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

Sponsor:	Takeda Pharma GmbH
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00770445

Purpose

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.

Condition	Intervention	Phase
Diabetes Mellitus	Drug: Pioglitazone and insulin Drug: Pioglitazone and metformin and insulin Drug: Metformin and insulin	Phase IV

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

Resource links provided by NLM:

MedlinePlus related topics: Diabetes

Drug Information available for: Insulin 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 change from Baseline in Matrix Metallo Proteinase 9. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from Baseline in Circadian (7 point) blood glucose profile. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in 24-hour blood pressure profile. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Intima Media Thickness. [ Time Frame: Week 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in 24-hour urine. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in 8-iso prostaglandin F2 alpha. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in albumin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Creatinine. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in C/A-quotient. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Homeostasis Model Assessment of insulin Sensitivity. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Total Cholesterol. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Low-Density Lipoprotein. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in High-Density Lipoprotein. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Triglycerides. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Glycosylated hemoglobin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Glucose. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Insulin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Intact Proinsulin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in C-peptide. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Adiponectin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in High Molecular Weight Adiponectin. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in High-Sensitivity C-Reactive Protein. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Fibrinogen. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in E-selectin [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Nuclear Factor-kappa B. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Plasminogen Activator Inhibitor-1. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Nitrotyrosine. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from baseline in Insulin Consumption. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in Endothelial function measured by Laser-Doppler-flowmetry. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Body Weight. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Electrocardiograms [ Time Frame: Wee 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Alanine aminotransferase Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Aspartate aminotransferase Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Gamma-glutamyl transferase Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Glomerular filtration rate Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Alkaline phosphatase Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Leucocytes Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Hemoglobin Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Thrombocytes Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Creatinine kinase Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Creatinine Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Capillary Blood Glucose Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Potassium Laboratory Safety Variable. [ Time Frame: Weeks 12 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	132
Study Start Date:	May 2008
Estimated Study Completion Date:	June 2010
Estimated Primary Completion Date:	June 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	Drug: Pioglitazone and insulin Pioglitazone 15 mg, tablets, orally, twice daily and metformin placebo-matching tablets, orally, twice daily and insulin glargine stable dose for up to 24 weeks.
2: Experimental	Drug: Pioglitazone and metformin and insulin Pioglitazone 15 mg, tablets, orally, twice daily and metformin 850 mg, tablets, orally, twice daily and insulin glargine stable dose for up to 24 weeks.
3: Active Comparator	Drug: Metformin and insulin Pioglitazone placebo-matching tablets, orally, twice daily and metformin 850 mg, tablets, orally, twice daily and insulin glargine stable dose for up to 24 weeks.

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.

Eligibility

Ages Eligible for Study:	35 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00770445

Contacts

Contact: Study Manager

+49 800 8253325

Locations

Germany
	Recruiting
Hamburg, Germany
Germany, Hessen
	Recruiting
Kassel, Hessen, Germany
	Recruiting
Wiesbaden, Hessen, Germany
	Recruiting
Frankfurt, Hessen, Germany
Germany, Nordrhein-Westfalen
	Recruiting
Wuppertal, Nordrhein-Westfalen, Germany
Germany, Rheinland-Pfalz
	Recruiting
Mainz, Rheinland-Pfalz, Germany
Germany, Thüringen
	Recruiting
Jena, Thüringen, Germany

Sponsors and Collaborators

Takeda Pharma GmbH

Investigators

Study Director:

Medical Director

Takeda Pharma GmbH

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 Pharma GmbH, Aachen (Germany) ( Medical Director )
Study ID Numbers:	ATS K028, 2007-006706-14, DE-PIO-028, U1111-1113-1888
Study First Received:	October 9, 2008
Last Updated:	January 6, 2010
ClinicalTrials.gov Identifier:	NCT00770445 History of Changes
Health Authority:	European Union: European Medicines Agency

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

Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes

Diabetes Mellitus, Lipoatrophic
Dyslipidemia
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
Insulin

ClinicalTrials.gov processed this record on February 08, 2010