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Eplerenone, ACE Inhibition and Albuminuria

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00315016
Recruitment Status : Completed
First Posted : April 17, 2006
Last Update Posted : May 28, 2012
Information provided by (Responsible Party):
Radboud University

Tracking Information
First Submitted Date  ICMJE April 14, 2006
First Posted Date  ICMJE April 17, 2006
Last Update Posted Date May 28, 2012
Study Start Date  ICMJE January 2007
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 1, 2008)
  • proteinuria [ Time Frame: 0, 4, 12, 24 and 30 weeks ]
  • blood pressure by home measurements [ Time Frame: 0, 4, 12, 24 and 30 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 14, 2006)
  • proteinuria
  • blood pressure measured by ABPM
  • differential protein excretion in 2 hr urines (b2-microglobulin, GST etc.)
  • GFR and RPF
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2008)
  • serum potassium [ Time Frame: 0, 3, days, 2, 4, 12, 24 and 30 weeks ]
  • haemoglobin [ Time Frame: 0, 4, 12, 24 and 30 weeks ]
  • urinary excretion of CTGF, TGF-b, collagen IV [ Time Frame: 0, 4, 12, 24 and 30 weeks ]
  • inulin and PAH clearance [ Time Frame: 0, 24 and 30 weeks ]
  • Quality of Life [ Time Frame: 0, 4, 12, 24 and 30 weeks ]
  • plasma aldosterone, renin [ Time Frame: 0, 24 and 30 weeks ]
  • plasma angiotensins and bradykinins [ Time Frame: 0, 24 and 30 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2006)
  • serum potassium
  • haemoglobin
  • urinary excretion of CTGF, TGF-b, collagen IV
  • endothelial function of forearm
  • Quality of Life
  • plasma aldosterone, renin
  • plasma angiotensins and bradykinins
  • endogenous hippuric acid clearance
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Eplerenone, ACE Inhibition and Albuminuria
Official Title  ICMJE Eplerenone, ACE Inhibition and Albuminuria
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Nephropathy
Intervention  ICMJE
  • Drug: eplerenone
    active comparator
    Other Name: Eplerenone or INSPRA
  • Drug: fosinopril
    doubling of fosinopril dose
    Other Name: fosinopril or Newace
  • Drug: placebo
    placebo (double dummy)
    Other Name: no other name
Study Arms  ICMJE
  • Placebo Comparator: 1
    placebo (double dummy)
    Intervention: Drug: placebo
  • Active Comparator: 2
    Intervention: Drug: eplerenone
  • Active Comparator: 3
    doubling of fosinopril dose
    Intervention: Drug: fosinopril
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.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 25, 2012)
Original Enrollment  ICMJE
 (submitted: April 14, 2006)
Actual Study Completion Date  ICMJE July 2011
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00315016
Other Study ID Numbers  ICMJE IRG 2005-316
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Radboud University
Study Sponsor  ICMJE Radboud University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jacob Deinum, MD University Medical Center Nijmegen St Radboud, The Netherlands
PRS Account Radboud University
Verification Date May 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP