Cystic FibrosisPhase 2NCT01132482
Effects of Sildenafil on CFTR-dependent Ion Transport Activity
A Phase 2 study testing Sildenafil in people with Cystic Fibrosis, run by National Jewish Health at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cystic Fibrosis
- What is being tested?
- Sildenafil
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2015to May 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 9Show fewer
- 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.
Who cannot join
- 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
Show all 16Show fewer
- 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
- 15) History of migraine headaches 16) Baseline BP of < 90/50 mm Hg
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
- Conditions
- Cystic Fibrosis
- Being tested
- Sildenafil, Placebo
- Keywords
- Cystic fibrosis, CFTR, Phosphodiesterase inhibitor, Nasal potential difference, Sweat test
- Medical subject headings
- Cystic Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SildenafilDrug
Also called Revatio
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.
PlaceboDrug
Patients receiving placebo will have sham dose escalation to maintain blinding.
| Study group | Role | What they receive |
|---|---|---|
| Sildenafil | Experimental | Subjects will receive escalating doses of sildenafil Receives: Drug: Sildenafil |
| Placebo | Placebo comparator | During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Sodium Conductance by Nasal Potential Difference (NPD)
Amount of sodium transported across the nasal epithelium
Measured: Baseline and day 28
Secondary outcomes (6)
Change in Chloride Conductance by NPD
Amount of chloride transport across the nasal epithelium
Measured: Baseline and day 28
Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis
Amount of chloride transport across the skin
Measured: Baseline and day 28
Change in Pulmonary Function by Spirometry
ppFEV1
Measured: Baseline and day 28
Change in Serum Sildenafil Pharmacokinetics
Trough sildenafil levels
Measured: 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.
Measured: 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.
Measured: Baseline and day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2010 (estimated)
- Study startOct 2015
- Primary completionMay 2017
- Study completionMay 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Jewish Health
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jennifer Taylor-Cousar, National Jewish Health
- Investigators
- Jennifer L Taylor-Cousar, MD, Principal investigator, National Jewish Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01132482
- Sponsor's protocol ID
- Sildenafil CFTR
- Status last verified
- Mar 2019
- First submitted
- 16 Apr 2010
- Last updated
- 19 Mar 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 17975008Dormer 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.
PubMed 15618584Lubamba 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.
PubMed 18006891Poschet 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.
PubMed 17586695Poschet 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.
PubMed 16612392Taylor-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.
PubMed 25466700
Study at a glance
From the registry record, last updated by the sponsor on 19 Mar 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study of the Effects of Sildenafil on CFTR-dependent Ion Transport Activity
- ClinicalTrials.gov ID
- NCT01132482
- Acronym / sponsor ID
- Sildenafil CFTR
- Conditions
- Cystic Fibrosis
- Keywords
- Cystic fibrosis, CFTR, Phosphodiesterase inhibitor, Nasal potential difference, Sweat test
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 19 participants (actual)
- Lead sponsor
- National Jewish HealthUniversity, hospital or other
- Study start
- Oct 2015
- Primary completion
- May 2017 (actual)
- Study completion
- May 2017 (actual)
- First posted
- 28 May 2010 (estimated)
- Results
- Posted 26 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sildenafil | Experimental | Drug: SildenafilSubjects will receive escalating doses of sildenafil |
| Placebo | Placebo comparator | Drug: PlaceboDuring the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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)
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SildenafilAlso: RevatioDuring 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. | Drug | Sildenafil |
| PlaceboPatients receiving placebo will have sham dose escalation to maintain blinding. | Drug | Placebo |
Primary outcome
Change in Sodium Conductance by Nasal Potential Difference (NPD)
Time frame: Baseline and day 28
Amount of sodium transported across the nasal epithelium
6 secondary outcomes
Change in Chloride Conductance by NPD
Time frame: Baseline and day 28
Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis
Time frame: Baseline and day 28
Change in Pulmonary Function by Spirometry
Time frame: Baseline and day 28
Change in Serum Sildenafil Pharmacokinetics
Time frame: Baseline and day 28
Change in CF Heath Related Quality of Life Questionnaire (CFQ-R)
Time frame: Baseline and day 28
Change in Lung Clearance Index
Time frame: Baseline and day 28
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Mar 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17975008Robert 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.
- Background: PubMed 15618584Dormer 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.
- Background: PubMed 18006891Lubamba 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.
- Background: PubMed 17586695Poschet 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.
- Background: PubMed 16612392Poschet 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.
- Background: PubMed 25466700Taylor-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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jennifer L Taylor-Cousar, MD principal investigator
National Jewish Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sildenafil in people with Cystic Fibrosis, run by National Jewish Health at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Sodium Conductance by Nasal Potential Difference (NPD) (time frame: Baseline and day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01132482, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Mar 2019.