Ramipril and Clopidogrel in Oxidative Stress, Vascular Inflammation and Endothelial Dysfunction in Type 2 Diabetes and Diabetic Nephropathy

Overview

The purpose of this study is to determine whether the combination with ramipril and clopidogrel leads to further improvement of endothelial function, reduction of oxidative stress and reduction of vascular inflammation, compared with ramipril monotherapy, in patients with Diabetes Mellitus type 2 and diabetic nephropathy.

Full Title of Study: “A Prospective, Randomized, Two Period, With an Intermediate Wash Out Period, Cross-over Study to Compare the Effects of Either Combined Therapy With Ramipril and Clopidogrel or Ramipril Monotherapy on Oxidative Stress, Vascular Inflammation and Endothelial Dysfunction in Patients With Type 2 Diabetes and Diabetic Nephropathy”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 2014

Detailed Description

– Cardiovascular disease is the leading cause of deaths in diabetic population with diabetic nephropathy. – Pharmacologic therapy for patients with diabetes and hypertension should be with a regimen that includes either an angiotensin-converting-enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) – Diabetic patients at increased cardiovascular risk should receive an antiplatelet agent for primary prevention. Methods: An open label,randomized, two period cross-over design study, involving patients with type 2 diabetes and diabetic nephropathy. After a 4 weeks wash out period for ACE inhibitors or Angiotensin receptor blockers (week 0, baseline) 60 patients will be randomized to receive ramipril(10 mg) only or ramipril (10 mg) and clopidogrel (75mg) for 12 weeks exchanging their treatment for a further 12 weeks, after a 2 week wash out period for clopidogrel. Patients will be examined and measurements will be taken at baseline (week 0), and at the end of 12, 14, and 26 weeks.

Interventions

  • Drug: Ramipril
    • Patients will receive 10 mg ramipril throughout the study. Each dose will be taken orally once daily. The duration of treatment with ramipril is 26 weeks
  • Drug: Clopidogrel
    • 12 weeks treatment with ramipril 10 mg and clopidogrel 75 mg once daily followed by a 2 week wash out period for clopidogrel and subsequently additional 12 weeks treatment wit both drugs after cross over.

Arms, Groups and Cohorts

  • Active Comparator: ramipril
    • Ramipril 10 mg tablets. Each dose will be taken orally with water once daily.
  • Active Comparator: clopidogrel and ramipril
    • clopidogrel 75mg tablet and ramipril 10mg. Each drug will be taken orally with water once daily

Clinical Trial Outcome Measures

Primary Measures

  • Changes in Asymmetric dimethylarginine (ADMA) blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
    • Time Frame: Baseline to week 12 and week 14 to week 26
    • The primary aim is to investigate the effect of the combined treatment with ramipril and clopidogrel versus ramipril monotherapy in ADMA as biomarker of endothelial dysfunction.
  • Changes in High-sensitivity C-reactive protein (HsCRP) blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
    • Time Frame: Baseline to week 12 and week 14 to week 26
    • The primary aim is to investigate the effect of the combined treatment with ramipril and clopidogrel versus ramipril monotherapy in hsCRP as biomarker of vascular inflammation
  • Changes in soluble CD40 Ligand (sCD40L)blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
    • Time Frame: Baseline to week 12 and week 14 to week 26
    • The primary aim is to investigate the effect of the combined treatment with ramipril and clopidogrel versus ramipril monotherapy in soluble CD40 Ligand as biomarker of vascular inflammation.
  • Changes in urine 8-isoprostane-F2 levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
    • Time Frame: Baseline to week 12 and week 14 to week 26
    • The primary aim is to investigate the effect of the combined treatment with ramipril and clopidogrel versus ramipril monotherapy in urine 8-isoprostane-F2 as biomarker of oxidative stress.
  • Reduction in albumine to creatine ratio after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
    • Time Frame: Baseline to week 12 and week 14 to week 26
    • The primary aim is to investigate the effect of the combined treatment with ramipril and clopidogrel versus ramipril monotherapy in albumine to creatine ratio as an index of cardiovascular disease

Secondary Measures

  • Changes in ADMA blood levels after treatment with ramipril
    • Time Frame: baseline to week 26
    • Evaluation of the effect of ramipril, as antihypertensive therapy, in endothelial dysfunction in patients with diabetes mellitus type 2 and diabetic nephropathy
  • Increase of Glomerular Filtration Rate (GFR) after combined treatment with ramipril and clopidogrel and after ramipril monotherapy
    • Time Frame: baseline to week 12 and week 14 to week 26
  • Change from baseline in carotid intima-media thickness after combined therapy with ramipril and clopidogrel and after ramipril monotherapy
    • Time Frame: baselibe to week 12 and week 14 to week 26

Participating in This Clinical Trial

Inclusion Criteria

type 2 diabetes patients with diabetic nephropathy in the range of micro- or macroalbuminuria and

  • HbA1c(glycosylated haemoglobin A1c <7% – Blood pressure ≤130/80 mmHg – LDL (Low Density Lipoproteins) <100 mg/dl – Informed consent Exclusion Criteria:

  • patients with diabetic nephropathy and estimated GFR <30ml/min with Modification of Diet in Renal Disease equation (MDRD equation) – baseline potassium > 5.2 meq/L – patients with nephrotic proteinuria defined as albumine to creatinine ratio (ACR)> 3.5 g/g or as proteinuria >3.5 g per 1.73 m2 per 24 hours – history or evidence of non-diabetic kidney disease – history of stroke, peripheral artery disease, coronary artery disease – history or evidence of a secondary form of hypertension – history of severe hepatic failure, malignancy, severe endocrinopathy,autoimmune disease or chronic inflammatory disease – any known bleeding or platelet disorder or platelets <100.000/μL – heart failure in New York Heart Association(NYHA) functional class II-IV – inability or unwillingness on the part of the patient to sign the Patient Consent Form – known hypersensitivity to ramipril or to clopidogrel – Women of child-bearing potential – use of oral anticoagulants or other antithrombotic treatment – use of glitazones – patients receiving statins should be on a stable dose of at least 3 months prior to study initiation and dose should be constant during the study – any surgical or medical condition which in the opinion of the investigator may expose the patient to a higher risk in participation in the study

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • AHEPA University Hospital
  • Collaborator
    • Aristotle University Of Thessaloniki
  • Provider of Information About this Clinical Study
    • Principal Investigator: Vaia Bougatsa, Medical Doctor-Resident of Internal Medicine – AHEPA University Hospital
  • Overall Official(s)
    • Fotios S Iliadis, Lecturer of Internal Medicine, Study Director, AHEPA University Hospital/ Aristotle University of Thessaloniki
    • Vaia F Bougatsa, Resident of Internal Medicine, Principal Investigator, AHEPA University Hospital/ Aristotle University of Thessaloniki
  • Overall Contact(s)
    • Fotios S Iliadis, Lecturer of Internal Medicine, +306974960728, iliadis@med.auth.gr

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