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

Primary Purpose

Inflammation, Hypertension

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Pioglitazone
Pioglitazone and ramipril
Ramipril
Sponsored by
Takeda
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Inflammation focused on measuring drug effects, Hypertension, Vascular Resistance, Drug Therapy, physiopathology, vascular

Eligibility Criteria

30 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Active Comparator

Arm Label

Pioglitazone 15 mg to 30 mg QD

Pioglitazone 15 mg to 30 mg QD + Ramipril 2.5 mg to 5 mg QD

Ramipril 2.5 mg to 5 mg QD

Arm Description

Outcomes

Primary Outcome Measures

Change in the high-sensitivity C-reactive Protein value.

Secondary Outcome Measures

Change from Baseline in Glucose tolerance as assessed by an oral glucose tolerance test.
Change from Baseline in Insulin sensitivity according to the Homeostatic Model Assessment - Sensitivity score and Insulin Secretion.
Change from Baseline in Glycosylated Hemoglobin levels.
Change from Baseline in C-Peptide levels.
Change from Baseline in Proinsulin intact levels.
Change from Baseline in 24 hours Blood Pressure Profile.
Change from Baseline in high-sensitivity C-reactive Protein levels.
Change from Baseline in Adiponectin levels.
Change from Baseline in Monocyte Chemoattractant Protein-1 levels.
Change from Baseline in Matrix metalloproteinase-9 levels.
Change from Baseline in P-selectin levels.
Change from Baseline in Plasminogen Activator Inhibitor-1 levels.
Change from Baseline in Relaxin levels.
Change from Baseline in Endothelin 1-21 levels.
Change from Baseline in Nitrotyrosine levels.
Change from Baseline in Asymmetric Dimethylarginine levels.
Change from Baseline in Myeloperoxidase levels.
Change from Baseline in levels of Oxidative Stress as assessed by Per-Ox-Assay.
Change from Baseline in Total Cholesterol levels.
Change from Baseline in Triglycerides levels.
Change from Baseline in High Density Lipoprotein levels.
Change from Baseline in Low Density Lipoprotein levels.
Change from Baseline in Oxidized Low Density Lipoprotein levels.
Change from Baseline in Soluble Intercellular Adhesion Molecule levels.
Change from Baseline in Soluble Vascular Cell Adhesion Molecule levels.
Change from Baseline in Osteoprotegrin levels.
Change from Baseline in 11-dihydroxy-thromboxan B2 levels.
Change from Baseline in Placental Growth Factor levels.

Full Information

First Posted
October 9, 2008
Last Updated
July 1, 2010
Sponsor
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT00770497
Brief Title
Efficacy Study of Pioglitazone and Ramipril Combination Therapy in Treating Non-diabetic Hypertensive Patients.
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.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2010
Overall Recruitment Status
Completed
Study Start Date
March 2007 (undefined)
Primary Completion Date
May 2008 (Actual)
Study Completion Date
May 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Takeda

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Inflammation, Hypertension
Keywords
drug effects, Hypertension, Vascular Resistance, Drug Therapy, physiopathology, vascular

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
172 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pioglitazone 15 mg to 30 mg QD
Arm Type
Experimental
Arm Title
Pioglitazone 15 mg to 30 mg QD + Ramipril 2.5 mg to 5 mg QD
Arm Type
Active Comparator
Arm Title
Ramipril 2.5 mg to 5 mg QD
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Other Intervention Name(s)
ACTOS®, AD4833
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Pioglitazone and ramipril
Other Intervention Name(s)
ACTOS®, AD4833
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Ramipril
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in the high-sensitivity C-reactive Protein value.
Time Frame
Week: 12.
Secondary Outcome Measure Information:
Title
Change from Baseline in Glucose tolerance as assessed by an oral glucose tolerance test.
Time Frame
Week: 12.
Title
Change from Baseline in Insulin sensitivity according to the Homeostatic Model Assessment - Sensitivity score and Insulin Secretion.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Glycosylated Hemoglobin levels.
Time Frame
Week: 12.
Title
Change from Baseline in C-Peptide levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Proinsulin intact levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in 24 hours Blood Pressure Profile.
Time Frame
Week: 12.
Title
Change from Baseline in high-sensitivity C-reactive Protein levels.
Time Frame
Weeks: 6 and 10.
Title
Change from Baseline in Adiponectin levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Monocyte Chemoattractant Protein-1 levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Matrix metalloproteinase-9 levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in P-selectin levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Plasminogen Activator Inhibitor-1 levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Relaxin levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Endothelin 1-21 levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Nitrotyrosine levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Asymmetric Dimethylarginine levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Myeloperoxidase levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in levels of Oxidative Stress as assessed by Per-Ox-Assay.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Total Cholesterol levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Triglycerides levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in High Density Lipoprotein levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Low Density Lipoprotein levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Oxidized Low Density Lipoprotein levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Soluble Intercellular Adhesion Molecule levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Soluble Vascular Cell Adhesion Molecule levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Osteoprotegrin levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in 11-dihydroxy-thromboxan B2 levels.
Time Frame
Weeks: 6 and 12.
Title
Change from Baseline in Placental Growth Factor levels.
Time Frame
Weeks: 6 and 12.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Adviser Clinical Research
Organizational Affiliation
Takeda Pharma Gmbh, Aachen (Germany)
Official's Role
Study Director
Facility Information:
City
Deggingen
State/Province
Baden-Württemberg
Country
Germany
City
Rottweil
State/Province
Baden-Württemberg
Country
Germany
City
Spaichingen
State/Province
Baden-Württemberg
Country
Germany
City
Weilersbach
State/Province
Bayern
Country
Germany
City
Hannover
State/Province
Niedersachsen
Country
Germany
City
Essen
State/Province
Nordrhein-Westfalen
Country
Germany
City
Köln
State/Province
Nordrhein-Westfalen
Country
Germany
City
Werne
State/Province
Nordrhein-Westfalen
Country
Germany
City
Mainz
State/Province
Rheinland-Pfalz
Country
Germany
City
Schauenburg
State/Province
Rheinland-Pfalz
Country
Germany
City
Dresden
State/Province
Sachsen
Country
Germany
City
Blankenhain
State/Province
Thüringen
Country
Germany
City
Berlin
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

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

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