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Statins in Proteinuric Nephropathies (ESPLANADE)

Primary Purpose

Chronic Nephropathy, Proteinuria, Hypertension

Status
Completed
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Fluvastatin
standard therapy
Sponsored by
Mario Negri Institute for Pharmacological Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Nephropathy

Eligibility Criteria

16 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hospital "Santa Maria della Gruccia" - Unit of Nephrology and Dialysis
  • Clinical Research Center for Rare Diseases
  • Hospital "S.Marte e S.Venere" - Unit of Nephrology and Dialysis
  • Hospital "Santa Maria dell'Annunziata" - Unit of Nephrology
  • Hospital "Casa Sollievo della Sofferenza" - Unit of Nephrology and Dialysis
  • Hospital "S.Giacomo Apostolo"
  • Hospital "Vittorio Emanuele II, S. Bambino, Ferrarotto" - Unit of Nephrology and Dialisys
  • Hospital "Ciaccio" - Unit of Nephrolofy and Dialysis
  • Hospital "Careggi Monna Tessa" - Unit of Nephrology and Dialysis
  • Hospital of Padova - Unit of Nephrology and Dialysis
  • Hospital "Civico e Benefratelli" - Unit of Nephrology and Hemodialysis
  • Hospital of Parma - Department of Medical Clinic
  • "Ospedali Riuniti" CNR I.B.I.M. - Unit of Nephrology
  • University of Sassari - Institute of Medical Pathology
  • Hospital "G.Mazzini" - Unit of Nephrology and Dialysis
  • Hospital of Mestre - Unit of Nephrology and Dialysis

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

standard therapy

fluvastatin

Arm Description

Standard therapy

40-80 mg/day

Outcomes

Primary Outcome Measures

24-hour urinary protein excretion rate, at the end of 6 months treatment phase

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.

Full Information

First Posted
September 12, 2005
Last Updated
April 27, 2010
Sponsor
Mario Negri Institute for Pharmacological Research
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1. Study Identification

Unique Protocol Identification Number
NCT00199927
Brief Title
Statins in Proteinuric Nephropathies
Acronym
ESPLANADE
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

2. Study Status

Record Verification Date
April 2010
Overall Recruitment Status
Completed
Study Start Date
March 2003 (undefined)
Primary Completion Date
December 2007 (Actual)
Study Completion Date
March 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Mario Negri Institute for Pharmacological Research

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Nephropathy, Proteinuria, Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
217 (Actual)

8. Arms, Groups, and Interventions

Arm Title
standard therapy
Arm Type
Active Comparator
Arm Description
Standard therapy
Arm Title
fluvastatin
Arm Type
Active Comparator
Arm Description
40-80 mg/day
Intervention Type
Drug
Intervention Name(s)
Fluvastatin
Intervention Description
Starting dose of Fluvastatin of 40 mg/day uptitrated to 80 mg/day
Intervention Type
Drug
Intervention Name(s)
standard therapy
Intervention Description
standard therapy
Primary Outcome Measure Information:
Title
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.
Secondary Outcome Measure Information:
Title
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Piero Ruggenenti, MD
Organizational Affiliation
Mario Negri Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital "Santa Maria della Gruccia" - Unit of Nephrology and Dialysis
City
Montevarchi
State/Province
Arezzo
ZIP/Postal Code
52100
Country
Italy
Facility Name
Clinical Research Center for Rare Diseases
City
Ranica
State/Province
Bergamo
ZIP/Postal Code
24020
Country
Italy
Facility Name
Hospital "S.Marte e S.Venere" - Unit of Nephrology and Dialysis
City
Acireale
State/Province
Catania
ZIP/Postal Code
95024
Country
Italy
Facility Name
Hospital "Santa Maria dell'Annunziata" - Unit of Nephrology
City
Bagno a Ripoli
State/Province
Firenze
ZIP/Postal Code
50011
Country
Italy
Facility Name
Hospital "Casa Sollievo della Sofferenza" - Unit of Nephrology and Dialysis
City
San Giovanni Rotondo
State/Province
Foggia
ZIP/Postal Code
71013
Country
Italy
Facility Name
Hospital "S.Giacomo Apostolo"
City
Castelfranco Veneto
State/Province
Treviso
ZIP/Postal Code
31033
Country
Italy
Facility Name
Hospital "Vittorio Emanuele II, S. Bambino, Ferrarotto" - Unit of Nephrology and Dialisys
City
Catania
ZIP/Postal Code
95100
Country
Italy
Facility Name
Hospital "Ciaccio" - Unit of Nephrolofy and Dialysis
City
Catanzaro
ZIP/Postal Code
88100
Country
Italy
Facility Name
Hospital "Careggi Monna Tessa" - Unit of Nephrology and Dialysis
City
Firenze
Country
Italy
Facility Name
Hospital of Padova - Unit of Nephrology and Dialysis
City
Padova
ZIP/Postal Code
31033
Country
Italy
Facility Name
Hospital "Civico e Benefratelli" - Unit of Nephrology and Hemodialysis
City
Palermo
ZIP/Postal Code
90100
Country
Italy
Facility Name
Hospital of Parma - Department of Medical Clinic
City
Parma
ZIP/Postal Code
43100
Country
Italy
Facility Name
"Ospedali Riuniti" CNR I.B.I.M. - Unit of Nephrology
City
Reggio Calabria
ZIP/Postal Code
89124
Country
Italy
Facility Name
University of Sassari - Institute of Medical Pathology
City
Sassari
ZIP/Postal Code
07100
Country
Italy
Facility Name
Hospital "G.Mazzini" - Unit of Nephrology and Dialysis
City
Teramo
ZIP/Postal Code
64100
Country
Italy
Facility Name
Hospital of Mestre - Unit of Nephrology and Dialysis
City
Venezia
ZIP/Postal Code
30174
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
20671225
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.
Results Reference
derived

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Statins in Proteinuric Nephropathies

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