Sildenafil Exercise: Role of PDE5 Inhibition

Study Overview
=================
Brief Summary
-----------------
Exercise intolerance is an understudied phenomenon in people with CF. The investigators hypothesized that vascular dysfunction plays a significant role, and can be partially reversed by administration of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil.

Detailed Description
-----------------
Cystic Fibrosis (CF) is the most common fatal genetic disease in Caucasians. The predicted median life expectancy age for patients with CF is 47.7 years compared to 78.8 years in the general U.S. population. Exercise intolerance, evaluated as a reduction in exercise capacity (VO2 peak), has been shown to predict mortality in patients with CF independent of lung function. A critical barrier to improving exercise tolerance in CF is the lack of knowledge regarding the different physiological mechanisms which contribute to decreased exercise capacity. The present investigation will not only evaluate the impact that sildenafil has on clinically relevant and patient oriented outcomes, it will also provide mechanistic insight. Phosphodiesterase type 5 (PDE5) inhibitors reduce inflammation, improve vascular health, increase microvascular O2 delivery and improve skeletal muscle function. Accordingly, the central hypothesis of the study is that treatment with the PDE5 inhibitor, sildenafil, can improve exercise capacity, vascular and cardiac function, and overall quality of life, all of which may contribute to improvement in exercise tolerance in people with CF

Official Title
-----------------
Mechanisms of Exercise Intolerance in Cystic Fibrosis: Role of PDE5 Inhibition

Conditions
-----------------
Cystic Fibrosis

Intervention / Treatment
-----------------
* Drug: Sildenafil 40mg oral capsule
* Drug: Placebo Oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of cystic fibrosis (CF) based on the following criteria: Positive sweat chloride concentration ≥60 milliequivalents (mEq)/liter (by pilocarpine iontophoresis) and/or genotype with two identifiable disease-causing mutations consistent with CF, and accompanied by one or more clinical features consistent with the CF phenotype Male or female patients ≥ 9 years of age forced expiratory volume at one second (FEV1) ≥ 30% predicted and ≤ 70% for patients ≥ 18 years of age and ≤ 80% for patients ≥ 18 years of age 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 Resting oxygen saturation (room air) >85% Patients with or without CF related diabetes Ability to perform spirometry reproducibly (according to American Thoracic Society criteria) Willingness to maintain chronic CF medication schedule (e.g. alternating month inhaled antibiotics) Exclusion Criteria: Children 8 yrs. old and younger Subjects who weigh < 20 Kgs 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 for women of child-bearing potential. History of significant hepatic disease (aspartate transaminase or alanine transaminase > 3 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension), History of significant cardiovascular disease (history of aortic stenosis, coronary artery disease, or life-threatening arrhythmia), History of severe neurological disease (e.g. history of stroke), History of severe hematologic disease (e.g. history of bleeding diathesis; current international normalized ratio (INR) > 2.0 History of severe ophthalmologic disease (e.g. history of retinal impairment or non-arteritic ischemic optic neuritis) History of severe renal impairment (creatinine >1.8 mg/dL.) Inability to swallow pills Previous organ transplantation Use of concomitant nitrates, α-blocker, or Ca channel blocker (currently or within one month of Visit 1) Use of concomitant medications known to be potent inhibitors of CYP3A4 [e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, rifampin (currently or within one month of initiation of study drug)] (NOTE: use of azithromycin is NOT a cause for exclusion) History of sputum or throat swab culture yielding Burkholderia cepacia or Mycobacteria massiliense within 2 years of screening History of migraine headaches. 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 Initiation of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy less than 1 month prior to first dose of sildenafil or placebo Use of anticoagulants Frank pulmonary hypertension[right ventricular systolic pressure (RVSP) >40 mm Hg by echocardiography) History of Priapism or known penile anatomical deformities

Ages Eligible for Study
-----------------
Minimum Age: 9 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be randomized 1:1 to the sildenafil or placebo groups
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sildenafil<br>active sildenafil 40 mg p.o. three times per day | Drug: Sildenafil 40mg oral capsule<br>* 40 mg, sildenafil capsule taken by mouth thrice daily<br>* Other names: sildenafil, revatio;|
| Placebo Comparator: Placebo Arm<br>placebo three times per day | Drug: Placebo Oral capsule<br>* Placebo capsule taken by mouth thrice daily<br>* Other names: placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Distance (6MWD) | capacity, an objective measurement of exercise tolerance, predicts mortality in patients with CF. The mechanisms for exercise intolerance in CF have yet to be fully elucidated and further understanding could improve clinical outcomes and survival in CF. Preliminary data from two independent proof-of-concept clinical trials support the use of sildenafil to improve exercise capacity, cardiac function, and quality of life in CF | Change in distance walked between week 1 and week 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CFQ-R respiratory domain score | The respiratory domain of the validated CF-specific quality of life measure. The CFQ-R Respiratory domain score (scale 0-100 with higher scores indicating better quality of life). | Quality of life assessed at weeks 1 and 12. | 
| Cardiac strain | Right ventricular strain will be calculated from cardiac magnetic resonance image (MRI) | Change in cardiac strain between weeks 1 and 12 | 
| Flow-Mediated Dilation (FMD) | Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function. | Change in FMD between weeks 1 and 12 | 
| Skeletal muscle function | Near infrared spectroscopy (NIRS) placed over the vastus lateralus and gastrocnemius will be used to measure changes in skeletal muscle O2 concentrations and consumption at rest and during exercise | Change in skeletal muscle function between weeks 1 and 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Exercise intolerance, Quality of life, Cardiac function