Cystic Fibrosis
Conditions
Keywords
cystic fibrosis, inflammation, pH, EBC, sputum biomarkers, phosphodiesterase inhibitors
Brief summary
The purpose of this study is to determine whether sildenafil can decrease inflammation in CF lung disease.
Detailed description
This study is an open-label study that examines the use of sildenafil (Revatio) in clinically stable patients with mild to moderate CF lung disease. The length of participation for each subject will be approximately 10 weeks, and will consist of a screening visit, a study visit for initiation of study drug if subject qualifies, interim visits to escalate drug dose, obtain drug levels, review concomitant medications and assess side effects, a visit at the end of the therapy period (to reassess inflammatory markers, laboratory studies and side effects,) and a follow-up assessment 2 weeks after subject completion.
Interventions
DRUGsildenafil
Sildenafil will be given 20mg po tid for 1 week, and then will be give 40mg po tid for 5 weeks.
Sponsors
National Jewish Health
Cystic Fibrosis Foundation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF based on the following criteria: * Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and/or * Genotype with two identifiable mutations consistent with CF, and accompanied by one or more clinical features consistent with the CF phenotype * Male or female patients ≥ 12 years of age * FEV1 ≥ 50% predicted (Knudson) 31 * 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 produce at least 1mL of sputum spontaneously, or be willing to undergo sputum induction * Ability to understand and sign a written informed consent or assent and comply with the requirements of the study * Chronic bacterial colonization (3 documented positive cultures in the prior 2 years of which at least one was obtained in the 3 months prior to randomization)
Exclusion criteria
* 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 * Daily use of systemic corticosteroids and/or NSAIDs within 4 weeks of the study or as needed use within 72 hours prior to the screening visit * 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 * 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) * 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 * Resting room air oxygen saturation \<93% * History of migraines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Sputum Elastase Activity | Baseline and 6 weeks | Exploratory analysis for efficacy of sildenafil on sputum biomarkers of inflammation, including sputum elastase. This measure will indicate whether sildenafil will increase or decrease sputum elastase activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Exhaled Breath Condensate pH | Baseline and 6 weeks | Endogenous airway acidification can be assessed by measuring pH in exhaled breath condensate, a non-invasive measure of response to therapy. This measure will indicate whether sildenafil will improve, worsen, or cause no change in exhaled breath condensate pH. |
| Change in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain, Average Unit Change From Baseline to 6 Weeks is Reported | 6 weeks | The CFQ-R is designed to measure CF-specific patient-reported health-related quality of life. It is a validated CF-specific quality of life measure. The CFQ-R Respiratory domain score (scale 0-100 with higher scores indicating better quality of life). This measure will indicate whether sildenafil will improve, worsen, or cause no change in the CFQ-R respiratory domain scores from baseline at 6 weeks. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJennifer L Taylor-Cousar, MD
National Jewish Health
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open-label (All Subjects) All subjects will receive oral sildenafil three times per day during the study. Study endpoints will be measured before the treatment period and at the end of the treatment period.
sildenafil: Sildenafil will be given 20mg po tid for 1 week, and then will be give 40mg po tid for 5 weeks. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Open-label (All Subjects) |
|---|---|
| Age, Continuous | 25.7 years STANDARD_DEVIATION 5.5 |
| FEV1% predicted | 77.5 % predicted STANDARD_DEVIATION 19.6 |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 27 |
| other Total, other adverse events | 24 / 27 |
| serious Total, serious adverse events | 2 / 27 |
Outcome results
Primary
Sputum Elastase
Time frame: Pre/post therapy
Population: Subjects who completed 6 weeks of sildenafil and had available data for pre/post 6 weeks of sildenafil were analyzed. One subject presented to the final study visit with 1 week of previously unreported symptoms consistent with pulmonary exacerbation, and therefore, efficacy data was not analyzed on that subject as pre-specified in the protocol.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Open-label (All Subjects) | Sputum Elastase | -57 micrograms/mL |
Secondary
CFQ-R
Time frame: Pre/post therapy
Secondary
Exhaled Breath Condensate pH
Time frame: Pre/post therapy
Secondary
Serum Sildenafil Levels
Time frame: Pre/during therapy