Efficacy of Pioglitazone and Metformin on Cardiovascular Risk in Subjects With Insulin-Treated Type 2 Diabetes Mellitus.

Condition(s) targeted: Diabetes Mellitus

Intervention: Pioglitazone and insulin (Drug); Pioglitazone and metformin and insulin (Drug); Metformin and insulin (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Takeda Pharma GmbH

Official(s) and/or principal investigator(s):
Medical Director, Study Director, Affiliation: Takeda Pharma GmbH

Overall contact:
Study Manager, Phone: +49 800 8253325

The purpose of this study is to determine the Anti-Inflammation Effects of Pioglitazone and Pioglitazone/Metformin Combination Therapy in Type 2 Diabetes Subjects Treated with Insulin.

Official title: Impact of Pioglitazone, Metformin and the Combination of Both on Cardiovascular Risk in Insulin-treated Patients With Type 2 Diabetes - The PIOcomb Study

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Primary outcome: The change from Baseline in Matrix Metallo Proteinase 9.

Secondary outcome:

Change from Baseline in Circadian (7 point) blood glucose profile.

Change from Baseline in 24-hour blood pressure profile.

Change from Baseline in Intima Media Thickness.

Change from Baseline in 24-hour urine.

Change from Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide.

Change from Baseline in 8-iso prostaglandin F2 alpha.

Change from Baseline in albumin.

Change from Baseline in Creatinine.

Change from Baseline in C/A-quotient.

Change from Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide.

Change from Baseline in Homeostasis Model Assessment of insulin Sensitivity.

Change from Baseline in Total Cholesterol.

Change from Baseline in Low-Density Lipoprotein.

Change from Baseline in High-Density Lipoprotein.

Change from Baseline in Triglycerides.

Change from Baseline in Glycosylated hemoglobin.

Change from Baseline in Glucose.

Change from Baseline in Insulin.

Change from Baseline in Intact Proinsulin.

Change from Baseline in C-peptide.

Change from Baseline in Adiponectin.

Change from Baseline in High Molecular Weight Adiponectin.

Change from Baseline in High-Sensitivity C-Reactive Protein.

Change from Baseline in Fibrinogen.

Change from Baseline in E-selectin

Change from Baseline in Nuclear Factor-kappa B.

Change from Baseline in Plasminogen Activator Inhibitor-1.

Change from Baseline in Nitrotyrosine.

Change from baseline in Insulin Consumption.

Change from Baseline in Endothelial function measured by Laser-Doppler-flowmetry.

Body Weight.

Electrocardiograms

Alanine aminotransferase Laboratory Safety Variable.

Aspartate aminotransferase Laboratory Safety Variable.

Gamma-glutamyl transferase Laboratory Safety Variable.

Glomerular filtration rate Laboratory Safety Variable.

Alkaline phosphatase Laboratory Safety Variable.

Leucocytes Laboratory Safety Variable.

Hemoglobin Laboratory Safety Variable.

Thrombocytes Laboratory Safety Variable.

Creatinine kinase Laboratory Safety Variable.

Creatinine Laboratory Safety Variable.

Capillary Blood Glucose Laboratory Safety Variable.

Potassium Laboratory Safety Variable.

Detailed description: It is established that matrix metalloproteinases play an essential role in the degradation of collagen and other extra cellular matrix macromolecules. In addition, matrix metalloproteinases are implicated in plaque rupture through their capacity to thin the protective cap of the plaque, thus rendering it more vulnerable. In fact, matrix metalloproteinase-9 levels are elevated in patients with unstable plaques and in patients with acute coronary syndrome. In patients with type 2 diabetes mellitus, matrix metalloproteinase-1 and matrix metalloproteinase-9 levels are usually elevated and the atherosclerotic plaques are more vulnerable compared to non-diabetic patients, confirming the role of this proteinase in the development of acute coronary syndrome. Therefore, therapeutic strategies that reduce blood glucose levels and attenuate inflammation and matrix metalloproteinases activity may be a tool for reducing cardiovascular risk in patients with diabetes.

The purpose of this trial is to investigate whether the anti-inflammatory effects of pioglitazone are maintained and sustained over a longer observation period when given in combination with insulin in comparison to the metformin plus insulin combination. The duration of treatment for patients completing the study is approximately 6 months.

Minimum age: 35 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Has Diabetes Mellitus type 2.

- A glycosylated hemoglobin level greater than or equal to 6. 5% and less than 8. 5%.

- Treatment with Insulin Glargine with or without Oral Antidiabetic Therapy since 3

months

- A body mass index greater than or equal to 28.

- 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:

- Has a history of type 1 diabetes mellitus.

- Has uncontrolled hypertension (systolic blood pressure greater than 160mmHg and/or

diastolic blood pressure greater than 95mmHg) or change of antihypertensive treatment within the last 2 weeks.

- Has acute infections.

- Has anamnestic history of hypersensitivity to the study drugs or to drugs with

similar chemical structure.

- Has a history of severe or multiple allergies.

- History of drug or alcohol abuse in the past 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.

- State after kidney transplantation.

- Serum potassium greater than 5. 5 mmol/L.

- History of primary hyperaldosteronism.

- Acute myocardial infarction, open heart surgery or cerebral event (stroke/ Transitory

Ischemic Attack) within the previous 12 months.

- 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:

- Pre-treatment with gemfibrozil within the last 12 weeks.

- Pre-treatment with rifampicin within the last 12 weeks.

- Treatment with thiazolidinediones within the past 3 months.

- If statin therapy applicable: Change of medication within the last 4 weeks.

- Has used non-steroidal anti-inflammatory agents including low dose ASA or

Cox-2-inhibitors if therapy has been initiated within the last 4 weeks.

- Treatment with any other investigational drug within 4 weeks before trial entry.

- Any elective surgery during study participation.

- 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.

- History of dehydration, precoma diabeticorum or shock or diabetic ketoacidosis within

the past year prior to screening visit.

- Acute or scheduled investigation with iodine containing radiopaque material.

- Uncontrolled unstable angina pectoris.

- Medical history of acute and clinically relevant pericarditis, myocarditis,

endocarditis, recent pulmonary embolism, hemodynamic relevant aortic stenosis, aortic aneurysm.

Study Manager, Phone: +49 800 8253325

Hamburg, Germany; Recruiting

Kassel, Hessen, Germany; Recruiting

Wiesbaden, Hessen, Germany; Recruiting

Frankfurt, Hessen, Germany; Recruiting

Wuppertal, Nordrhein-Westfalen, Germany; Recruiting

Mainz, Rheinland-Pfalz, Germany; Recruiting

Jena, Thüringen, Germany; Recruiting

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FDA Safety Alerts and Recalls

Starting date: May 2008
Ending date: September 2009
Last updated: August 19, 2009