Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Phase II Study of the Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Dehydrated airway surfaces resulting from sodium hyperabsorption and lack of chloride secretion are critical to the pathology that leads to the morbidity and mortality from Cystic Fibrosis (CF) lung disease. Previously published work in CF cell lines has demonstrated that by increasing cGMP and restoring inhibition of ENaC, sodium hyperabsorption may be reversed following administration of a phosphodiesterase inhibitor (PDEi,) such as sildenafil. Additionally it has been shown in CF cell lines and animal models, that phosphodiesterase inhibitors/analogues can enhance chloride secretion and/or correct surface localization of ΔF508 CFTR. The goal of this project is to translate the results of this work from the laboratory into a clinical trial in patients with CF using an FDA-approved therapy. The Specific Aims of this project are to: 1) Evaluate the effect of systemically administered phosphodiesterase inhibitors on ion transport in CF by measurement of Na+ and Cl- conductance by NPD and Na+ and Cl- concentration in sweat utilizing pilocarpine iontophoresis 2) To establish appropriate dosing of sildenafil in CF by performing a dose-escalation study during which patients are carefully monitored for side effects, plasma sildenafil levels are obtained and outcome measures are compared based on the dose of sildenafil administered. The results of this study in conjunction with those from an ongoing study examining the role of sildenafil as an anti-inflammatory in CF will aid in establishing safety, pharmacokinetics and mechanism of action of sildenafil in the treatment of CF lung disease.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and genotype with two F508del CFTR mutations, and accompanied by one or more clinical features consistent with the CF phenotype
2. Male or female subjects ≥ 18 years of age
3. FEV1 ≥ 50% predicted (Hankinson)
4. Clinically stable without evidence of acute upper or lower respiratory tract infection or current pulmonary exacerbation within the 14 days prior to the screening visit
5. Ability to reproducibly perform spirometry (according to ATS criteria)
6. Ability to understand and sign a written informed consent or assent and comply with the requirements of the study
7. Willing and able to perform nasal potential difference testing
8. No changes in use of nasal medications within 2 weeks of screening visit
9. If on Orkambi, has been on stable Orkambi dose for at least 4 weeks at day 1.

Exclusion Criteria:

1. History of hypersensitivity to sildenafil
2. Use of an investigational agent within the 4-week period prior to Visit 1 (Day 0)
3. Breastfeeding, pregnant, or verbal expression of unwillingness to practice an acceptable birth control method (abstinence, hormonal or barrier methods, partner sterilization or intrauterine device) during participation in the study
4. History of significant hepatic (SGOT or SGPT > 3 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension), cardiovascular (history of aortic stenosis, coronary artery disease, pulmonary hypertension with right ventricular systolic pressure >55 mmHg or life-threatening arrhythmia), neurological (history of stroke), hematologic (history of bleeding diathesis), ophthalmologic (history of retinal impairment or non-arteritic ischemic optic neuritis) or renal impairment (creatinine >1.8 mg/dL.)
5. Inability to swallow pills
6. Previous lung transplantation
7. Use of concomitant nitrates, α-blocker, or Ca channel blocker
8. Use of concomitant medications known to be potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin, verapamil)
9. Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the subject or the quality of the data
10. Weight less than 40 kg
11. History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of screening
12. History of nasal disease or nasal surgery that would, in the opinion of the investigator, impede accurate measurements of NPD
13. Use of anticoagulant medication (e.g. heparin, coumadin)
14. Resting room air oxygen saturation <93%
15. Use of nighttime oxygen

15) History of migraine headaches 16) Baseline BP of < 90/50 mm Hg

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sildenafil; Subjects will receive escalating doses of sildenafil	Drug: Sildenafil; During the course of the study, patients will receive 4 weeks of therapy: 28 days of placebo orally t.i.d. or 28 days of days of sildenafil orally t.i.d. Dosing of sildenafil will be escalated after the first week (20 mg orally t.i.d for the first week, then subjects will take 40 mg orally t.i.d. for 3 weeks). Patients not tolerating dose escalation will be discontinued from the study.; Other Names: Revatio
Placebo Comparator: Placebo; During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding.	Drug: Placebo; Patients receiving placebo will have sham dose escalation to maintain blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Sodium Conductance by Nasal Potential Difference (NPD)	Amount of sodium transported across the nasal epithelium	Baseline and day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Chloride Conductance by NPD	Amount of chloride transport across the nasal epithelium	Baseline and day 28
Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis	Amount of chloride transport across the skin	Baseline and day 28
Change in Pulmonary Function by Spirometry	ppFEV1	Baseline and day 28
Change in Serum Sildenafil Pharmacokinetics	Trough sildenafil levels	Baseline and day 28
Change in CF Heath Related Quality of Life Questionnaire (CFQ-R)	Respiratory domain of the CFQ-R; The range of scores is 0-100, with higher scores indicating better health.	Baseline and day 28
Change in Lung Clearance Index	The lung clearance index (LCI) measures how long it takes for an inert gas (e.g. nitrogen) to be washed out of the lungs during relaxed tidal breathing. A higher value of the LCI indicates worse disease. LCI is calculated as the number of functional residual capacity (FRC) turnovers required to reduce the end-tidal concentration of nitrogen to 1/40th of the starting concentration and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured FRC.	Baseline and day 28

Collaborators and Investigators

• Sponsor: National Jewish Health
• Investigators: Principal Investigator: Jennifer L Taylor-Cousar, MD, National Jewish Health

Publications and helpful links

General Publications

• 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.
• Taylor-Cousar JL, Wiley C, Felton LA, St Clair C, Jones M, Curran-Everett D, Poch K, Nichols DP, Solomon GM, Saavedra MT, Accurso FJ, Nick JA. Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease. J Cyst Fibros. 2015 Mar;14(2):228-36. doi: 10.1016/j.jcf.2014.10.006. Epub 2014 Nov 13.
• Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW. Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol. 2008 Feb;73(2):478-89. doi: 10.1124/mol.107.040725. Epub 2007 Nov 1.
• 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.
• Poschet JF, Timmins GS, Taylor-Cousar JL, Ornatowski W, Fazio J, Perkett E, Wilson KR, Yu HD, de Jonge HR, Deretic V. Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L712-9. doi: 10.1152/ajplung.00314.2006. Epub 2007 Jun 22.
• Poschet JF, Fazio JA, Timmins GS, Ornatowski W, Perkett E, Delgado M, Deretic V. Endosomal hyperacidification in cystic fibrosis is due to defective nitric oxide-cylic GMP signalling cascade. EMBO Rep. 2006 May;7(5):553-9. doi: 10.1038/sj.embor.7400674. Epub 2006 Apr 13.

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: April 16, 2010
• First Submitted That Met QC Criteria: May 26, 2010
• First Posted (Estimate): May 28, 2010

Study Record Updates

• Last Update Posted (Actual): March 19, 2019
• Last Update Submitted That Met QC Criteria: March 2, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Cystic fibrosis; CFTR; Phosphodiesterase inhibitor; Nasal potential difference; Sweat test
• 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; Sildenafil Citrate
• Other Study ID Numbers: Sildenafil CFTR