Efficacy Study of Pioglitazone and Ramipril Combination Therapy in Treating Non-diabetic Hypertensive Patients. - Full Text View

Sponsor:	Takeda Pharma GmbH
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00770497

Purpose

The purpose of this study is to determine the effects of pioglitazone, once daily (QD), on low grade inflammation and vascular function in hypertensive patients.

Condition	Intervention	Phase
Inflammation Hypertension	Drug: Pioglitazone Drug: Pioglitazone and ramipril Drug: Ramipril	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Effect of Pioglitazone Compared to a Combination Therapy With Ramipril and to a Ramipril Monotherapy on Low Grade Inflammation and Vascular Function in Patients With Increased Cardiovascular Risk and an Activated Inflammation. A Randomized Double-blinded Phase II Study.

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines High Blood Pressure

Drug Information available for: Ramipril Pioglitazone Pioglitazone hydrochloride

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Change in the high-sensitivity C-reactive Protein value. [ Time Frame: Week: 12. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from Baseline in Glucose tolerance as assessed by an oral glucose tolerance test. [ Time Frame: Week: 12. ] [ Designated as safety issue: No ]
Change from Baseline in Insulin sensitivity according to the Homeostatic Model Assessment - Sensitivity score and Insulin Secretion. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Glycosylated Hemoglobin levels. [ Time Frame: Week: 12. ] [ Designated as safety issue: No ]
Change from Baseline in C-Peptide levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Proinsulin intact levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in 24 hours Blood Pressure Profile. [ Time Frame: Week: 12. ] [ Designated as safety issue: No ]
Change from Baseline in high-sensitivity C-reactive Protein levels. [ Time Frame: Weeks: 6 and 10. ] [ Designated as safety issue: No ]
Change from Baseline in Adiponectin levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Monocyte Chemoattractant Protein-1 levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Matrix metalloproteinase-9 levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in P-selectin levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Plasminogen Activator Inhibitor-1 levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Relaxin levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Endothelin 1-21 levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Nitrotyrosine levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Asymmetric Dimethylarginine levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Myeloperoxidase levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in levels of Oxidative Stress as assessed by Per-Ox-Assay. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Total Cholesterol levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Triglycerides levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in High Density Lipoprotein levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Low Density Lipoprotein levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Oxidized Low Density Lipoprotein levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Soluble Intercellular Adhesion Molecule levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Soluble Vascular Cell Adhesion Molecule levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Osteoprotegrin levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in 11-dihydroxy-thromboxan B2 levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]
Change from Baseline in Placental Growth Factor levels. [ Time Frame: Weeks: 6 and 12. ] [ Designated as safety issue: No ]

Enrollment:	172
Study Start Date:	March 2007
Study Completion Date:	May 2008
Primary Completion Date:	May 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pioglitazone 15 mg to 30 mg QD	Drug: Pioglitazone Pioglitazone 15 mg, tablets, orally, once daily and ramipril placebo-matching tablets, orally, once daily for two weeks; increased to: Pioglitazone 30 mg, tablets, orally, once daily and ramipril placebo-matching tablets, orally, once daily for up to 10 weeks. Other Names: ACTOS® AD4833
Active Comparator: Pioglitazone 15 mg to 30 mg QD + Ramipril 2.5 mg to 5 mg QD	Drug: Pioglitazone and ramipril Pioglitazone 15 mg, tablets, orally, once daily and ramipril 2.5 mg, tablets, orally, once daily for two weeks; increased to: Pioglitazone 30 mg, tablets, orally, once daily and ramipril 5 mg, tablets, orally, once daily for up to 10 weeks. Other Names: ACTOS® AD4833
Active Comparator: Ramipril 2.5 mg to 5 mg QD	Drug: Ramipril Pioglitazone placebo-matching tablets, orally, once daily and ramipril 2.5 mg, tablets, orally, once daily for two weeks; increased to: Pioglitazone placebo-matching tablets, orally, once daily and ramipril 5 mg, tablets, orally, once daily for up to 10 weeks.

Detailed Description:

Patients with insulin resistance and an activated inflammation are prone for cardiovascular complications like myocardial infarction or stroke. Pharmacological interventions reducing vascular inflammation are thought to reduce cardiovascular risk in diabetic and in non-diabetic patients.

