Effects of Sildenafil on CFTR-dependent Ion Transport Activity

• Sponsor: National Jewish Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01132482
• Collaborator: (none)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 1

Study Details

Study Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 19 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: Oct 1, 2015
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: May 1, 2017

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Change in Sodium Conductance by Nasal Potential Difference (NPD) [Baseline and day 28]

   Amount of sodium transported across the nasal epithelium

Secondary Outcome Measures

1. Change in Chloride Conductance by NPD [Baseline and day 28]

   Amount of chloride transport across the nasal epithelium

2. Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis [Baseline and day 28]

   Amount of chloride transport across the skin

3. Change in Pulmonary Function by Spirometry [Baseline and day 28]

   ppFEV1

4. Change in Serum Sildenafil Pharmacokinetics [Baseline and day 28]

   Trough sildenafil levels

5. Change in CF Heath Related Quality of Life Questionnaire (CFQ-R) [Baseline and day 28]

   Respiratory domain of the CFQ-R; The range of scores is 0-100, with higher scores indicating better health.

6. Change in Lung Clearance Index [Baseline and day 28]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 21, 2015

More Information

Publications

• 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.
• 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. Epub 2007 Nov 15.
• 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. Epub 2006 Apr 13.
• 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. Epub 2007 Jun 22.
• 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. Epub 2007 Nov 1.
• 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.

• Responsible Party: Jennifer Taylor-Cousar, Assistant Professor, National Jewish Health
• ClinicalTrials.gov Identifier: NCT01132482
• Other Study ID Numbers: Sildenafil CFTR
• First Posted: May 28, 2010
• Last Update Posted: Mar 19, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Jennifer Taylor-Cousar, Assistant Professor, National Jewish Health: Cystic fibrosis; CFTR; Phosphodiesterase inhibitor; Nasal potential difference; Sweat test
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Period Title: Overall Study
STARTED	13	6
COMPLETED	12	6
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Sildenafil	Placebo	Total
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.	Total of all reporting groups
Overall Participants	12	6	18
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	27.1	28	27.6
Sex: Female, Male (Count of Participants)
Female	10 83.3%	2 33.3%	12 66.7%
Male	2 16.7%	4 66.7%	6 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	12 100%	6 100%	18 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%	6 100%	18 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del genotype with mild, stable lung disease

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	12	6
Mean (Standard Deviation) [mV]	-0.70 (9.18)	1.81 (7.99)

2. Secondary Outcome

Title	Change in Chloride Conductance by NPD
Description	Amount of chloride transport across the nasal epithelium
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with stable, mild lung disease

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	12	6
Mean (Standard Deviation) [mV]	2.53 (7.58)	-0.28 (8.93)

3. Secondary Outcome

Title	Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis
Description	Amount of chloride transport across the skin
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with mild, stable lung disease. One patient in the sildenafil group had insufficient sweat for analysis.

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	11	6
Mean (Standard Deviation) [mmol/L]	6.13 (14.4)	-0.42 (11.91)

4. Secondary Outcome

Title	Change in Pulmonary Function by Spirometry
Description	ppFEV1
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with mild, stable lung disease

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	12	6
Mean (Standard Deviation) [% predicted]	-0.92 (6.53)	-1.00 (3.69)

5. Secondary Outcome

Title	Change in Serum Sildenafil Pharmacokinetics
Description	Trough sildenafil levels
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with mild, stable lung disease

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	12	6
Mean (Standard Deviation) [ug/mL]	0 (0)	0 (0)

6. Secondary Outcome

Title	Change in CF Heath Related Quality of Life Questionnaire (CFQ-R)
Description	Respiratory domain of the CFQ-R; The range of scores is 0-100, with higher scores indicating better health.
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with mild, stable lung disease

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	12	6
Mean (Standard Deviation) [units on a scale]	-1.87 (14.26)	0.00 (14.04)

7. Secondary Outcome

Title	Change in Lung Clearance Index
Description	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.
Time Frame	Baseline and day 28

Outcome Measure Data

Analysis Population Description

Patients with CF homozygous for the F508del mutation with mild, stable lung disease who had valid data for measure

Arm/Group Title	Sildenafil	Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.	During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
Measure Participants	9	5
Mean (Standard Deviation) [LCI]	-0.33 (1.77)	-1.14 (2.94)

Adverse Events

Time Frame	Adverse events were collected from the time of screening to 1 week following the last dose of study drug (approximately 2 months).
Arm/Group Title	Sildenafil		Placebo
Arm/Group Description	Subjects will receive escalating doses of sildenafil 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.		During the placebo arm, subjects receiving placebo will have sham dose escalation to maintain blinding. Placebo: Patients receiving placebo will have sham dose escalation to maintain blinding.
All Cause Mortality
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/6 (0%)
Serious Adverse Events
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		0/6 (0%)
Gastrointestinal disorders
DIOS	1/12 (8.3%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary exacerbation	1/12 (8.3%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Sildenafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)		3/6 (50%)
Gastrointestinal disorders
Heartburn	1/12 (8.3%)	1	1/6 (16.7%)	1
Elevated ALT	1/12 (8.3%)	1	0/6 (0%)	0
Elevated AST	1/12 (8.3%)	1	0/6 (0%)	0
Distension/bloating, abdominal	0/12 (0%)	0	1/6 (16.7%)	1
General disorders
Pain, throat	2/12 (16.7%)	2	0/6 (0%)	0
Pain, head	5/12 (41.7%)	7	0/6 (0%)	0
Rhinorrhea	2/12 (16.7%)	2	1/6 (16.7%)	1
Fatigue	1/12 (8.3%)	1	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	2/12 (16.7%)	2	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pain, chest	2/12 (16.7%)	2	0/6 (0%)	0
cough	2/12 (16.7%)	2	0/6 (0%)	0
upper respiratory tract infection	0/12 (0%)	0	1/6 (16.7%)	1
Pulmonary exacerbation	1/12 (8.3%)	1	0/6 (0%)	0
Increased sputum clearance	1/12 (8.3%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Flushing	0/12 (0%)	0	1/6 (16.7%)	1
Rash	1/12 (8.3%)	1	0/6 (0%)	0

Limitations/Caveats

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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.