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

Overview[ - collapse ][ - ]

Purpose The purpose of this study is to determine the efficacy of pioglitazone compared to glibenclamide, once daily (QD), taken together with metformin and lifestyle modification in type 2 diabetic subjects with cardiovascular disease.
ConditionDiabetes Mellitus
InterventionDrug: Pioglitazone and Metformin
Drug: Glibenclamide and Metformin
PhasePhase 4
SponsorTakeda
Responsible PartyTakeda
ClinicalTrials.gov IdentifierNCT00770835
First ReceivedOctober 8, 2008
Last UpdatedJuly 11, 2011
Last verifiedJuly 2011

Tracking Information[ + expand ][ + ]

First Received DateOctober 8, 2008
Last Updated DateJuly 11, 2011
Start DateMarch 2009
Estimated Primary Completion DateMay 2011
Current Primary Outcome MeasuresIncrease from Baseline in the number of Endothelial Progenitor Cells (CD34+KDR+). [Time Frame: Baseline and Final Visit.] [Designated as safety issue: No]
Current Secondary Outcome Measures
  • Change from Baseline in Circulating Progenitor Cells Integrated Markers of cardiovascular risk (CD34+). [Time Frame: Baseline and Weeks 12 and 24.] [Designated as safety issue: No]
  • Change from Baseline in Flow Mediated Dilation Integrated Markers of cardiovascular risk. [Time Frame: Baseline and Final Visit.] [Designated as safety issue: No]
  • Modulation of Endothelial Progenitor Cell recruitment (vascular endothelial growth factor, erythropoietin and stromal cell-derived factor-1). [Time Frame: Weeks: 4, 12 and 24.] [Designated as safety issue: No]
  • Measure of Glucose Control (glycosylated hemoglobin and fasting plasma glucose). [Time Frame: Weeks: 4, 12 and 24.] [Designated as safety issue: No]
  • Measure of Lipid Parameters (total lipids, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B and apolipoprotein A1). [Time Frame: Weeks: 4, 12 and 24.] [Designated as safety issue: No]
  • Change from Baseline in lipid parameters (free fatty acids and oxidized low-density lipoprotein). [Time Frame: Baseline and Weeks 12 and 24.] [Designated as safety issue: No]
  • Change from Baseline in insulin sensitivity (insulin indexes by 2 hour oral glucose tolerance test with glucose, insulin and C-peptide estimation). [Time Frame: Baseline and Final Visit.] [Designated as safety issue: No]
  • 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). [Time Frame: Baseline and Weeks 12 and 24.] [Designated as safety issue: No]
  • Change from Baseline in Adipokines (adiponectin). [Time Frame: Baseline and Weeks 12 and 24.] [Designated as safety issue: No]
  • Change from Baseline in Oxidative Stress (maleic dialdehyde, ferric reducing antioxidant power and lipid hydroperoxide. [Time Frame: Baseline and Weeks 12 and 24.] [Designated as safety issue: No]
  • Urinary albumin excretion. [Time Frame: Weeks: 12 and 24.] [Designated as safety issue: No]

Descriptive Information[ + expand ][ + ]

Brief TitleEfficacy and Safety of Pioglitazone in Treating Subjects With Vascular Complications Associated With Type 2 Diabetes Mellitus.
Official TitleEffects of Pioglitazone on Endothelial Progenitor Cells in Type 2 Diabetic Patients With Vascular Complications - The SPLENDOR Study.
Brief Summary
The purpose of this study is to determine the efficacy of pioglitazone compared to
glibenclamide, once daily (QD), taken together with metformin and lifestyle modification in
type 2 diabetic subjects with cardiovascular disease.
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.
Study TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
ConditionDiabetes Mellitus
InterventionDrug: Pioglitazone and Metformin
Pioglitazone 30 mg, tablets, orally, once daily, metformin stable dose and lifestyle modification for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD-4833
Drug: Glibenclamide and Metformin
Glibenclamide 10 mg, tablets, orally, once daily and metformin stable dose and lifestyle modification for up to 24 weeks.
Other Names:
  • Diabeta
  • Glynase
  • Micronase
  • Daonil
  • Semi-Daonil
  • Euglucon
Study Arm (s)
  • Experimental: Pioglitazone and Metformin QD
    (along with lifestyle modification)
  • Active Comparator: Glibenclamide and Metformin QD
    (along with lifestyle modification)

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment39
Estimated Completion DateMay 2011
Estimated Primary Completion DateMay 2011
Eligibility 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.

- and/or two or more of the following major cardiovascular risk factors:

- hypertension (blood pressure >130/80 mmHg or treatment)

- dyslipidemia (low-density lipoprotein-cholesterol >100 mg/dl or treatment and/or
high-density lipoprotein-cholesterol <40 mg/dl in men and <45 mg/dl in women or
treatment)

- smoking (>10 cigarettes/day)

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.
GenderBoth
Ages40 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesItaly

Administrative Information[ + expand ][ + ]

NCT Number NCT00770835
Other Study ID NumbersIT-PIO-109
Has Data Monitoring CommitteeNo
Information Provided ByTakeda
Study SponsorTakeda
CollaboratorsNot Provided
Investigators Study Director: Medical Director Takeda
Verification DateJuly 2011

Locations[ + expand ][ + ]

Italy
Padova, Italy
Italy
Pisa, Italy