Intervention with ACE inhibitors like ramipril is an established and widely used treatment for patients with high blood pressure, proven to reduce cardiovascular risk. Treatment of non-diabetic patients with pioglitazone has shown to improve the cardiovascular risk profile in non-diabetic patients beyond its effect on blood glucose levels.

The purpose of this study is to evaluate effects on low grade inflammation and vascular function of pioglitazone in non-diabetic, hypertensive patients with pre treatment with angiotensin converting enzyme inhibitors (that will be replaced by the study medication at time of randomization).

Eligibility

Ages Eligible for Study:	30 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Has arterial hypertension.
Is on stable treatment with an Angiotensin Converting Enzyme inhibitor at least for 12 weeks.
Has a high sensitive C-Reactive Protein value greater than 1.0 mg/L and less than 10.0 mg/L.
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:

Manifests or has newly detected diabetes mellitus type 2 according to World Health Organization criteria.
Has Type 1 Diabetes.
Has acute infections.
Chronic inflammatory diseases which cause elevated CRP-values (e.g. rheumatic diseases, pyelonephritis or osteomyelitis).
Use of acetyl salicylic acid and/or Non-steroidal Anti-inflammatory Drugs or Cox-2-inhibitors within the last 4 weeks prior to screening visit, use of Rifampicin within the last 12 weeks prior to screening visit.
Uncontrolled hypertension (repeated blood pressure greater than 180/100 mmHg for at least three times within two weeks); persistent hypotension (systolic less than 90 mmHg) or hemodynamic instability.
Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures.
History of severe or multiple allergies.
Treatment with any other investigational drug within 3 months before trial entry.
Has a progressive, fatal disease.
History of drug or alcohol abuse within the last 5 years.
A history of significant cardiovascular (New York Heart Association stage I - IV, hemodynamic relevant aortic or mitral valve stenosis, hypertrophic obstructive cardiomyopathy), respiratory, gastrointestinal, hepatic (alanine aminotransferase greater than 2.5 times the normal reference range), renal (creatinine greater than 2.0 mg/dL), or hematological disease, history of macular edema.
State after kidney transplantation, hemodynamic relevant renal artery stenosis (bilateral or unilateral in case of single kidney).
Blood donation within the last 30 days.
Serum potassium greater than 5.5 mmol/L.
History of hyperaldosteronism.
Treatment with thiazolidinediones within 3 months prior to screening.
Acute myocardial infarction, open heart surgery or cerebral events (stroke/transient ischemic attack) within 30 days prior to screening visit.
If statin therapy applicable: Change of medication within the last 12 weeks.
History of angioneurotic edema (hereditary or idiopathic as consequence of previous Angiotensin Converting Enzyme inhibitor treatment).
Dialysis or hemofiltration.
Low Density Lipoprotein apheresis with dextran sulphate.
Allergic to toxic agents derived from insects.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00770497

Locations

Germany

Deggingen, Baden-Württemberg, Germany

Rottweil, Baden-Württemberg, Germany

Spaichingen, Baden-Württemberg, Germany

Weilersbach, Bayern, Germany

Hannover, Niedersachsen, Germany

Essen, Nordrhein-Westfalen, Germany

Köln, Nordrhein-Westfalen, Germany

Werne, Nordrhein-Westfalen, Germany

Mainz, Rheinland-Pfalz, Germany

Schauenburg, Rheinland-Pfalz, Germany

Dresden, Sachsen, Germany

Blankenhain, Thüringen, Germany

Berlin, Germany

Sponsors and Collaborators

Takeda Pharma GmbH

Investigators

Study Director:

Medical Adviser Clinical Research

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:	Medical Director, Takeda Pharma GmbH, Aachen (Germany)
ClinicalTrials.gov Identifier:	NCT00770497 History of Changes
Obsolete Identifiers:	NCT00975624
Other Study ID Numbers:	ATS K023, 2006-004028-35, D-PIO-110, U1111-1115-9194
Study First Received:	October 9, 2008
Last Updated:	July 1, 2010
Health Authority:	European Union: European Medicines Agency

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

drug effects
Hypertension
Vascular Resistance
Drug Therapy
physiopathology, vascular

Additional relevant MeSH terms:

Hypertension
Inflammation
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Pioglitazone
Ramipril
Hypoglycemic Agents
Physiological Effects of Drugs

Pharmacologic Actions
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012