NCT00503152

Brief Summary

In people with type 2 diabetes, microalbuminuria is a strong, independent risk factor for diabetic nephropathy and cardiovascular morbidity and mortality. ACE inhibitor therapy decreased the risk of microalbuminuria in hypertensive subjects with type 2 diabetes and normoalbuminuria by about 40%. Available data suggest that angiotensin II receptor blockers (ARBs) might have a similar renoprotective effect and that this effect might be increased by combined ACE inhibitor therapy. The study will evaluate the effects, at similar blood pressure control (systolic/diastolic \<130/80 mmHg), for a period of three years, of dual renin-angiotensin-system (RAS) blockade by benazepril and valsartan combination therapy as compared to single RAS blockade by benazepril or valsartan alone on microalbuminuria and cardiovascular events in high-risk patients with type 2 diabetes, creatinine \<1.5 mg/dl, no evidence of microalbuminuria but at high risk of renal disease, with hypertension and a urinary albumin excretion between 7 and 19 microgram/min. The relationship between albuminuria and cardiovascular outcomes will also be evaluated. The study is expected to show a more effective prevention of microalbuminuria and cardiovascular events with combined than with single drug ACE inhibitor or ARB therapy. As compared to ACE inhibitor, ARB therapy is expected to have a similar effect on microalbuminuria, but an inferior cardioprotective effect. Applied to clinical practice, the findings should help preventing renal and cardiovascular complications, and related treatment costs, of type 2 diabetes.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
612

participants targeted

Target at P75+ for phase_3 diabetes

Timeline
Completed

Started May 2007

Longer than P75 for phase_3 diabetes

Geographic Reach
1 country

9 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 1, 2007

Completed
3 months until next milestone

First Submitted

Initial submission to the registry

July 17, 2007

Completed
1 day until next milestone

First Posted

Study publicly available on registry

July 18, 2007

Completed
9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

July 1, 2016

Completed
2 months until next milestone

Study Completion

Last participant's last visit for all outcomes

September 1, 2016

Completed
Last Updated

September 6, 2019

Status Verified

September 1, 2019

Enrollment Period

9.2 years

First QC Date

July 17, 2007

Last Update Submit

September 3, 2019

Conditions

Diabetes

Outcome Measures

Primary Outcomes (1)

  • Development of persistent microalbuminuria (i.e. urinary albumin excretion rate >20 µg/min in at least 2 of 3 consecutive overnight urine collections confirmed in two consecutive visits). Whenever a patient will be found to have 2 of 3 collections in the

    2 times a year

Secondary Outcomes (1)

  • Regression to low-normal albuminuria (i.e. urinary albumin excretion rate <7 µg/min in at least 2 of 3 consecutive overnight urine collections confirmed in two consecutive visits); Albuminuria (considered as a continuous variable); Serum creatinine (v

    2 times a year

Study Arms (3)

benazepril

EXPERIMENTAL
Drug: Benazepril

valsartan

EXPERIMENTAL
Drug: Valsartan

benazepril/valsartan

EXPERIMENTAL
Drug: Benazepril/Valsartan

Interventions

BenazeprilDRUG

After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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).

benazepril
ValsartanDRUG

After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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).

valsartan
Benazepril/ValsartanDRUG

After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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).

benazepril/valsartan

Eligibility Criteria

Age40 Years - 80 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Males and females \>40 years old;
  • High-risk subjects with type 2 diabetes (WHO criteria);
  • History of diabetes not exceeding 25 years;
  • High blood pressure (systolic and/or diastolic blood pressure \>135/85 mmHg or concomitant treatment with blood pressure lowering medications);
  • Serum creatinine concentration \<1.5 mg/dl;
  • Overnight urinary albumin excretion (in at least 2 of 3 consecutive overnight urine collections) ≥ 7 and \<20 µg/min;
  • Legal capacity;
  • Written informed consent.

You may not qualify if:

  • Uncontrolled diabetes (glycated hemoglobin \>11%);
  • Specific contraindications or history of hypersensitivity to the study drugs;
  • Serum potassium ≥ 5.5 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (9)

Hospital "Azienda Ospedaliera di Treviglio e Caravaggio" - Diabetologic Ambulatory of Ponte San Pietro

Ponte San Pietro, Bergamo, Italy

Location

Clinical Research Center for Rare Diseases "Aldo e Cele Daccò"

Ranica, Bergamo, Italy

Location

Hospital "Azienda Ospedaliera di Treviglio e Caravaggio" Unit of Diabetology and Metabolic Diseases

Romano di Lombardia, Bergamo, Italy

Location

Hospital "Bolognini"

Seriate, Bergamo, Italy

Location

Hospital "Azienda Ospedaliera di Treviglio-Caravaggio"Unit of Diabetology and Metabolic Diseases

Treviglio, Bergamo, Italy

Location

Hospital "Casa Sollievo della Sofferenza" - Division of Endocrinology

San Giovanni Rotondo, Foggia, Italy

Location

Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" - Unit of Diabetology

Bergamo, Italy

Location

IRCCS San Raffaele - Unit of General Medicine

Milan, Italy

Location

Azienda USL 2

Olbia, Italy

Location

Related Publications (1)

  • Ruggenenti P, Cortinovis M, Parvanova A, Trillini M, Iliev IP, Bossi AC, Belviso A, Aparicio MC, Trevisan R, Rota S, Perna A, Peracchi T, Rubis N, Martinetti D, Prandini S, Gaspari F, Carrara F, De Cosmo S, Tonolo G, Mangili R, Remuzzi G; VARIETY Study Organization. Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study. PLoS Med. 2021 Jul 14;18(7):e1003691. doi: 10.1371/journal.pmed.1003691. eCollection 2021 Jul.

    PMID: 34260595DERIVED

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

benazeprilValsartan

Condition Hierarchy (Ancestors)

Glucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

TetrazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsValineAmino Acids, Branched-ChainAmino AcidsAmino Acids, Peptides, and ProteinsAmino Acids, Essential

Study Officials

  • Piero Ruggenenti, MD

    Mario Negri Institute for Pharmacological Research

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
phase 3
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

July 17, 2007

First Posted

July 18, 2007

Study Start

May 1, 2007

Primary Completion

July 1, 2016

Study Completion

September 1, 2016

Last Updated

September 6, 2019

Record last verified: 2019-09

Locations

IT(9)