Cystic Fibrosis
Conditions
Keywords
arterial stiffness, flow-mediated dilation, endothelial function, pulse wave velocity, inflammation, oxidative stress, pulmonary function test, Cystic Fibrosis, Lung Disease, Nitric Oxide, Exercise Capacity, CF, Muscle Function, Sildenafil, Viagra, Revatio
Brief summary
Cystic fibrosis (CF) has many health consequences. A reduction in the ability to perform exercise in patients with CF is related to greater death rates, steeper decline in lung function, and more frequent lung infections. However, the physiological mechanisms for this reduced exercise capacity are unknown. The investigators laboratory recently published the first evidence of systemic vascular dysfunction in patients with CF. Therefore, it is reasonable to suspect that the blood vessels are involved with exercise intolerance in CF. This study will look at how 1) blood flow and 2) artery function contribute to exercise capacity in CF.
Detailed description
The most disturbing aspect of Cystic Fibrosis (CF) is the associated premature death. Low exercise capacity predicts death in patients with CF and is also associated with a steeper decline in lung function and more lung infections. A critical barrier to improving exercise tolerance in patients with CF is the investigators lack of knowledge regarding the different physiological mechanisms which contribute to their lower exercise capacity. We have compelling data to indicate that the blood vessels may contribute to the low exercise capacity in CF. The impact of this proof of concept investigation will test Phosphodiesterase Type 5 inhibitors (PDE5) inhibitors as a potential therapy in CF and will explore blood flow and endothelial function as potential mechanisms which contribute to exercise intolerance in CF. Improvements in exercise capacity will not only contribute to a better quality of live for patients with CF, it will also increase longevity in these patients.
Interventions
DRUGSildenafil (Acute-1 hour)
Vascular function will be assessed 1 hour following oral ingestion of sildenafil (50 mg)
DRUGSildenafil (Subchronic-4 weeks)
Vascular function will be assessed 4 weeks following 20 mg three times per day (TID) of sildenafil for four weeks
DRUGPlacebo
Sugar pill designed to mimic the sildenafil treatment
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Augusta University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
. * Diagnosis of CF and healthy controls * Men and women (greater than 18 yrs. old) * Resting oxygen saturation (room air) greater than 90% * Forced expiratory volume (FEV1) percent predicted greater than 30% * Patients with or without CF related diabetes * Traditional CF-treatment medications * Ability to perform reliable/reproducible pulmonary function tests (PFT) * Clinically stable for 2 weeks (no exacerbations or need for antibiotic treatment within 2 weeks of testing or major change in medical status)
Exclusion criteria
. * Children less than 17 years old * Body mass less than 20 kg * A diagnosis of pulmonary arterial hypertension (PAH) * FEV1 less than 30% of predicted * Resting oxygen saturation (SpO2) less than 90% * Self-reported to be a smoker * Current use of any vaso-active medications * History of migraine headaches * Pregnant or nursing at the time of the investigation * A clinical diagnosis of cardiovascular disease, hypertension, or CF related diabetes
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Study: Percentage Flow-Mediated Dilation (FMD) | pre-treatment Baseline and 1 hour post-treatment | FMD determined one hour after ingestion of 50 mg Sildenafil or placebo |
| Baseline Diameter | pre-treatment Baseline and following 4 weeks sub-chronic treatment | Brachial Artery Diameter during FMD (pre-occlusion or baseline) |
| Peak Diameter | pre-treatment Baseline and following 4 weeks sub-chronic treatment | Peak Brachial Artery Diameter during FMD (post-occlusion) |
| Absolute Change in Diameter | pre-treatment Baseline and following 4 weeks sub-chronic treatment | Absolute change in brachial artery diameter taken from the FMD assessment |
| FEV1 (% Predicted) | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | Forced Expiratory Volume in the first second expressed as a percent predicted. |
| VO2 Peak (Absolute) | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | absolute (L/min) peak oxygen consumption during maximal exercise test |
| VO2 Peak (Relative) | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | relative (mL/kg/min) peak oxygen consumption during maximal exercise test |
| VO2 Peak (Percent Predicted) | pre-treatment Baseline and 1 hour post-treatment, and 4 weeks sub-chronic treatment | Maximal Oxygen consumption expressed as percent predicted taken from maximal exercise test. |
| VE Peak | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | peak ventilation (L/min) during maximal exercise test |
| RER Peak | pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment | peak respiratory exchange ratio during maximal exercise test |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Baseline characteristics reported for the overall study | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Acute Study (1 Hour): First Intervention | Lost to Follow-up | 2 | 0 | 0 |
| Met Inclusion Criteria | Prior history of migraine headaches | 0 | 1 | 0 |
| Sub-Chronic Study (4 Weeks) | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 23 years STANDARD_DEVIATION 11 |
| Body fat | 28.5 % STANDARD_DEVIATION 7.9 |
| Body mass index | 20.4 kg/m^2 STANDARD_DEVIATION 4 |
| Diastolic blood pressure | 65 mmHg STANDARD_DEVIATION 7 |
| Height | 160 cm STANDARD_DEVIATION 13 |
| O2 saturation | 98 % STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 8 Participants |
| Systolic blood pressure | 108 mmHg STANDARD_DEVIATION 11 |
| Weight | 54 kg STANDARD_DEVIATION 17 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Absolute Change in Diameter
Absolute change in brachial artery diameter taken from the FMD assessment
Time frame: pre-treatment Baseline and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | Absolute Change in Diameter | 0.21 mm | Standard Deviation 0.12 |
| Acute Study: Placebo | Absolute Change in Diameter | 0.27 mm | Standard Deviation 0.09 |
Primary
Acute Study: Percentage Flow-Mediated Dilation (FMD)
FMD determined one hour after ingestion of 50 mg Sildenafil or placebo
Time frame: pre-treatment Baseline and 1 hour post-treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Acute Study: Sildenafil | Acute Study: Percentage Flow-Mediated Dilation (FMD) | Pre | 7.8 percent flow mediated dilation | Standard Deviation 4.3 |
| Acute Study: Sildenafil | Acute Study: Percentage Flow-Mediated Dilation (FMD) | Post | 7.3 percent flow mediated dilation | Standard Deviation 4.8 |
| Acute Study: Placebo | Acute Study: Percentage Flow-Mediated Dilation (FMD) | Pre | 7.7 percent flow mediated dilation | Standard Deviation 4.3 |
| Acute Study: Placebo | Acute Study: Percentage Flow-Mediated Dilation (FMD) | Post | 6.6 percent flow mediated dilation | Standard Deviation 3.7 |
Primary
Baseline Diameter
Brachial Artery Diameter during FMD (pre-occlusion or baseline)
Time frame: pre-treatment Baseline and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | Baseline Diameter | 3.00 mm | Standard Deviation 0.59 |
| Acute Study: Placebo | Baseline Diameter | 3.06 mm | Standard Deviation 0.6 |
Primary
FEV1 (% Predicted)
Forced Expiratory Volume in the first second expressed as a percent predicted.
