Eplerenone, ACE Inhibition and Albuminuria - Full Text View

Sponsor:	Radboud University
Information provided by:	Radboud University
ClinicalTrials.gov Identifier:	NCT00315016

Purpose

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

Condition	Intervention	Phase
Diabetic Nephropathy	Drug: eplerenone Drug: fosinopril Drug: placebo	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Dose Comparison, Parallel Assignment, Safety/Efficacy Study
Official Title:	Eplerenone, ACE Inhibition and Albuminuria

Resource links provided by NLM:

MedlinePlus related topics: Diabetic Kidney Problems

Drug Information available for: Fosinopril sodium Fosinopril

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:

proteinuria [ Time Frame: 0, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: No ]
blood pressure by home measurements [ Time Frame: 0, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

serum potassium [ Time Frame: 0, 3, days, 2, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: Yes ]
haemoglobin [ Time Frame: 0, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: Yes ]
urinary excretion of CTGF, TGF-b, collagen IV [ Time Frame: 0, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: No ]
inulin and PAH clearance [ Time Frame: 0, 24 and 30 weeks ] [ Designated as safety issue: No ]
Quality of Life [ Time Frame: 0, 4, 12, 24 and 30 weeks ] [ Designated as safety issue: Yes ]
plasma aldosterone, renin [ Time Frame: 0, 24 and 30 weeks ] [ Designated as safety issue: No ]
plasma angiotensins and bradykinins [ Time Frame: 0, 24 and 30 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	72
Study Start Date:	January 2007
Estimated Study Completion Date:	December 2010
Estimated Primary Completion Date:	July 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Placebo Comparator placebo (double dummy)	Drug: placebo placebo (double dummy)
2: Active Comparator eplerenone	Drug: eplerenone active comparator
3: Active Comparator doubling of fosinopril dose	Drug: fosinopril doubling of fosinopril dose

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.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00315016

Contacts

Contact: Jacob Deinum, MD	0031243618819	j.deinum@aig.umcn.nl
Contact: Cornelis Kramers, MD	0031243618819	c.kramers@pharmtox.umcn.nl

Locations

Netherlands
University Medical Center Nijmegen St Radboud	Recruiting
Nijmegen, Netherlands, 6525 GA
Principal Investigator: Jacob Deinum, MD
Sub-Investigator: Cornelis Kramers, MD
Sub-Investigator: Gerald Vervoort, MD
Netherlands, Noord Brabant
Jeroen Bosch Hospital	Recruiting
's-Hertogenbosch, Noord Brabant, Netherlands
Contact: Paetrick M Netten, MD
Sub-Investigator: Paetrick M Netten, MD

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:

Jacob Deinum, MD

University Medical Center Nijmegen St Radboud, The Netherlands

More Information

No publications provided

Responsible Party:	Radboud University Nijmegen ( University Medical Center Nijmegen St Radboud )
Study ID Numbers:	IRG 2005-316
Study First Received:	April 14, 2006
Last Updated:	December 1, 2008
ClinicalTrials.gov Identifier:	NCT00315016 History of Changes
Health Authority:	Netherlands: Medicines Evaluation Board (MEB)

Keywords provided by Radboud University:

albuminuria
eplerenone
ACE inhibition
renal function
endothelial function

Additional relevant MeSH terms:

Fosinopril
Diabetic Nephropathies
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Signs and Symptoms
Urologic Diseases
Therapeutic Uses
Angiotensin-Converting Enzyme Inhibitors
Kidney Diseases
Diabetes Complications
Albuminuria

Urination Disorders
Diabetes Mellitus
Endocrine System Diseases
Enzyme Inhibitors
Cardiovascular Agents
Antihypertensive Agents
Pharmacologic Actions
Protease Inhibitors
Urological Manifestations
Eplerenone
Proteinuria
Aldosterone Antagonists

ClinicalTrials.gov processed this record on November 27, 2009