Effects of Sildenafil on CFTR-dependent Ion Transport Activity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01132482
Recruitment Status : Completed
First Posted : May 28, 2010
Last Update Posted : August 31, 2017
Information provided by (Responsible Party):
Jennifer Taylor-Cousar, National Jewish Health

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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Sildenafil Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Study of the Effects of Sildenafil on CFTR-dependent Ion Transport Activity
Study Start Date : October 2015
Actual Primary Completion Date : May 2017
Actual Study Completion Date : May 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

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 Name: 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.

Primary Outcome Measures :
  1. Sodium conductance by nasal potential difference (NPD) [ Time Frame: 5 visits over a 6-10 week period ]

Secondary Outcome Measures :
  1. Chloride conductance by NPD [ Time Frame: 5 visits over a 6-10 week period ]
  2. Sweat sodium concentration by pilocarpine iontophoresis [ Time Frame: 5 visits over a 6-10 week period ]
  3. Sweat chloride concentration by pilocarpine iontophoresis [ Time Frame: 5 visits over a 6-10 week period ]
  4. Pulmonary function by spirometry [ Time Frame: 5 visits over a 6-10 week period ]
  5. Serum sildenafil pharmacokinetics [ Time Frame: 5 visits over a 6-10 week period ]
  6. CF Heath Related Quality of Life Questionnaire (CFQ-R) [ Time Frame: 5 visits over a 6-10 week period ]
  7. Safety and adverse events [ Time Frame: 5 visits over a 6-10 week period ]
  8. Lung clearance index [ Time Frame: 5 visits over a 6-10 week period ]

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01132482

United States, Colorado
National Jewish Health
Denver, Colorado, United States, 80206
Sponsors and Collaborators
National Jewish Health
Principal Investigator: Jennifer L Taylor-Cousar, MD National Jewish Health


Responsible Party: Jennifer Taylor-Cousar, Assistant Professor, National Jewish Health Identifier: NCT01132482     History of Changes
Other Study ID Numbers: Sildenafil CFTR
First Posted: May 28, 2010    Key Record Dates
Last Update Posted: August 31, 2017
Last Verified: August 2017

Keywords provided by Jennifer Taylor-Cousar, National Jewish Health:
Cystic fibrosis
Phosphodiesterase inhibitor
Nasal potential difference
Sweat test

Additional relevant MeSH terms:
Cystic Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents