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Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes (CECSID)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Andrea M. Isidori, University of Roma La Sapienza
ClinicalTrials.gov Identifier:
NCT00692237
First received: June 4, 2008
Last updated: May 5, 2013
Last verified: May 2013

June 4, 2008
May 5, 2013
January 2008
September 2009   (final data collection date for primary outcome measure)
Left Ventricular Torsion Defined as Change in Ventricular Mid-wall Rotation (°) Measured by Cine-Cardiac Magnetic Resonance (CMR) Imaging With Tagging, Before and After Three Months of Treatment With Sildenafil and Placebo (100 mg/Day). [ Time Frame: 0 and + 3 months ] [ Designated as safety issue: Yes ]
Diabetic cardiomyopathy and hypertrophy are characterized by an increase in cardiac torsion Normal value of rotation are < 12°; in hypertrophic heart such values can raise up to 20-25°. A reduction in left ventricular wall rotation is a sign of improvement after removal of known causes of hypertrophy (for example after surgical repair of aortic stenosis). Based on previous studies a reduction of 3 degrees (°) is considered clinically significant.
Changes of cardiac performance, measured by cine-Magnetic Resonance Imaging (MRI) analysis of left ventricular torsion, before and after three months of treatment with 100 mg Sildenafil daily. [ Time Frame: 0 and + 3 months ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00692237 on ClinicalTrials.gov Archive Site
Ejection Fraction (EF) Defined as the Volume of Blood Ejected With Each Beat Was Measured on Cine-Cardiac Magnetic Resonance (CMR) Images Before and After Three Months Treatment With Sildenafil and Placebo (100 mg/Day). [ Time Frame: 0 and + 3 months ] [ Designated as safety issue: Yes ]
The volume of blood within a ventricle immediately before a contraction is known as the end-diastolic volume; the volume of blood left in a ventricle at the end of contraction is end-systolic volume. The difference between end-diastolic volume and end-systolic volumes is the volume of blood ejected with each beat. Ejection fraction (Ef) is the fraction of the end-diastolic volume that is ejected with each beat; expressed as percentage of EDV. This is a measure of cardiac performance that can be deteriorated in diabetic cardiomyopathy.
MRI: Left ventricular volume, Fibrosis area, Ejection fraction; blood pressure (holter 24 h); flow mediated dilatation of the brachial artery; VEGF levels, HOMA index, eGFR, Albuminuria (24 h), Oxidative stress markers [ Time Frame: 0 and + 3 months ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Cardiovascular Effects of Chronic Sildenafil in Men With Type 2 Diabetes
Cardiovascular Effects of Chronic Sildenafil (Viagra) Treatment in Diabetic Subjects With Endothelial Dysfunction.

Type 2 Diabetes Mellitus (T2DM) represents a model of endothelial dysfunction, where chronic nitric oxide deprivation, hyperglycaemia and hyperinsulinemia and fibrogenic mediators lead to cardiovascular remodelling associated with diabetic cardiomyopathy and in consequence to secondary complications of diabetes. Specific anti-oxidative and anti-fibrotic therapies are not currently available. Sildenafil (Viagra) has demonstrated the capability of significantly improving endothelial dysfunction and cardiac fibrosis in experimental animal models.

The purpose of the present study is performed to establish the effect of chronic high dose sildenafil treatment on heart performance in diabetic subjects.

Type 2 Diabetes Mellitus (T2DM) represents a model of endothelial dysfunction at central and peripheral levels, where chronic nitric oxide deprivation, due to hyperglycaemia, leads to a loss of vascular endothelium-relaxant function and ischaemia-reperfusion ventricular damage. Since haemodynamic and oxidative stress could trigger a pro-inflammatory process of the intracardiac vasculature, endothelial cells activated in turns can produce fibrogenic mediators and induce fibroblast activation and myocardial fibrosis. Moreover, the increase of insulin levels of T2DM induces cardiotoxicity increasing the expression of ventricular angiotensin II type 1 receptor (AT1). All these mechanisms lead to cardiovascular remodelling associated with diabetic cardiomyopathy that is characterized by an impairment of heart diastolic performance with a ventricular hypertrophy and a dilatation and an increase of heart torsion.

Specific anti-oxidative and anti-fibrotic therapies are not currently available. Phosphodiesterase 5 inhibitors (PDE5i) work to improve endothelial dysfunction by preventing the breakdown of cyclic guanosine monophosphate (cGMP), resulting in increased cellular content and consequent relaxation of smooth muscle cells of all systemic arteries and veins. PDE5i have therefore the potential to impact the cardiovascular performance, acting on all these mechanisms.

The aim of the study is to evaluate the cardiovascular effects of the chronic (3 months) high dose (100 mg daily) sildenafil treatment in patient with type 2 diabetes. We will analyze the changes in parameters of endothelial dysfunction and heart remodelling and in metabolic indices. We will evaluate the outcomes at day 90. Moreover we will estimate if the changes in endothelial function will be sustained 30 days after discontinuing treatment.

This is designed as a phase IV study on chronic treatment with a cohort size of 30 patients randomized to receive Sildenafil and 20 patients randomized to placebo. Accounting for a 15% drop off, a total enrollment of 60 patients is planned. Patients will begin a washout from PDE5i in the first visit (4 weeks before the beginning of the treatment). Evaluation of potential toxicity will be monitored throughout the course of treatment. Follow-up visits will take place at days + 30, +60, +90 (end of treatment) and +120. Plasma and serum monitoring of basal and postprandial glycaemia and insulinemia, hematochemical routine, VEGF, hormones and others cytokines and albuminuria will be made prior to treatment, at days 30, 60, 90, 120. Measurements of cine-MRI, FMD and blood pressure Holter 24h will be made at time 0 and at days 90.

The long-term objective is to identify a safe and easily administered treatment that improves functional outcome in diabetic patients.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
  • Diabetes Mellitus, Type 2
  • Endothelial Dysfunction
  • Drug: Sildenafil
    100 mg daily (3 capsules/day)
    Other Names:
    • - Viagra 25 mg
    • - Viagra 50 mg
  • Drug: Placebo
    Placebo 100 mg (3 capsules/day)
    Other Name: Placebo
  • Active Comparator: 1
    Sildenafil 100 mg
    Intervention: Drug: Sildenafil
  • Placebo Comparator: 2
    Placebo 100 mg
    Intervention: Drug: Placebo
Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012 May 15;125(19):2323-33. doi: 10.1161/CIRCULATIONAHA.111.063412. Epub 2012 Apr 11.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
59
December 2009
September 2009   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients with type 2 diabetes mellitus
  • Patients age 35-75
  • Metabolic control of diabetes by diet or oral treatment (unmodified in the last 3 months)
  • Blood pressure <160/100 mmHg, including subjects with controlled hypertension, treated with ACE-inhibitors/sartans, unmodified in the last 3 months

Exclusion Criteria:

  • Participation in another study with an investigational drug or device
  • HbA1c >12%
  • Alterations during ECG stress examination
  • Current use of nitrate agents
  • Proliferative retinopathy
  • Patients with history of cardiovascular and malignant disease
  • Psychosocial disturbance
  • Alcohol or drug dependence
  • Allergy or hypersensitivity to sildenafil or other Phosphodiesterase inhibitors.
Male
35 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
Italy
 
NCT00692237
746/07
Yes
Andrea M. Isidori, University of Roma La Sapienza
University of Roma La Sapienza
Not Provided
Principal Investigator: Andrea Lenzi, MD, PhD University of Roma La Sapienza
University of Roma La Sapienza
May 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP