Efficacy and Safety of Pioglitazone in Treating Subjects With Vascular Complications Associated With Type 2 Diabetes Mellitus.

Condition(s) targeted: Diabetes Mellitus

Intervention: Pioglitazone, Metformin and Lifestyle Modification (Drug); Glibenclamide, Metformin and Lifestyle Modification (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Takeda Italia Farmaceutici S.p.A.

Official(s) and/or principal investigator(s):
Medical Director, Study Director, Affiliation: Takeda Italia Farmaceutici S.p.A.

Overall contact:
Study Manager, Phone: +39 0295-794357

The purpose of this study is to determine the efficacy of pioglitazone compared to glibenclamide taken together with metformin and lifestyle modification in type 2 diabetic subjects with cardiovascular disease.

Official title: Effects of Pioglitazone on Endothelial Progenitor Cells in Type 2 Diabetic Patients With Vascular Complications - The SPLENDOR Study.

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

Primary outcome: Increase from Baseline in the number of Endothelial Progenitor Cells (CD34+KDR+).

Secondary outcome:

Change from Baseline in Circulating Progenitor Cells Integrated Markers of cardiovascular risk (CD34+).

Change from Baseline in Flow Mediated Dilation Integrated Markers of cardiovascular risk.

Modulation of Endothelial Progenitor Cell recruitment (vascular endothelial growth factor, erythropoietin and stromal cell-derived factor-1).

Measure of Glucose Control (glycosylated hemoglobin and fasting plasma glucose).

Measure of Lipid Parameters (total lipids, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B and apolipoprotein A1).

Change from Baseline in lipid parameters (free fatty acids and oxidized low-density lipoprotein).

Change from Baseline in insulin sensitivity (insulin indexes by 2 hour oral glucose tolerance test with glucose, insulin and C-peptide estimation).

Change from Baseline in Inflammation Markers (high-sensitivity C-reactive protein, IL-6, vascular adhesion molecules (E-selectin, vascular cell adhesion molecule-1), monocyte chemotactic protein-1 and tumor necrosis factor-alpha).

Change from Baseline in Adipokines (adiponectin).

Change from Baseline in Oxidative Stress (maleic dialdehyde, ferric reducing antioxidant power and lipid hydroperoxide.

Urinary albumin excretion.

Detailed description: Diabetes is one of the most common chronic diseases worldwide, affecting nearly 200 million people, almost all suffering from Type 2 Diabetes. It is the fourth leading cause of death in developed countries due to the negative impact of the disease on the cardiovascular system. Treatment, aimed to the reduction of this intrinsic cardiovascular risk, is based on tight control of glucose and all coexisting metabolic abnormalities as well as of biomarkers of inflammation and atherogenesis.

Macrovascular complications account for the vast majority of morbidity and mortality in diabetic patients, and there is growing evidence that pathophysiologic mechanisms other than hyperglycemia are responsible. The condition of the vascular endothelium in particular has been shown to effect the health and disease of the cardiovascular system.

The number and function of endothelial progenitor cells correlate inversely with cardiovascular risk factors and may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk.

Pioglitazone is an orally active thiazolidinedione derivative. It is a ligand for peroxisome proliferator-activated receptor-gamma activation that alters transcription of various genes regulating carbohydrate and lipid metabolism.

Minimum age: 40 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Females must be non-pregnant, non-lactating and post-menopausal.

- A glycosylated hemoglobin level greater than 7. 5% and less than 10%.

- Has an age of onset of Type 2 Diabetes greater than 35 years of age.

- Is on metformin monotherapy up to the maximum tolerated daily dose.

- Has a normal or only slightly impaired renal function (a modification of diet in

renal disease estimated glomerular filtration rate greater than 60 ml/min/1. 73m2.

- Antihypertensives, statins and any other hypolipidemic medications have been

initiated at least three months prior to enrollment; no dose modifications are allowed during the study.

- Has one or more cardiovascular comorbidities as follows:

- stable angina pectoris

- previous (greater than three months) transient ischemic attack, cerebrovascular

accident or carotid atherosclerosis as assessed by bilateral carotid artery ultrasonography

- peripheral vascular complications documented by a history of claudication or

rest pain, ultrasonography or angiography.

Exclusion Criteria:

- Has Type 1 Diabetes.

- Is on insulin therapy.

- Is severely obese defined as a body mass index greater than or equal to 40mg/m2

- Has diabetic retinopathy.

- Has evidence of hepatic dysfunction including liver transaminase greater than three

times the upper limit of normal.

- Is unable to remain on a stable dose of the following class of medications 30 days

prior to randomization and throughout the six months of the study:

- antihypertensives

- statins

- other hypolipidemic and antiplatelet drugs

- Has a history of alcohol or other drug abuse.

- Has had a new diagnosis of cancer or recurrent cancer within five years of screening.

- Has a need for chronic (greater than two weeks) immunosuppressive therapy.

- Has had heart failure based on the New York Heart Association Functional Class I

through IV.

- 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:

- Other antidiabetic drugs (except metformin)

- Fibrates

- Rifampicin

- Glibenclamide interacting drugs, including nonsteroidal anti-inflammatory agents

- Other drugs that are highly protein bound, including:

- sulphonamides

- chloramphenicol

- probenecid

- monoamine oxidase inhibitors

- fluoroquinolones antibiotics

- oral miconazole

- Has participated in another clinical study within the past three months.

Study Manager, Phone: +39 0295-794357

Pisa, Italy; Recruiting

Padova, Italy; Recruiting

ACTOS® Package Insert

FDA Safety Alerts and Recalls

Starting date: March 2009
Ending date: February 2010
Last updated: October 5, 2009