Effects of Sildenafil on CFTR-dependent Ion Transport Activity

This study has been withdrawn prior to enrollment.
(Study endpoints to be incorporated into larger multi-center trial with multiple efficacy/mechanistic endpoints.)
Sponsor:
Information provided by (Responsible Party):
Jennifer Taylor-Cousar, National Jewish Health
ClinicalTrials.gov Identifier:
NCT01132482
First received: April 16, 2010
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

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 Intervention Phase
Cystic Fibrosis
Drug: Sildenafil
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Study of the Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Resource links provided by NLM:


Further study details as provided by National Jewish Health:

Primary Outcome Measures:
  • Sodium conductance by nasal potential difference (NPD) [ Time Frame: 8 visits over a 10-12 week period ] [ Designated as safety issue: No ]
    We will measure sodium movement in the nose using a test known as a nasal potential difference (NPD) measurement. A tiny wire and tube will be placed in the nose and liquids containing different medicines will run in through the tube. The short version of the test takes about 15 minutes, and the long version of the test takes about 45 minutes.


Secondary Outcome Measures:
  • Chloride conductance by NPD [ Time Frame: 8 visits over 10-12 weeks ] [ Designated as safety issue: No ]
    We will measure chloride movement in the nose using a test known as a nasal potential difference measurement. A tiny wire and tube will be placed in the nose and liquids containing different medicines will run in through the tube. The short version of the test takes about 15 minutes, and the long version of the test takes about 45 minutes.

  • Sweat sodium concentration by pilocarpine iontophoresis [ Time Frame: 8 visits over 10-12 weeks ] [ Designated as safety issue: No ]
    We will measure sodium in your sweat. The procedure to measure sodium in sweat is known as a sweat test. To collect the sweat, a sticky pad will be attached to the skin on the arm for 5 minutes. A gel containing a medicine called pilocarpine is put on the pads and causes the sweat glands to produce more sweat. The pads are then removed and replaced by a disc to collect sweat for about 30 minutes. The entire procedure will also be done on the other arm.

  • Sweat chloride concentration by pilocarpine iontophoresis [ Time Frame: 8 visits over 10-12 weeks ] [ Designated as safety issue: No ]
    We will measure chloride in your sweat. The procedure to measure chloride in sweat is known as a sweat test. To collect the sweat, a sticky pad will be attached to the skin on the arm for 5 minutes. A gel containing a medicine called pilocarpine is put on the pads and causes the sweat glands to produce more sweat. The pads are then removed and replaced by a disc to collect sweat for about 30 minutes. The entire procedure will also be done on the other arm.

  • Pulmonary function by spirometry [ Time Frame: 4 visits over 10-12 weeks ] [ Designated as safety issue: No ]
  • Serum sildenafil pharmacokinetics [ Time Frame: 8 visits over 10-12 weeks ] [ Designated as safety issue: No ]
    Blood will be drawn and the amount of sildenafil in the blood will be measured.

  • CF Heath Related Quality of Life Questionnaire (CFQ-R) [ Time Frame: 4 visits over 10-12 weeks ] [ Designated as safety issue: No ]
    This questionnaire asks about how CF affects your daily life. Examples of questions include: "How do you feel about eating? How difficult is it for you do your treatments (including medications) every day? How often does CF get in the way of meeting your school, work, or personal goals?"

  • Safety and adverse events [ Time Frame: 8 visits over 10-12 weeks ] [ Designated as safety issue: Yes ]
    The number of patients who experience adverse events will be recorded and reported.


Enrollment: 0
Study Start Date: October 2014
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil
Subjects will receive escalating doses of sildenafil
Drug: Sildenafil
During the course of the study, patients will receive 6 weeks of therapy: 21 days of placebo orally t.i.d., and 21 days of days of sildenafil orally t.i.d. Dosing of sildenafil will be escalated weekly (20 mg orally t.i.d for the first week, 40 mg orally t.i.d. for the second week, and 80 mg orally t.i.d. for the third week). Patients not tolerating dose escalation will continue in the study at the maximum dose tolerated (e.g. a patient experiencing hypotension subsequent to the administration of an 80 mg dose will complete the third week of the study taking 40 mg).
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and genotype with two identifiable mutations consistent with CF, and accompanied by one or more clinical features consistent with the CF phenotype
  2. Male or female patients ≥ 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

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 50 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. History of migraines
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01132482

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

Publications:
Responsible Party: Jennifer Taylor-Cousar, Assistant Professor, National Jewish Health
ClinicalTrials.gov Identifier: NCT01132482     History of Changes
Other Study ID Numbers: Sildenafil CFTR
Study First Received: April 16, 2010
Last Updated: April 3, 2014
Health Authority: United States: Food and Drug Administration
United States: Cystic Fibrosis Foundation

Keywords provided by National Jewish Health:
Cystic fibrosis
CFTR
Phosphodiesterase inhibitor
Nasal potential difference
Sweat test

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

ClinicalTrials.gov processed this record on August 26, 2014