Does a Nasal Instillation of Vardenafil Normalize the Nasal Potential Difference in Cystic Fibrosis Patients?

Does a Nasal Instillation of Vardenafil Normalize the Nasal Potential Difference in Cystic Fibrosis Patients Homozygous for the F508del Mutation? A Randomized, Double Blind, Placebo-controlled Study.

The purpose of this study is to investigate the effect of a nasal instillation of Vardenafil on nasal potential difference in cystic fibrosis patients homozygous for the F508del mutation

Study Overview

• Status: Terminated
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Vardenafil; Drug: Placebo

Detailed Description

CFTR protein has been shown to be an ohmic, small conductance channel regulated by cAMP intracellular levels that are balanced by degradation through cyclic nucleotide phosphodiesterases (PDE). Several families of PDEs with varying selectivities for cAMP and/or cGMP have been identified.PDE5 is highly specific for cGMP and is involved in the regulation of the intracellular concentration of cGMP in various tissues. Recently, it has been shown, in a preclinical model of transgenic mice, that pharmacological doses of sildenafil and vardenafil, two clinically approved PDE5 inhibitors, stimulate chloride transport activity of the mutant F508del-protein (Lubamba et al, 2008); this parameter has been assessed by means of the nasal potential difference (NPD). An increasing effect of sildenafil on the expression of F508del-CFTR protein (Dormer et al,2005) was originally reported in nasal epithelial cells harvested from patients with cystic fibrosis and cultured on impermeable supports, a configuration that allows interaction of drugs with the apical side of epithelia.

This study aims at investigating the effect of a single local administration of vardenafil on NPD measurements in CF patients homozygous for the F508del mutation.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires St. Luc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Cystic fibrosis patients homozygous for the F508del mutation as confirmed by a genetic test
• Aged 14 years and older
• Male and female
• FEV1 >50% of predicted normal

Exclusion Criteria:

• Acute respiratory tract infection or pulmonary exacerbation requiring antibiotic intervention within 2 weeks of visit 1
• Any condition prohibiting the correct measurement of the NPD
• Active or passive smoking
• Planned treatment or treatment with another investigational drug or therapy within 1 month prior to randomisation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: baseline; visit 1
ACTIVE_COMPARATOR: Vardenafil; nasal instillation of Vardenafil ( visit 2 or 3)	Drug: Vardenafil; Nasal instillation of Vardenafil
PLACEBO_COMPARATOR: Placebo; Nasal instillation of placebo (visit 3 or 2)	Drug: Placebo; Nasal instillation of placebo matching in appearance with the Vardenafil instillation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cumulated changes in response to Chloride-free solution and isoproterenol (reflecting chloride transport)	Change from baseline (visit 1) and placebo to Vardenafil instillation

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in basal voltage value and in amiloride response (reflecting sodium transport)	Change from baseline (visit1) and placebo to Vardenafil instillation

Collaborators and Investigators

• Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Investigators: Principal Investigator: Patrick LEBECQUE, MD, PhD, Cliniques universitaires St.Luc (Université Catholique de Louvain); Principal Investigator: Teresinha LEAL, MD, PhD, Cliniques universitaires St.Luc ( Université Catholique de Louvain); Principal Investigator: Anissa LEONARD, MD, Cliniques universitaires St.Luc (Université Catholique de Louvain)

Publications and helpful links

General Publications

• Dormer RL, Harris CM, Clark Z, Pereira MM, Doull IJ, Norez C, Becq F, McPherson MA. Sildenafil (Viagra) corrects DeltaF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis. Thorax. 2005 Jan;60(1):55-9. doi: 10.1136/thx.2003.019778.
• Lubamba B, Lecourt H, Lebacq J, Lebecque P, De Jonge H, Wallemacq P, Leal T. Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med. 2008 Mar 1;177(5):506-15. doi: 10.1164/rccm.200703-344OC. Epub 2007 Nov 15.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): March 1, 2018

Study Registration Dates

• First Submitted: October 26, 2009
• First Submitted That Met QC Criteria: October 26, 2009
• First Posted (ESTIMATE): October 27, 2009

Study Record Updates

• Last Update Posted (ACTUAL): February 25, 2019
• Last Update Submitted That Met QC Criteria: February 21, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Vardenafil; Nasal instillation; Nasal Potential difference
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Vardenafil Dihydrochloride
• Other Study ID Numbers: VARD-99