Cystic Fibrosis
Conditions
Brief summary
This study evaluates the ability of the drug sildenafil to improved exercise capacity, cardiac performance during exercise, and quality of life in patients with moderate to severe CF lung disease. 3/4 of the subjects will receive sildenafil and 1/4 will receive placebo.
Detailed description
Over time, patients with Cystic Fibrosis (CF) develop disabling lung disease that progresses to chronic respiratory failure, exercise intolerance with marked limitation of physical activity, and premature death. Despite substantial improvements in care, patients with CF often develop pulmonary vascular disease (PVD) that leads to pulmonary hypertension. Previous studies have clearly linked severe pulmonary hypertension and right heart failure with high mortality in CF. Early clinical manifestations of PVD prior to the development of cor pulmonale include shortness of breath and dyspnea with exertion, but the extent to which PVD contributes to the decline in exercise tolerance and quality of life in patients with CF is not known. Early evidence of PVD could be recognized in CF patients through standardized exercise testing and echocardiographic evaluation. Identifying those CF patients with PVD prior to the onset of right ventricular dysfunction may allow pharmacologic intervention to attenuate the progression of cardiovascular disease and improve quality of life. Clinical trials have demonstrated that treatment with the phosphodiesterase type 5 inhibitor, sildenafil, can decrease pulmonary vascular resistance and improve exercise tolerance in non-CF patients with pulmonary hypertension. Because experimental and clinical studies have implicated impaired NO-cGMP signaling in the pathophysiology of lung disease in CF, sildenafil may provide a novel pharmacological approach for treating PVD in patients with CF lung disease.
Interventions
DRUGsildenafil
active sildenafil
DRUGplacebo
sugar pill that looks like sildenafil tablets
Sponsors
National Jewish Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of CF based on the following criteria: Positive sweat chloride ≥60mEq/liter (by pilocarpine iontophoresis) and/or Genotype with two identifiable mutations consistent with CF, and accompanied by one or more clinical features consistent with the CF phenotype 2. Male or female patients ≥ 18 years of age 3. FEV1 ≥ 20% predicted and ≤ 70% predicted (Hankinson) 4. 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 5. Ability to reproducibly perform spirometry (according to ATS criteria) 6. Ability to understand and sign a written informed consent or assent and comply with the requirements of the study 7. Willingness to maintain chronic CF medication schedule (e.g. alternating month inhaled antibiotics)
Exclusion criteria
1. History of hypersensitivity to sildenafil 2. Use of an investigational agent within the 4-week period prior to Visit 1 (Day 0) 3. 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. 4. History of significant hepatic disease (AST or ALT \> 5 times the upper limit of normal at screening, documented biliary cirrhosis, or portal hypertension), 5. History of significant cardiovascular disease (history of aortic stenosis, coronary artery disease, or life-threatening arrhythmia), 6. History of severe neurological disease (e.g. history of stroke), 7. History of severe hematologic disease (e.g. history of bleeding diathesis; current INR \> 2.0 8. History of severe ophthalmologic disease (e.g. history of retinal impairment or non-arteritic ischemic optic neuritis) 9. History of severe renal impairment (creatinine \>1.8 mg/dL.) 10. Inability to swallow pills 11. Previous organ transplantation 12. Use of concomitant nitrates, α-blocker, or Ca channel blocker (currently or within one month of Visit 1) 13. 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 14. History of sputum or throat swab culture yielding Burkholderia cepacia or Mycobacterium massiliense within 2 years of screening 15. Weight less than 40 kg at Screening 16. History of migraine headaches. 17. Resting room air oxygen saturation \<80% without supplemental oxygen 18. 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 19. Start of CFTR modulator therapy less than 1 month prior to first dose of sildenafil or placebo 20. Use of anticoagulants 21. Frank pulmonary hypertension (RVSP \>40 mmHg by ECHO)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minute Walk Distance | Weeks 1, 13 | Change in distance walked between week 1 and week 13 were compared. The difference between the two time points is reported. |
| Cardiopulmonary Exercise Test Work Rate | Weeks 1 and 13 | Work rate (the amount of energy being expended to cycle) was assessed at weeks 1 and 13. The change in maximum work measured during CPET between weeks 1 and 13 is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cystic Fibrosis Quality of Life-Revised Respiratory Domain Score | Assessed at weeks 1 and 13 | The CFQ-R Respiratory domain score (scale 0-100 with higher scores indicating better quality of life) was assessed at weeks 1 and 13. The change in the score between week 1 and week 13 is reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Subjects will be randomized in a 3:1 (sildenafil:placebo) fashion. Subjects randomized to the treatment arm will receive sildenafil 20 mg p.o. t.i.d for 1 week followed by 40 mg p.o. t.i.d. for 11 weeks.
sildenafil: active sildenafil | 9 |
| Placebo Subjects randomized to the placebo arm will receive placebo p.o. t.i.d for 1 week followed by 2 placebo tablets p.o. t.i.d. for 11 weeks.
placebo: sugar pill that looks like sildenafil tablets | 3 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Sildenafil | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 32.5 years STANDARD_DEVIATION 10.6 | 32.2 years STANDARD_DEVIATION 9.4 | 31.3 years STANDARD_DEVIATION 1.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 12 Participants | 3 Participants |
| Region of Enrollment United States | 9 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 3 |
| other Total, other adverse events | 9 / 9 | 3 / 3 |
| serious Total, serious adverse events | 2 / 9 | 0 / 3 |
Outcome results
Primary
6 Minute Walk Distance
Change in distance walked between week 1 and week 13 were compared. The difference between the two time points is reported.
Time frame: Weeks 1, 13
Population: All subjects who received 12 weeks of sildenafil 40 mg po tid or placebo po tid with the exception of 1 extreme outlier in the placebo group who was excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | 6 Minute Walk Distance | 25.2 meters | Standard Deviation 18.8 |
| Placebo | 6 Minute Walk Distance | 0.75 meters | Standard Deviation 5.44 |
Primary
Cardiopulmonary Exercise Test Work Rate
Work rate (the amount of energy being expended to cycle) was assessed at weeks 1 and 13. The change in maximum work measured during CPET between weeks 1 and 13 is reported.
Time frame: Weeks 1 and 13
Population: Patients who received sildenafil 40 mg po tid or placebo po tid for 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Cardiopulmonary Exercise Test Work Rate | -0.20 watts | Standard Deviation 2.96 |
| Placebo | Cardiopulmonary Exercise Test Work Rate | -0.27 watts | Standard Deviation 4.15 |
Secondary
Cystic Fibrosis Quality of Life-Revised Respiratory Domain Score
The CFQ-R Respiratory domain score (scale 0-100 with higher scores indicating better quality of life) was assessed at weeks 1 and 13. The change in the score between week 1 and week 13 is reported.
Time frame: Assessed at weeks 1 and 13
Population: Subjects who received sildenafil 40 mg po tid or placebo tid for 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sildenafil | Cystic Fibrosis Quality of Life-Revised Respiratory Domain Score | 8.62 units on a scale | Standard Deviation 18.23 |
| Placebo | Cystic Fibrosis Quality of Life-Revised Respiratory Domain Score | -9.23 units on a scale | Standard Deviation 3.23 |