Preventing ESRD in Overt Nephropathy of Type 2 Diabetes - Full Text View

Sponsor:	Mario Negri Institute for Pharmacological Research
Collaborator:	Agenzia Italiana del Farmaco
Information provided by (Responsible Party):	Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:	NCT00494715

Purpose

Nephropathy of type 2 diabetes is the leading cause of end stage renal disease (ESRD) world-wide and is associated with a dramatic excess cardiovascular morbidity and mortality. Two randomized trials found that angiotensin II receptor blockers (ARBs) reduce the incidence of ESRD by about 30%, but have no appreciable effects on cardiovascular mortality. Available data suggest that ACE inhibitors might be similarly renoprotective and even more cardioprotective, but large scale trials on ACE inhibitors, alone or combined with ARBs, in overt nephropathy of type 2 diabetes are missing.

This study will compare the effects, at comparable blood pressure control (systolic/diastolic <130/80 mmHg), of dual renin-angiotensin-system (RAS) blockade by half dose of benazepril and valsartan combination therapy as compared to single RAS blockade by benazepril or valsartan alone at full dose, 20 mg and 160 mg respectively, on ESRD and cardiovascular events in high-risk patients with type 2 diabetes and overt nephropathy, defined as serum creatinine >1.8 mg/dl and < 3.2 mg/dl and spot morning urine albumin to creatinine ratio >1000mg/g for the patients without previous ACE inhibitor and ARB therapy and >500mg/g for the patients with previous ACE inhibitor or ARB therapy and no specific contraindications to the study drugs. The relationships between renal and cardiovascular outcomes will also be evaluated.

102 patients will be treated for at least 3 years. At comparable blood pressure control, the study is expected to show a more effective reduction in ESRD and cardiovascular events with combined than with single drug ACE inhibitor or ARB therapy. As compared to ARB, ACE inhibitor therapy is expected to have a similar effect on ESRD, but a superior cardioprotective effect. Applied to clinical practice, the findings should help reducing renal and cardiovascular complications, and related treatment costs, of type 2 diabetes.

Condition	Intervention	Phase
Diabetes	Drug: Benazepril Drug: Valsartan Drug: Benazepril/Valsartan	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, Probe Trial to Evaluate Whether,at Comparable Blood Pressure Control,Combined Therapy With ACEI BEN and ARB VAL Reduces Progression to ESRD More Effectively Than BEN or VAL Alone in High Risk Patients With Type 2 Diabetes and Overt Nephropathy

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Diabetes Diabetes Type 2

Drug Information available for: Benazepril hydrochloride Benazepril Valsartan Lotrel

U.S. FDA Resources

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

Primary Outcome Measures:

Progression to ESRD (i.e. need for renal replacement therapy by chronic dialysis or renal transplantation) [ Time Frame: 4 times a year ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Doubling of serum creatinine (versus baseline), Rate of GFR decline, Incidence of fatal and non-fatal cardiovascular events (stroke, acute myocardial infarction, sudden death), Albumin to creatinine ratio and 24-hour urinary protein excretion. [ Time Frame: 4 times a year ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	102
Study Start Date:	May 2007
Estimated Study Completion Date:	December 2015
Estimated Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Benazepril	Drug: Benazepril Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).
Experimental: valsartan	Drug: Valsartan Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).
Experimental: benazepril/valsartan	Drug: Benazepril/Valsartan Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).

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Eligibility

Ages Eligible for Study:	40 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Males and females >40 years old;
High-risk subjects with type 2 diabetes (WHO criteria);
Serum creatinine concentration of 1.8 mg/dl or more (but less than 3.5 mg/dl);
Urinary albumin to creatinine ratio >1000mg/g for the patients without previous ACE inhibitor and ARB therapy and >500mg/g for the patients with previous ACE inhibitor or ARB therapy (in spot morning urine)
Legal capacity;
Written informed consent.

Exclusion Criteria:

Specific contraindications or history of hypersensitivity to the study drugs or other;
Serum potassium ≥ 6 mEq/L despite diuretic therapy, and optimized metabolic and acid/base control;
Bilateral renal artery stenosis;
Previous history of allergy or intolerance, or evidence of immunologically-mediated renal disease, systemic diseases, cancer;
Drug or alcohol abuse;
Any chronic clinical conditions that may affect completion of the trial or confound data interpretation;
Pregnancy or lactating;
Women of childbearing potential without following a scientifically accepted form of contraception;
Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequence of the trial;
Evidence of an uncooperative attitude;
Any evidence that patient will not be able to complete the trial follow-up.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00494715

