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

Phase 4

• Conditions: Diabetes Type 2; Diabetic Nephropathy; Vascular Disease
• Interventions: Drug: Ramipril; Drug: Clopidogrel

• Registration Number: NCT01743014
• Lead Sponsor: AHEPA University Hospital

Brief Summary

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.

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.

Study Timeline

• Study Start: 2012-07
• Status Verified: 2012-11
• Study First Submitted: 2012-11-21
• Study First Submitted QC: 2012-12-04
• Last Update Submitted: 2012-12-04
• Study First Posted: 2012-12-06
• Last Update Posted: 2012-12-06
• Primary Completion: 2014-07
• Study Completion: 2015-07

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 60

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
ramipril	Ramipril	Ramipril 10 mg tablets. Each dose will be taken orally with water once daily.
clopidogrel and ramipril	Ramipril	clopidogrel 75mg tablet and ramipril 10mg. Each drug will be taken orally with water once daily
clopidogrel and ramipril	Clopidogrel	clopidogrel 75mg tablet and ramipril 10mg. Each drug will be taken orally with water once daily

Primary Outcome Measures

Name	Time	Method
Changes in Asymmetric dimethylarginine (ADMA) blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy	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	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	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	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	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 Outcome Measures

Name	Time	Method
Changes in ADMA blood levels after treatment with ramipril	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	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	baselibe to week 12 and week 14 to week 26

Trial Locations

Locations (2)

Aristotle University of Thessaloniki/ AHEPA University Hospital; 🇬🇷 Thessaloniki, Greece

AHEPA University Hospital; 🇬🇷 Thessaloniki, Greece