METC); Netherlands: Medicines Evaluation Board (MEB); Netherlands: The Central Committee on Research Involving Human Subjects (CCMO); New Zealand: Food Safety Authority; New Zealand: Health Research Council; New Zealand: Health and Disability Ethics Committees; New Zealand: Institutional Review Board; New Zealand: Medsafe; Norway: Data Inspectorate; Norway: Directorate for Health and Social Affairs; Norway: Norwegian Institute of Public Health; Norway: Norwegian Medicines Agency; Norway: Norwegian Social Science Data Services; Norway: The National Committees for Research Ethics in Norway; Romania: Ministry of Public Health; Romania: National Medicines Agency; Romania: State Institute for Drug Control; Russia: Ethics Committee; Russia: Ministry of Health and Social Development of the Russian Federation; Russia: Pharmacological Committee, Ministry of Health; South Africa: Department of Health; South Africa: Medicines Control Council; South Africa: National Health Research Ethics Council; South Korea: Institutional Review Board; South Korea: Korea Food and Drug Administration (KFDA); Spain: Comité Ético de Investigación Clínica; Spain: Ethics Committee; Spain: Ministry of Health; Spain: Ministry of Health and Consumption; Spain: Spanish Agency of Medicines; Switzerland: Ethikkommission; Switzerland: Federal Office of Public Health; Switzerland: Laws and standards; Switzerland: Swissmedic; United Kingdom: Department of Health; United Kingdom: Food Standards Agency; United Kingdom: Medicines and Healthcare Products Regulatory Agency; United Kingdom: National Health Service; United Kingdom: Research Ethics Committee; United Nations: International Atomic Energy Agency; United States: Federal Government; United States: Food and Drug Administration; United States: Institutional Review Board; Latvia: State Agency of Medicines; Sweden: Institutional Review Board; Sweden: Medical Products Agency; Sweden: Regional Ethical Review Board; Sweden: Swedish National Council on Medical Ethics; Sweden: Swedish Research Council; Sweden: The National Board of Health and Welfare

Keywords provided by Takeda Global Research & Development Center, Inc.:

Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic

Dyslipidemia
Hyperglycemia
Drug Therapy

Additional relevant MeSH terms:

Hypoglycemic Agents
Metabolic Diseases
Pioglitazone
Physiological Effects of Drugs
Metformin

Diabetes Mellitus, Type 2
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 08, 2010