Time frame: pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | FEV1 (% Predicted) | 81 percent predicted | Standard Deviation 16 |
| Acute Study: Placebo | FEV1 (% Predicted) | 75 percent predicted | Standard Deviation 12 |
| Acute Study: Placebo | FEV1 (% Predicted) | 75 percent predicted | Standard Deviation 16 |
| Sub-chronic Study: Sildenafil | FEV1 (% Predicted) | 82 percent predicted | Standard Deviation 15 |
Primary
Peak Diameter
Peak Brachial Artery Diameter during FMD (post-occlusion)
Time frame: pre-treatment Baseline and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | Peak Diameter | 3.22 mm | Standard Deviation 0.6 |
| Acute Study: Placebo | Peak Diameter | 3.30 mm | Standard Deviation 0.6 |
Primary
RER Peak
peak respiratory exchange ratio during maximal exercise test
Time frame: pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | RER Peak | 1.31 ratio | Standard Deviation 0.15 |
| Acute Study: Placebo | RER Peak | 1.17 ratio | Standard Deviation 0.12 |
| Acute Study: Placebo | RER Peak | 1.22 ratio | Standard Deviation 0.13 |
| Sub-chronic Study: Sildenafil | RER Peak | 1.18 ratio | Standard Deviation 0.14 |
Primary
VE Peak
peak ventilation (L/min) during maximal exercise test
Time frame: pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | VE Peak | 65 L/min | Standard Deviation 19 |
| Acute Study: Placebo | VE Peak | 81 L/min | Standard Deviation 23 |
| Acute Study: Placebo | VE Peak | 77 L/min | Standard Deviation 24 |
| Sub-chronic Study: Sildenafil | VE Peak | 72 L/min | Standard Deviation 21 |
Primary
VO2 Peak (Absolute)
absolute (L/min) peak oxygen consumption during maximal exercise test
Time frame: pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | VO2 Peak (Absolute) | 1.5 L/min | Standard Deviation 0.4 |
| Acute Study: Placebo | VO2 Peak (Absolute) | 1.7 L/min | Standard Deviation 0.5 |
| Acute Study: Placebo | VO2 Peak (Absolute) | 1.6 L/min | Standard Deviation 0.5 |
| Sub-chronic Study: Sildenafil | VO2 Peak (Absolute) | 1.6 L/min | Standard Deviation 0.5 |
Primary
VO2 Peak (Percent Predicted)
Maximal Oxygen consumption expressed as percent predicted taken from maximal exercise test.
Time frame: pre-treatment Baseline and 1 hour post-treatment, and 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | VO2 Peak (Percent Predicted) | 72 percent predicted | Standard Deviation 12 |
| Acute Study: Placebo | VO2 Peak (Percent Predicted) | 77 percent predicted | Standard Deviation 13 |
| Acute Study: Placebo | VO2 Peak (Percent Predicted) | 72 percent predicted | Standard Deviation 13 |
| Sub-chronic Study: Sildenafil | VO2 Peak (Percent Predicted) | 75 percent predicted | Standard Deviation 12 |
Primary
VO2 Peak (Relative)
relative (mL/kg/min) peak oxygen consumption during maximal exercise test
Time frame: pre-treatment Baseline, 1 hour post-treatment, and following 4 weeks sub-chronic treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Study: Sildenafil | VO2 Peak (Relative) | 28.5 mL/kg/min | Standard Deviation 5.6 |
| Acute Study: Placebo | VO2 Peak (Relative) | 29.3 mL/kg/min | Standard Deviation 6.1 |
| Acute Study: Placebo | VO2 Peak (Relative) | 26.8 mL/kg/min | Standard Deviation 6.4 |
| Sub-chronic Study: Sildenafil | VO2 Peak (Relative) | 29.5 mL/kg/min | Standard Deviation 6.4 |