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Cystic Fibrosis and Endothelial Function: At Rest and During Exercise

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ryan Harris, Georgia Regents University
ClinicalTrials.gov Identifier:
NCT01772758
First received: October 16, 2012
Last updated: August 8, 2016
Last verified: August 2016
  Purpose
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.

Condition Intervention Phase
Cystic Fibrosis
Drug: BH4
Dietary Supplement: Vitamin C, 1000mg
Dietary Supplement: Vitamin E, 600IU
Dietary Supplement: Alpha Lipoic Acid, 600mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: Influence of Cystic Fibrosis on Vascular Endothelial Function at Rest and During Exercise

Resource links provided by NLM:


Further study details as provided by Augusta University:

Primary Outcome Measures:
  • Acute Change in Blood flow regulation during exercise [ Time Frame: change from Baseline (2-3hours) ] [ Designated as safety issue: No ]
    Brachial artery blood flow and velocities (both antegrade and retrograde) will be determined during baseline and 60% maximal work rate intensity.

  • Acute Change in Flow mediated dilation [ Time Frame: change from Baseline (2-3hours) ] [ Designated as safety issue: No ]
    Flow-Mediated Dilation will be determined at baseline and 2 and 3 hours following acute antioxidant and BH4 treatment, respectively

  • Acute Change in Arterial Stiffness [ Time Frame: change from Baseline (2-3hours) ] [ Designated as safety issue: No ]
    Pulse wave velocity will be determined at baseline and 2 and 3 hours following acute antioxidant and BH4 treatment, respectively


Secondary Outcome Measures:
  • Acute Change in Biomarkers of oxidative stress [ Time Frame: change from Baseline (2-3hours) ] [ Designated as safety issue: No ]
    Ascorbyl and alkoxyl free radicals 8-isoprostane lipid hydroperoxide will all be determined at baseline and 2 and 3 hours following acute antioxidant and BH4 treatment, respectively


Enrollment: 36
Study Start Date: August 2011
Study Completion Date: September 2015
Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Antioxidant Cocktail
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.
Dietary Supplement: Vitamin C, 1000mg
Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Dietary Supplement: Vitamin E, 600IU
Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Dietary Supplement: Alpha Lipoic Acid, 600mg
Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Experimental: Tetrahydrobiopterin (BH4)
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.
Drug: 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.)
Other Names:
  • Tetrahydrobiopterin
  • Kuvan

Detailed Description:
There have been major advances in research and medical therapies to target improvements in lung function; however, non-pulmonary factors have been neglected. Based on our recent discovery that patients with CF have systemic vascular endothelial dysfunction, it is reasonable to suspect the involvement of the blood vessels in the pathophysiology of exercise intolerance in CF - a concept that has yet to be examined. Thus 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. Our central hypothesis is that cystic fibrosis facilitates a whole body oxidative stress which contributes independently to both endothelial dysfunction and exercise intolerance. In support of our central hypothesis, we have generated compelling preliminary data to demonstrate the efficacy of antioxidants to improve endothelial function and exercise capacity in patients with CF. In addition, we have identified a robust inverse relationship between oxidative stress and exercise intolerance in patients with CF, such that patients with the highest basal levels of oxidative stress have the lowest exercise capacity. Further, we have identified that patients with CF have an exaggerated oxidative stress response to sub-maximal exercise when compared to healthy controls. Specific Aim 1: To test the hypothesis that oxidative stress contributes to endothelial dysfunction in patients with cystic fibrosis Brachial artery flow-mediated dilation (FMD), microvascular function, and markers of oxidant status (alkoxyl and ascorbyl free radical, 8-isoprostane, lipid hydroperoxide, total antioxidant capacity, and lipid soluble antioxidants) will be measured at baseline and 2 hours following the ingestion of an oral anti-oxidant cocktail (vitamin C, E, alpha-lipoic acid) or placebo cocktail (double blind, randomized, cross-over design) in patients with CF. Based on our preliminary data, we predict that the antioxidant cocktail will restore endothelial function and oxidant status to control values, whereas no change will be observed following placebo. Specific Aim 2: To test the hypothesis that oxidative stress contributes to exercise intolerance in patients with cystic fibrosis Exercise capacity (VO2 peak) and indices of gas exchange (O2 uptake kinetics, expired CO2, VE/VO2, VE/VCO2) will be determined using the Godfrey graded maximal exercise test on a cycle ergometer 2 hours following the ingestion of either an antioxidant cocktail or placebo cocktail (double blind, randomized, cross-over design) in patients with CF. Based on our preliminary data, we predict that patients with CF will exhibit an improvement in exercise capacity following the antioxidant cocktail, whereas no change will be observed following the placebo cocktail. Specific Aim 3: Test the hypothesis that chronic dosing of an anti-oxidant cocktail will improve endothelial function and contribute to an improvement in exercise capacity in patients with cystic fibrosis Following completion of Aims 1 and 2, endothelial function, exercise capacity (VO2 peak), and the indices of gas exchange (indicated above), will be performed, only in patients with CF, at baseline, 4 weeks, 8 weeks, and 12 weeks following an anti-oxidant cocktail taken once a day. Secondary outcomes will include measurements of arterial stiffness (pulse wave velocity), the Physioflow Enduro, and biomarkers of nitric oxide bioavailability. This chronic experiment will test the mechanism that an increase in endothelial function will improve exercise capacity in CF.
  Eligibility

Ages Eligible for Study:   7 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01772758

Locations
United States, Georgia
Georgia Prevention Center/ Laboratory of Integrative and Exercise Physiology
Augusta, Georgia, United States, 30912
Sponsors and Collaborators
Augusta University
Investigators
Principal Investigator: Ryan Harris, PhD, CES Augusta University
  More Information

Additional Information:
Responsible Party: Ryan Harris, Principal Investigator, Georgia Regents University
ClinicalTrials.gov Identifier: NCT01772758     History of Changes
Other Study ID Numbers: CFD Study 
Study First Received: October 16, 2012
Last Updated: August 8, 2016
Health Authority: United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: Yes

Additional relevant MeSH terms:
Fibrosis
Cystic Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Vitamins
Vitamin E
Tocopherols
Tocotrienols
Alpha-Tocopherol
Ascorbic Acid
Thioctic Acid
Antioxidants
Micronutrients
Growth Substances
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Protective Agents
Vitamin B Complex

ClinicalTrials.gov processed this record on September 23, 2016