Efficacy of Pioglitazone/Metformin Combination Therapy in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia. - Full Text View

Sponsor:	Takeda Pharma GmbH
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00770653

Purpose

The purpose of this study is to compare pioglitazone and metformin combination therapy, twice daily (BID), to glimepiride and metformin combination therapy for treating diabetic subjects with dyslipidemia.

Condition	Intervention	Phase
Diabetes Mellitus Dyslipidemias	Drug: Pioglitazone and Metformin Drug: Glimepiride and Metformin	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Effects of a Pioglitazone/Metformin Fixed Combination in Comparison to Metformin in Combination With Glimepiride on Diabetic Dyslipidemia

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Cholesterol Diabetes Diabetes Medicines Diabetes Type 2

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

U.S. FDA Resources

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

Primary Outcome Measures:

The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.

Secondary Outcome Measures:

Change From Baseline in High-Density Lipoprotein Cholesterol. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between HDL-Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.
Change From Baseline in High-Density Lipoprotein/Low-Density Lipoprotein Ratio. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at week 24 or final visit and High-Density Lipoprotein/Low-Density Lipoprotein Ratio collected at baseline.
Change From Baseline in Triglycerides. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Triglycerides collected at week 24 or final visit and Triglycerides collected at baseline.
Change From Baseline in Low-Density Lipoprotein Subfractions. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Low-Density Lipoprotein Subfractions collected at week 24 or final visit and Low-Density Lipoprotein Subfractions collected at baseline.
Change From Baseline in Low-Density Lipoprotein Cholesterol. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Low-Density Lipoprotein Cholesterol collected at week 24 or final visit and Low-Density Lipoprotein Cholesterol collected at baseline.
Change From Baseline in Glycosylated Hemoglobin. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between 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 24 or final visit and Glycosylated Hemoglobin collected at baseline.
Change From Baseline in Fasting Intact Proinsulin. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Fasting Intact Proinsulin collected at week 24 or final visit and Fasting Intact Proinsulin collected at baseline.
Change From Baseline in Fasting Glucose. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Fasting Glucose collected at week 24 or final visit and Fasting Glucose collected at baseline.
Change From Baseline in Adiponectin. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Adiponectin collected at week 24 or final visit and Adiponectin collected at baseline.
Change From Baseline in High Sensitivity C-reactive Protein (Original). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of High Sensitivity C-reactive Protein collected at week 24 or final visit and High Sensitivity C-reactive Protein collected at baseline.
Change From Baseline in High Sensitivity C-reactive Protein (≤ 10 mg/L). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at week 24 or final visit and High Sensitivity C-reactive Protein less than or equal to 10 mg/L collected at baseline.
Change From Baseline in Systolic Blood Pressure. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Systolic Blood Pressure measured at week 24 or final visit and Systolic Blood Pressure measured at baseline.
Change From Baseline in Diastolic Blood Pressure. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between Diastolic Blood Pressure measured at week 24 or final visit and Diastolic Blood Pressure measured at baseline.
Intake of Study Medication Greater Than 80% and Less Than 120%. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the Intake of study medication greater than 80% at week 24 or final visit and Baseline and the Intake of study medication greater than 80% at baseline.
Change From Baseline in Nitrotyrosine. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Nitrotyrosine collected at week 24 or final visit and Nitrotyrosine collected at baseline.
Change From Baseline in Soluble CD40 Ligand. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Soluble CD40 Ligand collected at week 24 or final visit and Soluble CD40 Ligand collected at baseline.
Change From Baseline in Matrix Metallo Proteinase-9. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Baseline in Matrix Metallo Proteinase-9 collected at week 24 or final visit and Baseline in Matrix Metallo Proteinase-9 collected at baseline.
Change From Baseline in Soluble Intracellular Adhesion Molecule. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Baseline in Soluble Intracellular Adhesion molecule at week 24 or final visit and Baseline in Soluble Intracellular Adhesion molecule collected at baseline.
Change From Baseline in Soluble Vascular Cell Adhesion Molecule. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Soluble Vascular Cell Adhesion Molecule collected at week 24 or final visit and Soluble Vascular Cell Adhesion Molecule collected at baseline.
Change From Baseline in Thromboxane B2. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Thromboxane B2 collected at week 24 or final visit and Thromboxane B2 collected at baseline.
Change From Baseline in Platelet Function. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Platelet Function by PFA 100 collected at week 24 or final visit and Platelet Function by PFA 100 collected at baseline.
Change From Baseline in E-Selectin. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of E-Selectin collected at week 24 or final visit and E-Selectin collected at baseline.
Change From Baseline in Von-Willebrand Factor. [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the value of Von-Willebrand Factor collected at week 24 or final visit and Von-Willebrand Factor collected at baseline.
Change From Baseline in Erythrocyte Deformability (0.30%). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 0.30 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (0.60%) [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 0.60 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (1.20). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 1.20 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (3.00). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 3.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (6.00). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 6.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (12.00). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 12.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (30.00). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 30.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.
Change From Baseline in Erythrocyte Deformability (60.00). [ Time Frame: Baseline and Week 24. ] [ Designated as safety issue: No ]
The change between the 60.00 percent value of Erythrocyte (Red Blood Cell) Deformability collected at week 24 or final visit and Erythrocyte Deformability collected at baseline.

