Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Phase II Study of the Effects of Sildenafil on CFTR-dependent Ion Transport Activity

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01132482

Enrollment

Registered

2010-05-28

Start date

2015-10-31

Completion date

2017-05-31

Last updated

2019-03-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cystic Fibrosis

Keywords

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

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.

Interventions

DRUGSildenafil

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.

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Change in Sweat Chloride Concentration by Pilocarpine Iontophoresis	Baseline and day 28	Amount of chloride transport across the skin
Change in Pulmonary Function by Spirometry	Baseline and day 28	ppFEV1
Change in Chloride Conductance by NPD	Baseline and day 28	Amount of chloride transport across the nasal epithelium
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.
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.
Change in Serum Sildenafil Pharmacokinetics	Baseline and day 28	Trough sildenafil levels

Countries

United States

Participant flow

Participants by arm

Arm	Count
Sildenafil 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.	12
Placebo 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.	6
Total	18

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0

Baseline characteristics

Characteristic	Sildenafil	Total	Placebo
Age, Continuous	27.1 years	27.6 years	28 years
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	12 Participants	18 Participants	6 Participants
Region of Enrollment United States	12 participants	18 participants	6 participants
Sex: Female, Male Female	10 Participants	12 Participants	2 Participants
Sex: Female, Male Male	2 Participants	6 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 6
other Total, other adverse events	10 / 12	3 / 6
serious Total, serious adverse events	1 / 12	0 / 6