Clinical trial NCT01743014: Ramipril and Clopidogrel in Oxidative Stress, Vascular Inflammation and Endothelial Dysfunction in Type 2 Diabetes and Diabetic Nephropathy
Official title: 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: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Type 2
Diabetic Nephropathy
Vascular Disease
Keywords: diabetes
diabetic nephropathy
vascular inflammation
oxidative stress
endothelial dysfunction
Asymmetric dimethylarginine
High sensitivity CRP
albumine to creatinine ratio
isoprostane
clopidogrel
ramipril
carotid intima media thickness
Lead sponsor: AHEPA University Hospital
Sponsor class: OTHER
Collaborators: name: Aristotle University Of Thessaloniki
First posted: 2012-12-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in Asymmetric dimethylarginine (ADMA) blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
timeFrame: Baseline to week 12 and week 14 to week 26
measure: Changes in High-sensitivity C-reactive protein (HsCRP) blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
timeFrame: Baseline to week 12 and week 14 to week 26
measure: Changes in soluble CD40 Ligand (sCD40L)blood levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
timeFrame: Baseline to week 12 and week 14 to week 26
measure: Changes in urine 8-isoprostane-F2 levels after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
timeFrame: Baseline to week 12 and week 14 to week 26
measure: Reduction in albumine to creatine ratio after the combined treatment with ramipril and clopidogrel compared with ramipril monotherapy
timeFrame: Baseline to week 12 and week 14 to week 26
Secondary outcomes:
measure: Changes in ADMA blood levels after treatment with ramipril
timeFrame: baseline to week 26
measure: Increase of Glomerular Filtration Rate (GFR) after combined treatment with ramipril and clopidogrel and after ramipril monotherapy
timeFrame: baseline to week 12 and week 14 to week 26
measure: Change from baseline in carotid intima-media thickness after combined therapy with ramipril and clopidogrel and after ramipril monotherapy
timeFrame: baselibe to week 12 and week 14 to week 26
Other outcomes:
Locations:
city: Thessaloniki
country: Greece
facility: AHEPA University Hospital
city: Thessaloniki
country: Greece
facility: Aristotle University of Thessaloniki/ AHEPA University Hospital
Study officials:
affiliation: AHEPA University Hospital/ Aristotle University of Thessaloniki
name: Fotios S Iliadis, Lecturer of Internal Medicine
role: STUDY_DIRECTOR
affiliation: AHEPA University Hospital/ Aristotle University of Thessaloniki
name: Vaia F Bougatsa, Resident of Internal Medicine
role: PRINCIPAL_INVESTIGATOR
References:
citation: Natale P, Palmer SC, Saglimbene VM, Ruospo M, Razavian M, Craig JC, Jardine MJ, Webster AC, Strippoli GF. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD008834. doi: 10.1002/14651858.CD008834.pub4.