Enrollment:	305
Study Start Date:	April 2007
Study Completion Date:	May 2009
Primary Completion Date:	May 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pioglitazone 15 mg and Metformin 850 mg BID	Drug: Pioglitazone and Metformin Pioglitazone 15 mg/metformin 850 mg combination tablets, orally, twice daily and glimepiride placebo-matching tablets, orally, once daily and metformin placebo-matching tablets, orally, twice daily for up to 24 weeks. Other Names: ACTOS® AD-4833 OPIMET
Active Comparator: Glimepiride 2 mg and Metformin 850 mg BID	Drug: Glimepiride and Metformin Pioglitazone/metformin placebo-matching combination tablets, orally, twice daily and glimepiride 2 mg, tablets, orally, once daily and metformin 850 mg, tablets, orally, twice daily for up to 24 weeks. Other Names: Amaryl Glista

Detailed Description:

Insulin resistance is a major endocrinopathy preceding the development of hyperglycemia, diabetic dyslipidemia and cardiovascular disease in type 2 diabetes. The most common pattern of dyslipidemia in patients with type 2 diabetes are elevated triglyceride levels, decreased hih-density lipoprotein cholesterol and a predominance of small dense low-density lipoprotein particles. Each of these dyslipidemia features is associated with an increased risk of cardiovascular events.

Pioglitazone and Metformin are established drugs which can be used for the treatment of type 2 diabetes. This study will investigate the effects of treatment with fixed Pioglitazone/Metformin combination therapy of Metformin and Glimepiride in Metformin-pretreated type 2 diabetic patients with dyslipidemia.

Total participation time in this study is anticipated to be approximately 24 weeks.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Type 2 diabetes according to the American Diabetes Association Criteria.
Treatment with individual maximal tolerated dose of metformin (850 - 2000 mg) as monotherapy within the last 12 weeks.
Glycosylated Hemoglobin greater than or equal to 6.5% and less than or equal to 9%.
Dyslipidemia defined as high-density lipoprotein cholesterol less than or equal to 1.03 mmol/l (40 mg/dL) and/or triglycerides greater than or equal to 1.7 mmol/l (150 mg/dL).
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.

Exclusion Criteria:

Type 1 diabetes mellitus.
Insulin-dependent type 2 diabetes mellitus.
Treatment or history of treatment with any insulin formulation other than emergency for more than 2 weeks.
Treatment with other oral antidiabetic drugs in addition to metformin within the last 12 weeks.
Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures.
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:
- Heparin (and heparin-like drugs)
- coumarin
- phenprocoumon
- hirudin
- Protein C
- Fondaparinux
- antithrombin III
- Peroxisome Proliferation Activating Receptor (gamma) agonists
- Treatment within the last 12 weeks with:
  - fibrates
  - gemfibrozil
  - niacin
  - months
  - Rifampicin
- Changes in dosage of any statin treatment to lower low-density lipoprotein within 2 weeks before study entry and during study participation interval.
- Changes in dosage of any anticoagulant treatment with acetyl salicylic acid and/or clopidogrel within 2 weeks before study entry and during study participation interval.
- Start of statin and/or anticoagulant treatment during study participation interval.
History of severe or multiple allergies and/ or acute severe infections.
Have had more than one unexplained episode of severe hypoglycemia (defined as requiring assistance of another person due to disabling hypoglycemia) within 6 months prior to screening visit.
Progressive fatal disease.
Any elective surgery during study participation.
History of drug or alcohol abuse within the last 5 years.
A history of significant cardiovascular (New York Heart Association stage I - IV), respiratory, gastrointestinal, hepatic (alanine aminotransferase and/or aspartate aminotransferase greater than 2.5 times the upper limit of the normal reference range), renal (serum creatinine greater than 1.2 mg/dL in women and greater than 1.5 mg/dL in men, glomerular filtration rate less than 60 ml/min as estimated by the Cockroft-Gault formula), neurological, psychiatric and/or hematological disease as judged by the investigator, history of macular edema.
Blood donation within the last 30 days.

Responsible Party:	Medical Director, Takeda Pharma GmbH, Aachen (Germany)
ClinicalTrials.gov Identifier:	NCT00770653 History of Changes
Other Study ID Numbers:	ATS K024, 2006-004455-37, D-PIO-114, U1111-1114-1678
Study First Received:	October 9, 2008
Results First Received:	September 13, 2010
Last Updated:	September 13, 2010
Health Authority:	European Union: European Medicines Agency