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 Overview

• Status: Completed
• Conditions: Diabetic Nephropathy
• Intervention / Treatment: Drug: placebo; Drug: eplerenone; Drug: fosinopril

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • University Medical Center Nijmegen st Radboud
  • Noord Brabant
    • 's-Hertogenbosch, Noord Brabant, Netherlands
      • Jeroen Bosch Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1; placebo (double dummy)	Drug: placebo; placebo (double dummy); Other Names: no other name
Active Comparator: 2; eplerenone	Drug: eplerenone; active comparator; Other Names: Eplerenone or INSPRA
Active Comparator: 3; doubling of fosinopril dose	Drug: fosinopril; doubling of fosinopril dose; Other Names: fosinopril or Newace

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
proteinuria	0, 4, 12, 24 and 30 weeks
blood pressure by home measurements	0, 4, 12, 24 and 30 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Jacob Deinum, MD, University Medical Center Nijmegen St Radboud, The Netherlands

Publications and helpful links

General Publications

• Chung EY, Ruospo M, Natale P, Bolignano D, Navaneethan SD, Palmer SC, Strippoli GF. Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2020 Oct 27;10:CD007004. doi: 10.1002/14651858.CD007004.pub4.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: April 14, 2006
• First Submitted That Met QC Criteria: April 14, 2006
• First Posted (Estimate): April 17, 2006

Study Record Updates

• Last Update Posted (Estimate): May 28, 2012
• Last Update Submitted That Met QC Criteria: May 25, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: endothelial function; renal function; eplerenone; albuminuria; ACE inhibition
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Urination Disorders; Proteinuria; Diabetic Nephropathies; Albuminuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Natriuretic Agents; Diuretics; Hormone Antagonists; Angiotensin-Converting Enzyme Inhibitors; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Eplerenone; Fosinopril
• Other Study ID Numbers: IRG 2005-316