Blood Flow and Vascular Function in Cystic Fibrosis

Study Overview
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Brief Summary
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Cystic fibrosis (CF) has many health consequences. A reduction in the ability to perform exercise in patients with CF is related to greater death rates, steeper decline in lung function, and more frequent lung infections. However, the physiological mechanisms for this reduced exercise capacity are unknown. The investigators laboratory recently published the first evidence of systemic vascular dysfunction in patients with CF. Therefore, it is reasonable to suspect that the blood vessels are involved with exercise intolerance in CF. This study will look at how 1) blood flow and 2) artery function contribute to exercise capacity in CF.

Detailed Description
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The most disturbing aspect of Cystic Fibrosis (CF) is the associated premature death. Low exercise capacity predicts death in patients with CF and is also associated with a steeper decline in lung function and more lung infections. A critical barrier to improving exercise tolerance in patients with CF is the investigators lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. We have compelling data to indicate that the blood vessels may contribute to the low exercise capacity in CF. The impact of this proof of concept investigation will test Phosphodiesterase Type 5 inhibitors (PDE5) inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. Improvements in exercise capacity will not only contribute to a better quality of live for patients with CF, it will also increase longevity in these patients.

Official Title
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Role of Blood Flow and Vascular Function on Exercise Capacity in Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Sildenafil (Acute-1 hour)
* Drug: Sildenafil (Subchronic-4 weeks)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria. Diagnosis of CF and healthy controls Men and women (greater than 18 yrs. old) Resting oxygen saturation (room air) greater than 90% Forced expiratory volume (FEV1) percent predicted greater than 30% Patients with or without CF related diabetes Traditional CF-treatment medications Ability to perform reliable/reproducible pulmonary function tests (PFT) Clinically stable for 2 weeks (no exacerbations or need for antibiotic treatment within 2 weeks of testing or major change in medical status) Exclusion Criteria. Children less than 17 years old Body mass less than 20 kg A diagnosis of pulmonary arterial hypertension (PAH) FEV1 less than 30% of predicted Resting oxygen saturation (SpO2) less than 90% Self-reported to be a smoker Current use of any vaso-active medications History of migraine headaches Pregnant or nursing at the time of the investigation A clinical diagnosis of cardiovascular disease, hypertension, or CF related diabetes

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acute Study: Sildenafil first, then Placebo<br>In randomized order, on two separate days, endothelial function and exercise capacity will be determined 1 hour following a single dose of sildenafil (50 mg) or placebo. | Drug: Sildenafil (Acute-1 hour)<br>* Vascular function will be assessed 1 hour following oral ingestion of sildenafil (50 mg)<br>* Other names: Revatio;Drug: Placebo<br>* Sugar pill designed to mimic the sildenafil treatment<br>|
| Experimental: Acute Study: Placebo first, then Sildenafil<br>In randomized order, on two separate days, endothelial function and exercise capacity will be determined 1 hour following a single dose of sildenafil (50 mg) or placebo. | Drug: Sildenafil (Acute-1 hour)<br>* Vascular function will be assessed 1 hour following oral ingestion of sildenafil (50 mg)<br>* Other names: Revatio;Drug: Placebo<br>* Sugar pill designed to mimic the sildenafil treatment<br>|
| Experimental: Sub-Chronic Study Sildenafil<br>Following the acute study, patients will be instructed to take 20 mg of sildenafil, three times a day, for 4 weeks. Endothelial function will be determined within 48 hours following the last dose. | Drug: Sildenafil (Subchronic-4 weeks)<br>* Vascular function will be assessed 4 weeks following 20 mg three times per day (TID) of sildenafil for four weeks<br>* Other names: Revatio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Study: Percentage Flow-Mediated Dilation (FMD) | FMD determined one hour after ingestion of 50 mg Sildenafil or placebo | pre-treatment Baseline and 1 hour post-treatment | 
| Baseline Diameter | Brachial Artery Diameter during FMD (pre-occlusion or baseline) | pre-treatment Baseline and following 4 weeks sub-chronic treatment | 
| Peak Diameter | Peak Brachial Artery Diameter during FMD (post-occlusion) | pre-treatment Baseline and following 4 weeks sub-chronic treatment | 
| Absolute Change in Diameter | Absolute change in brachial artery diameter taken from the FMD assessment | pre-treatment Baseline and following 4 weeks sub-chronic treatment | 
| FEV1 (% Predicted) | Forced Expiratory Volume in the first second expressed as a percent predicted. | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | 
| VO2 Peak (Absolute) | absolute (L/min) peak oxygen consumption during maximal exercise test | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | 
| VO2 Peak (Relative) | relative (mL/kg/min) peak oxygen consumption during maximal exercise test | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | 
| VO2 Peak (Percent Predicted) | Maximal Oxygen consumption expressed as percent predicted taken from maximal exercise test. | pre-treatment Baseline and 1 hour post-treatment, and 4 weeks sub-chronic treatment | 
| VE Peak | peak ventilation (L/min) during maximal exercise test | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | 
| RER Peak | peak respiratory exchange ratio during maximal exercise test | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CF, pulse wave velocity, inflammation, oxidative stress, pulmonary function test, Cystic Fibrosis, Lung Disease, Nitric Oxide, Exercise Capacity, Muscle Function, Sildenafil, Viagra, Revatio, arterial stiffness, flow-mediated dilation, endothelial function