Statins in Proteinuric Nephropathies (ESPLANADE)

This study has been completed.
Sponsor:
Information provided by:
Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:
NCT00199927
First received: September 12, 2005
Last updated: April 27, 2010
Last verified: April 2010
  Purpose

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.


Condition Intervention Phase
Chronic Nephropathy
Proteinuria
Hypertension
Drug: Fluvastatin
Drug: standard therapy
Phase 3

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Mario Negri Institute for Pharmacological Research:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 217
Study Start Date: March 2003
Study Completion Date: March 2008
Primary Completion Date: December 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: standard therapy
Standard therapy
Drug: standard therapy
standard therapy
Active Comparator: fluvastatin
40-80 mg/day
Drug: Fluvastatin
Starting dose of Fluvastatin of 40 mg/day uptitrated to 80 mg/day

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

Ages Eligible for Study:   16 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00199927

Locations
Italy
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
Firenze, Italy
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
Sponsors and Collaborators
Mario Negri Institute for Pharmacological Research
Investigators
Principal Investigator: Piero Ruggenenti, MD Mario Negri Institute
  More Information

No publications provided by Mario Negri Institute for Pharmacological Research

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Piero Ruggenenti, Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier: NCT00199927     History of Changes
Other Study ID Numbers: ESPLANADE
Study First Received: September 12, 2005
Last Updated: April 27, 2010
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Hypertension
Kidney Diseases
Proteinuria
Cardiovascular Diseases
Signs and Symptoms
Urination Disorders
Urologic Diseases
Urological Manifestations
Vascular Diseases
Angiotensin Receptor Antagonists
Fluvastatin
Anticholesteremic Agents
Antimetabolites
Enzyme Inhibitors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 30, 2014