Diabetes & Vardenafil (DiVa)

Monitoring of Endothelial Dysfunction During Chronic Administration of Vardenafil in Patients With Type 2 Diabetes Mellitus: A Longitudinal, Randomised, Placebo-controlled, Double Blind, Phase II b, Clinical Trial

Given the protective effect of nitric oxide (NO) on the endothelium and the results obtained so far in short-term, continuous treatment with phosphodiesterase-5 (PDE5) inhibitors on parameters of endothelial function, we hypothesise that chronic treatment with vardenafil can prevent or delay the deterioration of systemic endothelial function in patients with type 2 diabetes mellitus. The favourable effect of PDE5 inhibitors on sexual function in these patients has been convincingly demonstrated in the past. Here we hypothesise that vardenafil treatment can have beneficial effects on the vascular physiology in other body districts, possibly preventing the development of microangiopathy and atherosclerotic cardiovascular disease in these patients.

The main goal of this study is therefore to monitor the endothelial dysfunction during continuous treatment with vardenafil for 6 months; object of the study will be endothelin 1 and other known parameters of endothelial damage in newly diagnosed patients with type 2 diabetes mellitus.

Study Overview

• Status: Completed
• Conditions: Erectile Dysfunction; Endothelial Dysfunction; Type 2 Diabetes Mellitus (T2DM)
• Intervention / Treatment: Drug: Vardenafil; Drug: Placebo

Detailed Description

Phosphodiesterase-5 (PDE5) inhibitors are currently used in the therapy of erectile dysfunction (ED), which is considered to be an early symptom of cardiovascular disease (CD). Impairment of endothelial function is the early lesion preceding atherosclerosis and is common to ED, CD and vascular complications of diabetes mellitus (DM). Continuous administration of the PDE5 inhibitors tadalafil or sildenafil for four weeks in men with increased cardiovascular risk or type 2 DM has been shown to improve endothelial function measured by flow-mediated dilation and reduction of inflammatory markers. The goal of this study is to investigate whether chronic, long-term treatment with vardenafil improves and/or prevents deterioration of systemic endothelial function in patients with type 2 DM. Study design: longitudinal, double-blind, randomised, placebo-controlled interventional study. Patients: 106 male patients (n determined by power analysis) with type 2 DM diagnosed and classified according to the guidelines of the European Association for the Study of Diabetes. Beside the antidiabetic treatment, patients will be randomly assigned to receive either placebo or vardenafil, 10 mg p.o. two times a day for 24 weeks. Exclusion criteria: all contraindications to treatment with PDE5 inhibitors. Age range: 40-60 years. Sample size determined by power analysis assuming variations of the primary end point of ± 10% from baseline at 0.05 α level with a power of 80%, a two-sided test and a dropout rate of 15%. Primary end point: serum endothelin 1 levels (decreased/not increased in the verum group vs. not decrease/increased in the placebo group). Other parameters and measurements: Complete clinical workup, weight, height, waist-hip ratio, serum lipids and glucose, hemoglobin glycated (HbA1c), micro- and macroalbuminuria, homocysteine, high reactive C-protein (hsCRP), interleukin-6 (IL-6), Tumor necrosis factor (TNF)α, fibrinogen, adiponectin, testosterone, sex hormone-binding globulin (SHBG) and estradiol. All parameters measured at baseline, 4 weeks, 12 weeks and 24 weeks on medication as well as 4 and 24 weeks after discontinuation of the study drug. Study duration: two years. Statistics: descriptive statistics, ANCOVA and multiple regression analysis or non-parametric tests as appropriate by STATA. Ethics: The trial will be registered. Ethics committee approval and patient informed consent will be obtained. Expected outcome and objective: Monitoring of endothelial function deterioration in type 2 DM during chronic administration of Vardenafil. Possibility for a long term-follow up study. Publication in a high impact factor journal.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Modena, Italy, 41126
    • Unit of Endocrinology Azienda USL

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male gender
• Signed written Consent Form
• Type 2 diabetes mellitus diagnosed within 5 years before enrolment in the study
• Body Mass Index (BMI) < 35
• ED (severe, moderate or light according to the International Index of Erectile Function - erectile function domain score < 26 (Rosen et al. 1997))
• Age range: 40-65 years.

Exclusion Criteria:

• Systemic diseases except type 2 diabetes mellitus
• Absence of ED
• Psychiatric disorders
• All contraindications to treatment with PDE5 inhibitors, such as retinitis pigmentosa, non-arteritic anterior ischaemic optic neuropathy, history of coronary artery disease, recent myocardial infarction, unstable angina, systemic arterial hypotension, nitric-oxide donors therapy, severe hepatic and renal failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vardenafil; The study protocol consists of a Screening/Enrolment Phase lasting up to 4 weeks, a Treatment Phase of 24 weeks, and Follow-up/Observation Treatment-free Phase of 24 weeks after the Treatment Phase. During treatment phase, patients enrolled in the Study Group were treated with vardenafil 10 mg twice/daily.	Drug: Vardenafil; Vardenafil 10 mg twice daily for six months; Other Names: Levitra
Placebo Comparator: Control; The study protocol consists of a Screening/Enrolment Phase lasting up to 4 weeks, a Treatment Phase of 24 weeks, and Follow-up/Observation Treatment-free Phase of 24 weeks after the Treatment Phase. During treatment phase, patients enrolled in the Control Group were treated with tablets twice/daily identical to the Study Group, but containing placebo.	Drug: Placebo; Placebo two tablets daily for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelin-1	change in serum endothelin 1 concentration	"6 months"

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow Mediated Dilation	Change of flow mediated dilation evaluated by ultrasonography at brachial artery	"baseline"
Flow Mediated dilation (FMD)	Change of FMD levels	"6 months"
Flow Mediated Dilation	Change of FMD levels	"One year"

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
carotid Intima Media Thickness	Change of ultrasonographic evaluation of intima-media thickness at both right and left carotid arteries	"baseline"
carotid Intima Media Thickness (IMT)	Change in IMT levels	"6 months"
carotid Intima Media Thickness	change in IMT levels	"One year"

Collaborators and Investigators

• Sponsor: Azienda USL Modena
• Investigators: Principal Investigator: Manuela Simoni, MD, PhD, Azienda USL Modena

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 24, 2014
• First Submitted That Met QC Criteria: August 18, 2014
• First Posted (Estimate): August 19, 2014

Study Record Updates

• Last Update Posted (Estimate): August 19, 2014
• Last Update Submitted That Met QC Criteria: August 18, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: ED; T2DM
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Sexual Dysfunctions, Psychological; Sexual Dysfunction, Physiological; Diabetes Mellitus; Diabetes Mellitus, Type 2; Erectile Dysfunction; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Vardenafil Dihydrochloride
• Other Study ID Numbers: EudraCT number 2009-014137-25