Contacts

Contact: giuseppe remuzzi, MD

0039 035 319888

gremuzzi@marionegri.it

Locations

Italy
Clinical Research Center for Rare Diseases "Aldo e Cele Daccò"	Recruiting
Ranica, Bergamo, Italy
Contact: Stefano Rota, MD 0039 035 4535321
Sub-Investigator: Stefano Rota, MD
Hospital "Bolognini"	Recruiting
Seriate, Bergamo, Italy
Principal Investigator: Ruggero Mangili, MD
Hospital "S.Marta e S.Venera"	Recruiting
Acireale, Catania, Italy
Contact: Maurizio Garozzo, MD mauriziocom@hotmail.com
Principal Investigator: Giovanni Battaglia, MD
Sub-Investigator: Maurizio Garozzo, MD
Hospital " Casa Sollievo della Sofferenza" - Unit of Nephrology	Recruiting
San Giovanni Rotondo, Foggia, Italy
Contact: Filippo Aucella, MD 0039 0882 410367
Sub-Investigator: Rachele Grifa, MD
Principal Investigator: Filippo Aucella, MD
Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" - Unit of Diabetology	Recruiting
Bergamo, Italy
Contact: Roberto Trevisan, MD 0039 035 266968 rtrevisan@ospedaliriuniti.bergamo.it
Principal Investigator: Roberto Trevisan, MD
Sub-Investigator: Elena Mondo, MD
Hospital "Vittorio Emanuele-Ferrarotto-Santo Bambino"	Not yet recruiting
Catania, Italy
Contact: Antonio Granata, MD antonio.granata4@tin.it
Principal Investigator: Antonio Granata, MD
IRCCS San Raffaele - Unit of General Medicine	Recruiting
Milan, Italy
Contact: Paolo Manunta, MD 0039 02 26431 manunta.paolo@hsr.it
Sub-Investigator: Marialuisa Querques, MD
Principal Investigator: Paolo Manunta, MD
University "Federico II"	Recruiting
Napoli, Italy
Contact: Antonio Pisani, MD antonio.pisani@libero.it
Principal Investigator: Antonio Pisani, MD
Sub-Investigator: Gennaro Argentino, MD
Hospital "Azienda Ospedaliera di Parma" - Unit of Nephrology	Recruiting
Parma, Italy
Contact: Salvatore David, MD 0039 0521 293561 davidren@unipr.it
Principal Investigator: Salvatore David, MD
Hospital "Azienda Ospedaliera di Treviglio e Caravaggio" - Ambulatory of Ponte San Pietro	Recruiting
Ponte San Pietro, Italy
Contact: Antonio Belviso, MD 0039 035 603449 belvisoa@tiscali.it
Principal Investigator: Antonio Belviso, MD
Hospital "Azienda Ospedaliera di Treviglio e Caravaggio" Unit of Diabetology and Metabolic Diseases	Not yet recruiting
Romano di Lombardia, Italy
Contact: Antonio Bossi, MD 0039 0363 4241 antonio_bossi@ospedale.treviglio.bg.it
Principal Investigator: Antonio Bossi, MD
Sub-Investigator: Ilian Iliev, MD
University - AUSL 1 - Institute of Medical Pathology	Recruiting
Sassari, Italy
Contact: Andrea Satta, MD 0039 079 228442 amesatta@uniss.it
Principal Investigator: Andrea Satta, MD
Sub-Investigator: Giovanna Farre, MD
Hospital "G:Mazzini"	Recruiting
Teramo, Italy
Contact: Goffredo Del Rosso, MD goffredo.delrosso@aslteramo.it
Principal Investigator: Goffredo Del Rosso, MD
Sub-Investigator: Patrizia Santarelli, MD
Hospital "Azienda Ospedaliera di Treviglio-Caravaggio"Unit of Diabetology and Metabolic Diseases	Recruiting
Treviglio, Italy
Contact: Antonio Bossi, MD 0039 0363 4241 antonio_bossi@ospedale.treviglio.bg.it
Principal Investigator: Antonio Bossi, MD
Sub-Investigator: Aneliya Parvanova, MD
Slovenia
Clinical Department of Endocrinology, Diabetes and Metabolic Diseases University Medical Centre Ljubljana	Recruiting
Ljubljana, Slovenia, 1000
Contact: Andrej Janez, MD andrej.janez@kclj.si

Sponsors and Collaborators

Mario Negri Institute for Pharmacological Research

Agenzia Italiana del Farmaco

Investigators

Study Director:

Giuseppe Remuzzi, MD

Mario Negri Institute for Pharmacological Research

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):

Cohen DL, Townsend RR. Is there added value to adding ARB to ACE inhibitors in the management of CKD? J Am Soc Nephrol. 2009 Aug;20(8):1666-8. Epub 2008 Sep 5.

Responsible Party:	Mario Negri Institute for Pharmacological Research
ClinicalTrials.gov Identifier:	NCT00494715 History of Changes
Other Study ID Numbers:	VALID, 2006-005951-14
Study First Received:	June 29, 2007
Last Updated:	May 24, 2012
Health Authority:	Italy: Ministry of Health

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Kidney Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Benazepril
Valsartan
Angiotensin-Converting Enzyme Inhibitors

Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on May 24, 2012