Clinical trial NCT00315016: Eplerenone, ACE Inhibition and Albuminuria
Official title: Eplerenone, ACE Inhibition and Albuminuria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetic Nephropathy
Keywords: albuminuria
eplerenone
ACE inhibition
renal function
endothelial function
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2006-04-17
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: proteinuria
timeFrame: 0, 4, 12, 24 and 30 weeks
measure: blood pressure by home measurements
timeFrame: 0, 4, 12, 24 and 30 weeks
Secondary outcomes:
measure: serum potassium
timeFrame: 0, 3, days, 2, 4, 12, 24 and 30 weeks
measure: haemoglobin
timeFrame: 0, 4, 12, 24 and 30 weeks
measure: urinary excretion of CTGF, TGF-b, collagen IV
timeFrame: 0, 4, 12, 24 and 30 weeks
measure: inulin and PAH clearance
timeFrame: 0, 24 and 30 weeks
measure: Quality of Life
timeFrame: 0, 4, 12, 24 and 30 weeks
measure: plasma aldosterone, renin
timeFrame: 0, 24 and 30 weeks
measure: plasma angiotensins and bradykinins
timeFrame: 0, 24 and 30 weeks
Other outcomes:
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Hospital
state: Noord Brabant
city: Nijmegen
country: Netherlands
facility: University Medical Center Nijmegen St Radboud
Study officials:
affiliation: University Medical Center Nijmegen St Radboud, The Netherlands
name: Jacob Deinum, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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(10):CD007004. doi: 10.1002/14651858.CD007004.pub4.