Cystic Fibrosis
Conditions
Keywords
CF, cystic fibrosis, exercise
Brief summary
Perhaps one of the most disturbing aspects of Cystic Fibrosis (CF) is the associated premature death. Oxidative stress has been observed in patients with CF and exercise intolerance has been shown to predict mortality in patients with CF, regardless of how healthy their lungs are. A critical barrier to improving the quality of life and longevity in patients with CF is our lack of knowledge regarding the different reasons why patients with CF cannot exercise to the level of their peers. We have collected preliminary data to support our central hypothesis that oxidative stress contributes to the impairment in blood vessel function at rest and during exercise which ultimately oxygen transport and delivery resulting in exercise intolerance. Exercise is therapeutic medicine for patients with CF and this investigation represents a major breakthrough in the approach to begin understanding the physiological mechanisms which contribute to exercise intolerance in these patients.
Detailed description
The overall goals of this proposal are to provide mechanistic evidence that oxidative stress contributes to 1) endothelial dysfunction and 2) exercise intolerance in patients with CF. This study consists of two separate sub-studies, or protocols. Protocol 1: AOC tested the effect of an antioxidant cocktail (AOC) on endothelial function at rest and during exercise in CF patients. Protocol 2: BH4 tested the effect of tetrahydrobiopterin (BH4) on endothelial function at rest and during exercise in CF patients.
Interventions
DRUGBH4 5mg
Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects received an oral dose of 5 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.)
DRUGBH4 20mg
Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects received an oral dose of 20 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.)
DIETARY_SUPPLEMENTAntioxidant Cocktail
Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Sponsors
Augusta University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Diagnosis of CF and healthy controls * Men and women (\> 18 yrs. old) * Boys and girls (7 -17 yrs. old) * FEV1 percent predicted \> 30% * Resting oxygen saturation (room air) \>90% * Patients with or without CFRD * Traditional CF-treatment medications * Ability to perform reliable/reproducible PFTs * 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 6 yrs. old and younger * FEV1 percent predicted \< 30% * Resting oxygen saturation (room air) \< 90% * Clinical diagnosis of heart disease * Pulmonary artery hypertension * Febrile illness within two weeks of visit * Current smokers * Currently pregnant or nursing * Individuals on vaso-active medications (i.e. nitrates, beta blockers, ACE inhibitors, etc.) * Inability to swallow pills * Patients with B. Cepacia (only \ 3% of our CF center patient population)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Flow-Mediated Dilation (FMD) | pre-treatment Baseline and 2-3 hours post-treatment | Brachial artery FMD induced by reactive hyperemia assessed vascular endothelial function at baseline and several hours after treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Protocol 1: AOC measurements at baseline and 2 hours following the antioxidant cocktail that is comprised of over the counter vitamins (vitamin C 1000mg, vitamin E 600 IU, and alpha lipoic acid 600 mg) that will be given in two doses, 30 minutes apart.
Vitamin C, 1000mg: Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Vitamin E, 600IU: Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Alpha Lipoic Acid, 600mg: Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID | 18 |
| Protocol 2: BH4 (5mg) measurements at baseline and 3 hours following the single dose of 5mg/kg Kuvan® or sapropterin dihydrochloride which is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4).BH4 has been shown in past studies to increase NO bioavailability.
BH4: Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects will receive an oral dose of 20 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.) | 17 |
| Protocol 2: BH4 (20mg) measurements at baseline and 3 hours following the single dose of 20mg/kg Kuvan® or sapropterin dihydrochloride which is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4).BH4 has been shown in past studies to increase NO bioavailability.
BH4: Kuvan® or sapropterin dihydrochloride is a synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin (BH4). Subjects will receive an oral dose of 20 mg/kg of Kuvan® (Biomarin Pharmaceuticals Inc.) | 12 |
| Healthy Controls baseline measurements were done with no intervention | 17 |
| Total | 64 |
Baseline characteristics
| Characteristic | Total | Healthy Controls | Protocol 1: AOC | Protocol 2: BH4 (20mg) | Protocol 2: BH4 (5mg) |
|---|---|---|---|---|---|
| Age, Continuous | 17.3 years STANDARD_DEVIATION 7 | 15.7 years STANDARD_DEVIATION 5.2 | 17.9 years STANDARD_DEVIATION 7.5 | 19 years STANDARD_DEVIATION 8 | 17 years STANDARD_DEVIATION 7 |
| Height | 160.3 cm STANDARD_DEVIATION 14 | 162.9 cm STANDARD_DEVIATION 14.7 | 158.6 cm STANDARD_DEVIATION 14.2 | 162.1 cm STANDARD_DEVIATION 11.1 | 158.1 cm STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 35 Participants | 9 Participants | 10 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 29 Participants | 8 Participants | 8 Participants | 6 Participants | 7 Participants |
| Weight | 53.8 kg STANDARD_DEVIATION 15.3 | 52.5 kg STANDARD_DEVIATION 16.5 | 53.1 kg STANDARD_DEVIATION 14.7 | 57.8 kg STANDARD_DEVIATION 14.7 | 53.0 kg STANDARD_DEVIATION 14.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 17 | 0 / 17 | 0 / 12 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 | 0 / 17 | 0 / 12 |
Outcome results
Primary
Percentage Flow-Mediated Dilation (FMD)
Brachial artery FMD induced by reactive hyperemia assessed vascular endothelial function at baseline and several hours after treatment.
Time frame: pre-treatment Baseline and 2-3 hours post-treatment
Population: Participants included patients diagnosed with cystic fibrosis and healthy age-matched controls.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Protocol 1: AOC | Percentage Flow-Mediated Dilation (FMD) | Pre treatment | 5.64 percentage of change in FMD | Standard Deviation 2.8 |
| Protocol 1: AOC | Percentage Flow-Mediated Dilation (FMD) | Post treatment | 7.58 percentage of change in FMD | Standard Deviation 4.16 |
| Protocol 2: BH4 (5mg) | Percentage Flow-Mediated Dilation (FMD) | Pre treatment | 5.32 percentage of change in FMD | Standard Deviation 3.53 |
| Protocol 2: BH4 (5mg) | Percentage Flow-Mediated Dilation (FMD) | Post treatment | 4.81 percentage of change in FMD | Standard Deviation 2.83 |
| Protocol 2: BH4 (20mg) | Percentage Flow-Mediated Dilation (FMD) | Post treatment | 7.39 percentage of change in FMD | Standard Deviation 3.41 |
| Protocol 2: BH4 (20mg) | Percentage Flow-Mediated Dilation (FMD) | Pre treatment | 6.29 percentage of change in FMD | Standard Deviation 3.21 |
| Healthy Controls | Percentage Flow-Mediated Dilation (FMD) | Pre treatment | 7.21 percentage of change in FMD | Standard Deviation 3.17 |