Eplerenone, ACE Inhibition and Albuminuria

Phase 2

Completed

• Conditions: Diabetic Nephropathy
• Interventions: Drug: placebo; Drug: eplerenone; Drug: fosinopril

• Registration Number: NCT00315016
• Lead Sponsor: Radboud University Medical Center

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2006-04-14
• Study First Submitted QC: 2006-04-14
• Study First Posted: 2006-04-17
• Study Start: 2007-01
• Primary Completion: 2011-07
• Study Completion: 2011-07
• Status Verified: 2012-05
• Last Update Submitted: 2012-05-25
• Last Update Posted: 2012-05-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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).

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	placebo	placebo (double dummy)
2	eplerenone	eplerenone
3	fosinopril	doubling of fosinopril dose

Primary Outcome Measures

Name	Time	Method
proteinuria	0, 4, 12, 24 and 30 weeks
blood pressure by home measurements	0, 4, 12, 24 and 30 weeks

Secondary Outcome Measures

Name	Time	Method
serum potassium	0, 3, days, 2, 4, 12, 24 and 30 weeks
haemoglobin	0, 4, 12, 24 and 30 weeks
urinary excretion of CTGF, TGF-b, collagen IV	0, 4, 12, 24 and 30 weeks
inulin and PAH clearance	0, 24 and 30 weeks
Quality of Life	0, 4, 12, 24 and 30 weeks
plasma aldosterone, renin	0, 24 and 30 weeks
plasma angiotensins and bradykinins	0, 24 and 30 weeks

Trial Locations

Locations (2)

Jeroen Bosch Hospital; 🇳🇱 's-Hertogenbosch, Noord Brabant, Netherlands

University Medical Center Nijmegen St Radboud; 🇳🇱 Nijmegen, Netherlands