Statins in Proteinuric Nephropathies (ESPLANADE)
End stage renal disease (ESRD) is rapidly growing worldwide. Patients with ESRD have increased morbidity and mortality mostly because of a dramatic excess of cardiovascular disease. Thus, preventing or limiting the progression of chronic nephropathies, in addition to limit the incidence of ESRD, may also postpone death. Drugs that inhibit the renin angiotensin system, such as Angiotensin-Converting-Enzyme inhibitors (ACEi) and Angiotensin II receptor antagonists (ATA), are reno- and cardio-protective in the long-term. There are data that statins,in addition to limit cardiovascular events may have specific reno-protective properties.
Thus we designed a study aimed to evaluate whether statins associated to ACEi and ATA may have an additional reno-protective effect.
ESPLANADE is a multicenter, prospective, randomized, parallel group study in which, after 2 months treatment with ACEi and ATA, two groups of 90 patients, with or without type 2 diabetes, are randomized to 6 months Fluvastatin (40 or 80 mg/day) treatment YES or NO.Twenty Italian Nephrology Units are involved in the trial. The study is fully coordinated by the Clinical Research Center for Rare Disease Aldo e Cele Daccò, Villa Camozzi, Ranica.
Drug: standard therapy
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Prospective, Randomized, Multicenter Trial Testing the Antiproteinuric Effect of Statins Added to Combined ACE-inhibitor and Angiotensin Receptor Antagonist Therapy in Proteinuric, Chronic Nephropathies|
- 24-hour urinary protein excretion rate, at the end of 6 months treatment phase [ Time Frame: At 0, 2,3,4,5,6,7,8,9,10 months. ] [ Designated as safety issue: Yes ]
- Urinary protein/creatinine ratio; glomerular filtration rate (GFR); lipid profile. In a subgroup: renal plasma flow (RPF); filtration fraction albumin; IgG and IgM fractional clearance; insulin sensitivity; urinary endothelin excretion. [ Designated as safety issue: Yes ]
|Study Start Date:||March 2003|
|Study Completion Date:||March 2008|
|Primary Completion Date:||December 2007 (Final data collection date for primary outcome measure)|
Active Comparator: standard therapy
Drug: standard therapy
Active Comparator: fluvastatin
Starting dose of Fluvastatin of 40 mg/day uptitrated to 80 mg/day
INTRODUCTION End stage renal disease (ESRD) is rapidly growing worldwide and costs of providing ESRD care will soon outstrip the available resources. In addition to a poor quality of life, patients with ESRD have 10 to 20 timer higher mortality than age-, race- and gender-matched healthy controls, with > 50% of this excess burden being attributable to cardiovascular risk. Thus, preventing or limiting progression of chronic nephropathies, may serve to limit the incidence not only of ESRD, but also the excess of cardiovascular complications associated with chronic renal disease.
Several data are available that proteinuria is an important determinant of progression to ESRD and a risk factor for increased cardiovascular morbidity and mortality. Drugs, such as Angiotensin-Converting-Enzyme inhibitors (ACEi) and Angiotensin II receptor antagonists (ATA), that decrease proteinuria are also reno- and cardio-protective in the long-term.The combination of these drugs may reduce proteinuria more effectively than the two drugs alone. Preliminary data are also available that statins, in addition to ameliorate the lipid profile may have specific renoprotective properties and, combined to ACEi and ATA, may synergize their antiproteinuric effects in experimental models of chronic renal disease.Moreover, the addition of statins to antihypertensive treatment with or without inhibitors of the renin-angiotensin system has an additive effect on reducing proteinuria also in humans.Whether also in humans combining statins to ACEi and ATA may reduce proteinuria more effectively than ACEi and ATA alone is therefore worth investigating.
- To assess whether statins combined to ACEi and ATA more effectively than ACEi and ATA alone reduce urinary protein excretion rate in chronic proteinuric nephropathies.
- To assess the effect of statins combined to ACEi and ATA vs. the combination of ACEi and ATA alone on other outcome variables including urinary protein/creatinine ratio, glomerular filtration rate (GFR), lipid profile and, in a subgroup endothelial function. - To evaluate by correlation and multivariate analyses the relationship between baseline /follow-up covariates and the above outcome variables in the study group as a whole and within each treatment group.
To assess treatment tolerability DESIGN This is be a prospective, randomized, parallel group study in which, following a 2 month Wash-out period from previous treatment (if any) with ACEi, ATA, potassium sparing diuretics or statins, patients will enter a two-month Run-In phase on renin angiotensin system (RAS) inhibitor therapy (ACE inhibition by benazepril for one month and ACE inhibition plus angiotensin II antagonism by combined treatment with benazepril and valsartan for one further month). At completion of the Run-in period and after a baseline evaluation, patients will be randomized to a six-month Treatment period with or without fluvastatin. Regardless of the randomization group, all patients will be offered optimal conservative treatment including optimal blood pressure control(systolic/diastolic blood pressure <130/80 mmHg) and life-style recommendations such as stop smoking and controlled protein and sodium intake.
180 patients will be enrolled in the study.
|Hospital "Santa Maria della Gruccia" - Unit of Nephrology and Dialysis|
|Montevarchi, Arezzo, Italy, 52100|
|Clinical Research Center for Rare Diseases|
|Ranica, Bergamo, Italy, 24020|
|Hospital "S.Marte e S.Venere" - Unit of Nephrology and Dialysis|
|Acireale, Catania, Italy, 95024|
|Hospital "Santa Maria dell'Annunziata" - Unit of Nephrology|
|Bagno a Ripoli, Firenze, Italy, 50011|
|Hospital "Casa Sollievo della Sofferenza" - Unit of Nephrology and Dialysis|
|San Giovanni Rotondo, Foggia, Italy, 71013|
|Hospital "S.Giacomo Apostolo"|
|Castelfranco Veneto, Treviso, Italy, 31033|
|Hospital "Vittorio Emanuele II, S. Bambino, Ferrarotto" - Unit of Nephrology and Dialisys|
|Catania, Italy, 95100|
|Hospital "Ciaccio" - Unit of Nephrolofy and Dialysis|
|Catanzaro, Italy, 88100|
|Hospital "Careggi Monna Tessa" - Unit of Nephrology and Dialysis|
|Hospital of Padova - Unit of Nephrology and Dialysis|
|Padova, Italy, 31033|
|Hospital "Civico e Benefratelli" - Unit of Nephrology and Hemodialysis|
|Palermo, Italy, 90100|
|Hospital of Parma - Department of Medical Clinic|
|Parma, Italy, 43100|
|"Ospedali Riuniti" CNR I.B.I.M. - Unit of Nephrology|
|Reggio Calabria, Italy, 89124|
|University of Sassari - Institute of Medical Pathology|
|Sassari, Italy, 07100|
|Hospital "G.Mazzini" - Unit of Nephrology and Dialysis|
|Teramo, Italy, 64100|
|Hospital of Mestre - Unit of Nephrology and Dialysis|
|Venezia, Italy, 30174|
|Principal Investigator:||Piero Ruggenenti, MD||Mario Negri Institute|