Sildenafil Exercise: Role of PDE5 Inhibition

NCT04039087 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: Sildenafil Exercise
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 2

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.

Conditions

Cystic Fibrosis

Keywords

Exercise intolerance; Quality of life; Cardiac function

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score

  Quality of life assessed at weeks 1 and 12.

• Cardiac strain

  Change in cardiac strain between weeks 1 and 12

• Flow-Mediated Dilation (FMD)

  Change in FMD between weeks 1 and 12

• Skeletal muscle function

  Change in skeletal muscle function between weeks 1 and 12

Study Arms (2)

Sildenafil

ACTIVE COMPARATOR

active sildenafil 40 mg p.o. three times per day

Drug: Sildenafil 40mg oral capsule

Placebo Arm

PLACEBO COMPARATOR

placebo three times per day

Drug: Placebo Oral capsule

Interventions

Sildenafil 40mg oral capsule DRUG

40 mg, sildenafil capsule taken by mouth thrice daily

Also known as: sildenafil, revatio

Sildenafil

Placebo Oral capsule DRUG

Placebo capsule taken by mouth thrice daily

Also known as: placebo

Placebo Arm

Eligibility Criteria

• Age: 9 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)
• History of sputum or throat swab culture yielding Burkholderia cepacia or Mycobacteria massiliense within 2 years of screening

Sponsors & Collaborators

• National Jewish Health: lead
• Augusta University: collaborator
• Cystic Fibrosis Foundation: collaborator

Study Sites (2)

National Jewish Health

Denver, Colorado, 80206, United States

Location

Augusta University

Augusta, Georgia, 30912, United States

Location

Related Publications (2)

• 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.

  PMID: 25466700 BACKGROUND

• Rodriguez-Miguelez P, Lee N, Tucker MA, Csanyi 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.

  PMID: 30168731 BACKGROUND

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jennifer Taylor-Cousar, MD, MSCS

  National Jewish Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The participants, care provider, investigator and those assessing the outcomes will be blinded to treatment designation.
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director, Clinical Research Services; Professor, Departments of Medicine and Pediatrics,

Model Details: Subjects will be randomized 1:1 to the sildenafil or placebo groups

Study Record Dates

• First Submitted: July 28, 2019
• First Posted: July 31, 2019
• Study Start: September 5, 2019
• Primary Completion: June 30, 2024
• Study Completion: June 30, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)