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

• ClinicalTrials.gov Identifier: NCT00770653
• Recruitment Status: Completed
• First Posted: October 10, 2008
• Results First Posted: October 6, 2010
• Last Update Posted: October 6, 2010
• Sponsor: Takeda
• Information provided by: Takeda

Tracking Information

• First Submitted Date: October 9, 2008
• First Posted Date: October 10, 2008
• Results First Submitted Date: September 13, 2010
• Results First Posted Date: October 6, 2010
• Last Update Posted Date: October 6, 2010
• Study Start Date: April 2007
• Actual Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 13, 2010)

The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol. [ Time Frame: Baseline and Week 24. ]

The increase in High-Density Lipoprotein (HDL) Cholesterol collected at week 24 or final visit and HDL-Cholesterol collected at baseline.

• Original Primary Outcome Measures (submitted: October 9, 2008): The Mean Increase From Baseline in High-Density Lipoprotein Cholesterol. [ Time Frame: Week: 24. ]
• Change History: Complete list of historical versions of study NCT00770653 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: September 13, 2010)

• Change From Baseline in High-Density Lipoprotein Cholesterol. [ Time Frame: Baseline and Week 24. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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. ]
  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.

Original Secondary Outcome Measures (submitted: October 9, 2008)

• Change from Baseline in Lipid profile (high-density lipoprotein cholesterol, high-density lipoprotein /low-density lipoprotein ratio and triglycerides). [ Time Frame: Final Treatment Visit ]
• Change from Baseline in Lipid profile (low-density lipoprotein subfractions, low-density lipoprotein cholesterol and total cholesterol). [ Time Frame: Final Treatment Visit ]
• Change from Baseline in Glycemic control (glycosylated hemoglobin, fasting insulin, fasting glucose, fasting intact proinsulin, adiponectin). [ Time Frame: Final Treatment Visit ]
• Change from Baseline in Inflammation (high sensitivity C-reactive protein). [ Time Frame: Final Treatment Visit ]
• Change from Baseline in blood pressure. [ Time Frame: Final Treatment Visit ]
• Change from Baseline in Inflammation: (Soluble CD40 Ligand, Matrix Metallo Proteinase-9, Soluble Intracellular Adhesion molecule and Soluble Vascular Cell Adhesion Molecule). [ Time Frame: Final Treatment Visit ]
• Change from Baseline in Thrombocyte function (Thromboxane B2, platelet function as assessed by PFA 100, Nitrotyrosine, E-Selectin, von-Willebrand Factor and erythrocyte deformability). [ Time Frame: Final Treatment Visit ]
• Compliance to treatment: intake of study medication greater than 80% and less than 120%. [ Time Frame: Final Treatment Visit ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy of Pioglitazone/Metformin Combination Therapy in Subjects With Type 2 Diabetes Mellitus and Dyslipidemia.
• Official Title: Effects of a Pioglitazone/Metformin Fixed Combination in Comparison to Metformin in Combination With Glimepiride on Diabetic Dyslipidemia
• Brief Summary: 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.

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Diabetes Mellitus
• Dyslipidemias

Intervention

• 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
• 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

Study Arms

• Experimental: Pioglitazone 15 mg and Metformin 850 mg BID
  Intervention: Drug: Pioglitazone and Metformin
• Active Comparator: Glimepiride 2 mg and Metformin 850 mg BID
  Intervention: Drug: Glimepiride and Metformin

• Publications *: Pfützner A, Schöndorf T, Tschöpe D, Lobmann R, Merke J, Müller J, Lehmann U, Fuchs W, Forst T. PIOfix-study: effects of pioglitazone/metformin fixed combination in comparison with a combination of metformin with glimepiride on diabetic dyslipidemia. Diabetes Technol Ther. 2011 Jun;13(6):637-43. doi: 10.1089/dia.2010.0233. Epub 2011 Apr 2.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 19, 2009): 305
• Original Estimated Enrollment (submitted: October 9, 2008): 300
• Actual Study Completion Date: May 2009
• Actual Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT00770653
• Other Study ID Numbers: ATS K024; 2006-004455-37 ( EudraCT Number ); D-PIO-114 ( Other Identifier: Takeda Pharma GmbH ); U1111-1114-1678 ( Registry Identifier: WHO )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Medical Director, Takeda Pharma GmbH, Aachen (Germany)
• Study Sponsor: Takeda
• Collaborators: Not Provided

Investigators

• Study Director: Medical Adviser Clinical Research; Takeda Pharma Gmbh, Aachen (Germany)

• PRS Account: Takeda
• Verification Date: September 2010