Effects of Sildenafil on CFTR-dependent Ion Transport Activity

NCT01132482 | Completed Phase 2 Results DMC

• 1 other identifier: Sildenafil CFTR
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cystic Fibrosis

Keywords

Cystic fibrosis; CFTR; Phosphodiesterase inhibitor; Nasal potential difference; Sweat test

Outcome Measures

Primary Outcomes (1)

• Change in Sodium Conductance by Nasal Potential Difference (NPD)

  Amount of sodium transported across the nasal epithelium

  Baseline and day 28

Secondary Outcomes (6)

• Change in Chloride Conductance by NPD

  Baseline and day 28

• Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis

  Baseline and day 28

• Change in Pulmonary Function by Spirometry

  Baseline and day 28

• Change in Serum Sildenafil Pharmacokinetics

  Baseline and day 28

• Change in CF Heath Related Quality of Life Questionnaire (CFQ-R)

  Baseline and day 28

Study Arms (2)

Sildenafil

EXPERIMENTAL

Subjects will receive escalating doses of sildenafil

Drug: Sildenafil

Placebo

PLACEBO COMPARATOR

During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding.

Drug: Placebo

Interventions

Sildenafil DRUG

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.

Also known as: Revatio

Sildenafil

Placebo DRUG

Patients receiving placebo will have sham dose escalation to maintain blinding.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Male or female subjects ≥ 18 years of age
• FEV1 ≥ 50% predicted (Hankinson)
• 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
• Ability to reproducibly perform spirometry (according to ATS criteria)
• Ability to understand and sign a written informed consent or assent and comply with the requirements of the study
• Willing and able to perform nasal potential difference testing
• No changes in use of nasal medications within 2 weeks of screening visit
• If on Orkambi, has been on stable Orkambi dose for at least 4 weeks at day 1.

You may not qualify if:

• History of hypersensitivity to sildenafil
• Use of an investigational agent within the 4-week period prior to Visit 1 (Day 0)
• 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
• 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.)
• Inability to swallow pills
• Previous lung transplantation
• Use of concomitant nitrates, α-blocker, or Ca channel blocker
• Use of concomitant medications known to be potent inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin, verapamil)
• 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
• Weight less than 40 kg
• History of sputum or throat swab culture yielding Burkholderia cepacia within 2 years of screening
• History of nasal disease or nasal surgery that would, in the opinion of the investigator, impede accurate measurements of NPD
• Use of anticoagulant medication (e.g. heparin, coumadin)
• Resting room air oxygen saturation \<93%
• Use of nighttime oxygen

Sponsors & Collaborators

• National Jewish Health: lead

Study Sites (1)

National Jewish Health

Denver, Colorado, 80206, United States

Location

Related Publications (6)

• 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.

  PMID: 17975008 BACKGROUND

• 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.

  PMID: 15618584 BACKGROUND

• 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.

  PMID: 18006891 BACKGROUND

• 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.

  PMID: 17586695 BACKGROUND

• 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.

  PMID: 16612392 BACKGROUND

• 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.

  PMID: 25466700 BACKGROUND

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

This study was a small, single center one. However, the study was appropriately powered to detect a differences in the primary outcomes.

Results Point of Contact

• Title: Jennifer Taylor-Cousar, Principal Investigator
• Organization: National Jewish Health

Taylor-CousarJ@NJHealth.org

3032702764

Study Officials

• Jennifer L Taylor-Cousar, MD

  National Jewish Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 16, 2010
• First Posted: May 28, 2010
• Study Start: October 1, 2015
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: March 19, 2019
• Results First Posted: February 26, 2019

Record last verified: 2019-03

Locations

US (1)