Official Title: “Eplerenone, ACE Inhibition and Albuminuria”

The purpose of this study is to determine whether eplerenone is more effective than doubling the dose of ACE inhibitor in reducing urinary protein (albumin) loss in diabetes mellitus

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

In patients with proteinuric renal diseases renal function almost invariably deteriorates, independent from the original renal disease. It has been demonstrated that the rapidity of renal function deterioration is determined by blood pressure and proteinuria1. Treatment modalities that lower proteinuria in general tend to attenuate the deterioration of renal function. As such, ACE-inhibitors have been proven to be of particular value in the treatment of patients with proteinuria, since these drugs consistently lower proteinuria. More recently, similar antiproteinuric effects have been described for the angiotensin receptor blockers (ARBs). Theoretically, ACE inhibitors may have advantages over ARBs because they are supposed to increase bradykinin levels. Bradykinin has also been implicated in the development of nephropathy in mice. About its role in human diabetic nephropathy few if any data exist. The effect of ACE inhibition or ARBs is not complete, since addition of either drug to the other may further improve albuminuria. This may be explained by insufficient dosage of single drug therapy or because of an escape phenomenon. The latter has been amply described for ACE inhibitors. Especially with chronic ACE inhibition angiotensin II levels may be near normal. This may lead to persistent angiotensin II effects, among which aldosterone stimulation.

Even though most investigators have emphasized the role of the renin-angiotensin system in progressive renal injury, aldosterone has received little attention. However, its profibrotic effects make aldosterone a potentially important player in the field, even more so because the escape of aldosterone during treatment with ACE-inhibitors or ARBs. Moreover, in addition to these theoretical considerations, evidence is emerging that mineralocorticoid receptor blockade with spironolactone added to ACE-inhibitors or ARBs indeed has an additive, favourable effect on proteinuria. These findings warrant a search for the value of such agents in albuminuria and exploration of the mechanisms by which mineralocorticoid blockade may exert its beneficial effects.

Primary aim:

1. To study whether the combination of eplerenone and a standard dose of ACE-inhibition has an additive effect on albuminuria in patients with albuminuric nephropathy compared to ACE-I alone, or double dose of ACE-inhibitor.

Intervention(s) in this Clinical Trial

• Drug: eplerenone
• Drug: fosinopril

Primary Measures

• proteinuria
• bloodpressure by home measurements
• differential protein excretion in 2 hr urines (b2-microglobulin, GST etc.)
• GFR and RPF

Secondary Measures

• serum potassium
• haemoglobin
• urinary excretion of CTGF, TGF-b, collagen IV
• inuline/PAH clearance
• endothelial function of forearm
• Quality of Life
• plasma aldosterone, renin
• plasma angiotensins and bradykinins
• endogenous hippuric acid clearance

Inclusion Criteria:

• documented diabetic renal disease with albuminuria >0.020 g/L, stable renal function (i.e. increase of serum creatinine <25% / 6 months), creatinine clearance > 40 ml/min/1.73 m2 , in spite of maximal ACE-inhibition (40 mg fosinopril/day)
• blood pressure < 140/90 mm Hg ( at baseline)
• serum potassium < 5.0 mmol/l (at baseline).

Exclusion Criteria:

• use of NSAID’s or immunosuppressive drugs
• use of ARBs, intolerance for ACE inhibition.
• use of diuretics that increase potassium such as triamterene, spironolactone or eplerenone
• pregnancy
• rash or cough on one on the drugs
• severe heart disease or instable angina

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Radboud University

Overall Clinical Trial Officials and Contacts

Jacob Deinum, MD Principal Investigator University Medical Center Nijmegen St Radboud, The Netherlands  

Overall Contact: Jacob Deinum, MD 0031243618819 j.deinum@aig.umcn.nl

Information obtained from ClinicalTrials.gov on October 06, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00315016

Study ID Number: IRG 2005-316

ClinicalTrials.gov Identifier: NCT00315016

Health Authority: Netherlands: Medicines Evaluation Board (MEB)