Clinical trial NCT00199927: Statins in Proteinuric Nephropathies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Nephropathy
Proteinuria
Hypertension
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
First posted: 2005-09-20
Enrollment: 217
Sex: ALL
Minimum age (years): 16
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

AIMS Primary

- 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.

Secondary

* 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.

Eligibility criteria: Inclusion Criteria:

* age \>16 years
* hypertension, defined as a systolic or diastolic blood pressure \> 140 or 90 mmHg respectively (or less in patients with concomitant antihypertensive therapy)
* creatinine clearance \>20 ml/min/1.73m2 (with variation of less than 30% in the 3 months prior to study entry)
* urinary protein excretion rate persistently \> 1 g/24 hours (average of at least two measurements in two urine collections two weeks apart) without evidence of urinary tract infection or overt heart failure (New York Heart Association class III or more)
* written informed consent

Exclusion criteria:

* specific contraindication to statin therapy because of a previous coronary event or serum LDL-cholesterol levels \> 190 mg/dL despite a low cholesterol (\<200 mg/day) diet and a saturated fatty acid in take less than 7% of total calories will not be included
* chronic treatment with corticosteroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs
* acute myocardial infarction or cerebrovascular accident in the six months preceding the study - severe uncontrolled hypertension (diastolic blood pressure \>115 and/or systolic blood pressure \>220 mmHg)
* evidence or suspicion of renovascular disease, obstructive uropathy, type 1 diabetes mellitus, vasculitides, cancer
* elevated serum aminotransferase concentrations - chronic cough
* history of poor tolerance or allergy to ACEi, ATA or statins
* drug or alcohol abuse
* pregnancy, breast feeding and ineffective contraception
* legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the trial.

Primary outcomes:
measure: 24-hour urinary protein excretion rate, at the end of 6 months treatment phase
timeFrame: At 0, 2,3,4,5,6,7,8,9,10 months.
Secondary outcomes:
measure: 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.
Other outcomes:
Locations:
city: Montevarchi
country: Italy
facility: Hospital "Santa Maria della Gruccia" - Unit of Nephrology and Dialysis
state: Arezzo
city: Ranica
country: Italy
facility: Clinical Research Center for Rare Diseases
state: Bergamo
city: Acireale
country: Italy
facility: Hospital "S.Marte e S.Venere" - Unit of Nephrology and Dialysis
state: Catania
city: Bagno a Ripoli
country: Italy
facility: Hospital "Santa Maria dell'Annunziata" - Unit of Nephrology
state: Firenze
city: San Giovanni Rotondo
country: Italy
facility: Hospital "Casa Sollievo della Sofferenza" - Unit of Nephrology and Dialysis
state: Foggia
city: Castelfranco Veneto
country: Italy
facility: Hospital "S.Giacomo Apostolo"
state: Treviso
city: Catania
country: Italy
facility: Hospital "Vittorio Emanuele II, S. Bambino, Ferrarotto" - Unit of Nephrology and Dialisys
city: Catanzaro
country: Italy
facility: Hospital "Ciaccio" - Unit of Nephrolofy and Dialysis
city: Firenze
country: Italy
facility: Hospital "Careggi Monna Tessa" - Unit of Nephrology and Dialysis
city: Padova
country: Italy
facility: Hospital of Padova - Unit of Nephrology and Dialysis
city: Palermo
country: Italy
facility: Hospital "Civico e Benefratelli" - Unit of Nephrology and Hemodialysis
city: Parma
country: Italy
facility: Hospital of Parma - Department of Medical Clinic
city: Reggio Calabria
country: Italy
facility: "Ospedali Riuniti" CNR I.B.I.M. - Unit of Nephrology
city: Sassari
country: Italy
facility: University of Sassari - Institute of Medical Pathology
city: Teramo
country: Italy
facility: Hospital "G.Mazzini" - Unit of Nephrology and Dialysis
city: Venezia
country: Italy
facility: Hospital of Mestre - Unit of Nephrology and Dialysis
Study officials:
affiliation: Mario Negri Institute
name: Piero Ruggenenti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ruggenenti P, Perna A, Tonelli M, Loriga G, Motterlini N, Rubis N, Ledda F, Rota S Jr, Satta A, Granata A, Battaglia G, Cambareri F, David S, Gaspari F, Stucchi N, Carminati S, Ene-Iordache B, Cravedi P, Remuzzi G; ESPLANADE Study Group. Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial. Clin J Am Soc Nephrol. 2010 Nov;5(11):1928-38. doi: 10.2215/CJN.03380410. Epub 2010 Jul 29.