Sildenafil Exercise: Role of PDE5 Inhibition

• ClinicalTrials.gov Identifier: NCT04039087
• Recruitment Status: Recruiting
• First Posted: July 31, 2019
• Last Update Posted: September 2, 2021
• Sponsor: National Jewish Health
• Collaborators: Augusta University; Cystic Fibrosis Foundation
• Information provided by (Responsible Party): Jennifer Taylor-Cousar, National Jewish Health

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cystic Fibrosis	Drug: Sildenafil 40mg oral capsule; Drug: Placebo Oral capsule	Phase 2; Phase 3

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects will be randomized 1:1 to the sildenafil or placebo groups
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The participants, care provider, investigator and those assessing the outcomes will be blinded to treatment designation.
• Primary Purpose: Supportive Care
• Official Title: Mechanisms of Exercise Intolerance in Cystic Fibrosis: Role of PDE5 Inhibition
• Actual Study Start Date: September 5, 2019
• Estimated Primary Completion Date: June 2022
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Sildenafil; active sildenafil 40 mg p.o. three times per day	Drug: Sildenafil 40mg oral capsule; 40 mg, sildenafil capsule taken by mouth thrice daily; Other Name: sildenafil, revatio
Placebo Comparator: Placebo Arm; placebo three times per day	Drug: Placebo Oral capsule; Placebo capsule taken by mouth thrice daily; Other Name: placebo

Outcome Measures

Primary Outcome Measures :

1. 6 Minute Walk Distance (6MWD) [ Time Frame: Change in distance walked between week 1 and week 12. ]
   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

Secondary Outcome Measures :

1. CFQ-R respiratory domain score [ Time Frame: Quality of life assessed at weeks 1 and 12. ]
   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).
2. Cardiac strain [ Time Frame: Change in cardiac strain between weeks 1 and 12 ]
   Right ventricular strain will be calculated from cardiac magnetic resonance image (MRI)
3. Flow-Mediated Dilation (FMD) [ Time Frame: Change in FMD between weeks 1 and 12 ]
   Brachial artery FMD induced by reactive hyperemia will be used to assess vascular endothelial function.
4. Skeletal muscle function [ Time Frame: Change in skeletal muscle function between weeks 1 and 12 ]
   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

Eligibility Criteria

• Ages Eligible for Study: 9 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Nora H Murphy, BS; 3032702861; murphyn@njhealth.org

Contact: Jennifer Taylor-Cousar, MD, MSCS; 3032702764; taylorcousarj@njhealth.org

Locations

United States, Colorado

National Jewish Health; Recruiting

Denver, Colorado, United States, 80206

Contact: Nora H Murphy, BS 303-270-2861 murphyn@njhealth.org

Contact: Jennifer Taylor-Cousar, MD, MSCS 3032702764 taylorcousar-j@njhealth.org

Principal Investigator: Jennifer Taylor-Cousar, MD, MSCS

United States, Georgia

Augusta University; Not yet recruiting

Augusta, Georgia, United States, 30912

Contact: Reva Crandall, RRT 706-721-5483 rcrandall@augusta.edu

Contact: Ryan Harris, PhD 706-721-5998 rharris@augusta.edu

Principal Investigator: Ryan Harris, PhD

Sponsors and Collaborators

National Jewish Health

Augusta University

Cystic Fibrosis Foundation

Investigators

• Principal Investigator: Jennifer Taylor-Cousar, MD, MSCS; National Jewish Health

More Information

Publications:

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.

Rodriguez-Miguelez P, Lee N, Tucker MA, Csányi G, McKie KT, Forseen C, Harris RA. Sildenafil improves vascular endothelial function in patients with cystic fibrosis. Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1486-H1494. doi: 10.1152/ajpheart.00301.2018. Epub 2018 Aug 31.

• Responsible Party: Jennifer Taylor-Cousar, Medical Director, Clinical Research Services; Professor, Departments of Medicine and Pediatrics,, National Jewish Health
• ClinicalTrials.gov Identifier: NCT04039087
• Other Study ID Numbers: Sildenafil Exercise
• First Posted: July 31, 2019
• Last Update Posted: September 2, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jennifer Taylor-Cousar, National Jewish Health:

Exercise intolerance; Quality of life; Cardiac function

Additional relevant MeSH terms:

Cystic Fibrosis; Fibrosis; Pathologic Processes; Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Sildenafil Citrate; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents