Cystic Fibrosis
Conditions
Keywords
Exercise intolerance, Quality of life, Cardiac function
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
While cystic fibrosis (CF) is most common in people of European ancestry, it can occur in individuals of any ethnicity. 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
Interventions
DRUGSildenafil 40mg oral capsule
40 mg, sildenafil capsule taken by mouth thrice daily
DRUGPlacebo Oral capsule
Placebo capsule taken by mouth thrice daily
Sponsors
National Jewish Health
Augusta University
Cystic Fibrosis Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The participants, care provider, investigator and those assessing the outcomes will be blinded to treatment designation.
Intervention model description
Subjects will be randomized 1:1 to the sildenafil or placebo groups
Eligibility
Sex/Gender
ALL
Age
9 Years to No maximum
Healthy volunteers
No
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 ≤ 80% for patients ≥ 18 years of age and ≤ 85% 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minute Walk Distance (6MWD) | Change in distance walked between week 1 and week 13 | Exercise 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
| Measure | Time frame | Description |
|---|---|---|
| Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | Quality of life assessed at weeks 1 and 13 | 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). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJennifer Taylor-Cousar, MD, MSCS
National Jewish Health
Participant flow
Recruitment details
Participants were recruited from National Jewish Health in Denver, Colorado, and from Augusta University in Augusta, Georgia. Children and adults were enrolled at Augusta University and only adults were recruited at National Jewish Health. Participants were identified using the Cystic Fibrosis Foundation Patient Registry (CFFPR) and when attending CF clinic at the respective clinics. Potential participants were approached in person at clinic or by telephone between September 2019 and June 2024.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 32.1 Years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 |
| other Total, other adverse events | 6 / 15 | 6 / 16 |
| serious Total, serious adverse events | 1 / 15 | 0 / 16 |
Outcome results
None listed