Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Sildenafil Exercise: Role of PDE5 Inhibition

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04039087
Recruitment Status : Recruiting
First Posted : July 31, 2019
Last Update Posted : October 22, 2019
Sponsor:
Collaborators:
Augusta University
Cystic Fibrosis Foundation
Information provided by (Responsible Party):
Jennifer Taylor-Cousar, National Jewish Health

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


Layout table for study information
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


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




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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04039087


Contacts
Layout table for location contacts
Contact: Nora H Murphy, BS 3032702861 murphyn@njhealth.org
Contact: Jennifer Taylor-Cousar, MD, MSCS 3032702764 taylorcousarj@njhealth.org

Locations
Layout table for location information
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
Layout table for investigator information
Principal Investigator: Jennifer Taylor-Cousar, MD, MSCS National Jewish Health

Publications:
Layout table for additonal information
Responsible Party: Jennifer Taylor-Cousar, Medical Director, Clinical Research Services; Professor, Departments of Medicine and Pediatrics,, National Jewish Health
ClinicalTrials.gov Identifier: NCT04039087     History of Changes
Other Study ID Numbers: Sildenafil Exercise
First Posted: July 31, 2019    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
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:
Layout table for 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