Cystic Fibrosis and Endothelial Function: At Rest and During Exercise

• Sponsor: Augusta University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01772758
• Collaborator: (none)
• Enrollment: 64
• Location: 1
• Arms: 4
• Duration (Months): 58.7
• Patients Per Site Per Month: 1.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: BH4 5mg; Drug: BH4 20mg; Dietary Supplement: Antioxidant Cocktail	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Other
• Official Title: Influence of Cystic Fibrosis on Vascular Endothelial Function at Rest and During Exercise
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Jun 21, 2016
• Actual Study Completion Date: Jun 21, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Dietary Supplement: Antioxidant Cocktail; Vitamin C (1000 mg) , Vitamin E (600 IU) , and alpha-lipoic acid (600 mg). all BID
Experimental: 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.	Drug: BH4 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.); Other Names: Tetrahydrobiopterin Kuvan
Experimental: 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.	Drug: BH4 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.); Other Names: Tetrahydrobiopterin Kuvan
No Intervention: Healthy Controls baseline measurements were done with no intervention

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgia Prevention Institute/ 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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Laboratory of Integrative and Exercise Physiology Website

Publications

None provided.

• Responsible Party: Ryan Harris, Principal Investigator, Augusta University
• ClinicalTrials.gov Identifier: NCT01772758
• Other Study ID Numbers: CFD Study
• First Posted: Jan 21, 2013
• Last Update Posted: Jun 20, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Ryan Harris, Principal Investigator, Augusta University: CF, cystic fibrosis, exercise
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Antioxidants

Study Results

Participant Flow

Arm/Group Title	Protocol 1: AOC	Protocol 2: BH4 (5mg)	Protocol 2: BH4 (20mg)	Healthy Controls
Arm/Group Description	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	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.)	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.)	measurements were done with no intervention
Period Title: Overall Study
STARTED	18	17	12	17
COMPLETED	18	17	12	17
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Protocol 1: AOC	Protocol 2: BH4 (5mg)	Protocol 2: BH4 (20mg)	Healthy Controls	Total
Arm/Group Description	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	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.)	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.)	baseline measurements were done with no intervention	Total of all reporting groups
Overall Participants	18	17	12	17	64
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	17.9 (7.5)	17 (7)	19 (8)	15.7 (5.2)	17.3 (7.0)
Sex: Female, Male (Count of Participants)
Female	10 55.6%	10 58.8%	6 50%	9 52.9%	35 54.7%
Male	8 44.4%	7 41.2%	6 50%	8 47.1%	29 45.3%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	158.6 (14.2)	158.1 (14.1)	162.1 (11.1)	162.9 (14.7)	160.3 (14.0)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	53.1 (14.7)	53.0 (14.6)	57.8 (14.7)	52.5 (16.5)	53.8 (15.3)

Outcome Measures

1. Primary Outcome

Title	Percentage Flow-Mediated Dilation (FMD)
Description	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

Outcome Measure Data

Analysis Population Description

Participants included patients diagnosed with cystic fibrosis and healthy age-matched controls.

Arm/Group Title	Protocol 1: AOC	Protocol 2: BH4 (5mg)	Protocol 2: BH4 (20mg)	Healthy Controls
Arm/Group Description	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	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.)	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.)	measurements were done with no intervention
Measure Participants	18	17	12	17
Pre treatment	5.64 (2.80)	5.32 (3.53)	6.29 (3.21)	7.21 (3.17)
Post treatment	7.58 (4.16)	4.81 (2.83)	7.39 (3.41)

Adverse Events

Arm/Group Title	Antioxidant Cocktail: CF Patients		Antioxidant Cocktail: Healthy Controls		Tetrahydrobiopterin (BH4): 5mg		Tetrahydrobiopterin (BH4): 20mg
Arm/Group Description	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		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		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.)		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.)
All Cause Mortality
	Antioxidant Cocktail: CF Patients		Antioxidant Cocktail: Healthy Controls		Tetrahydrobiopterin (BH4): 5mg		Tetrahydrobiopterin (BH4): 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Antioxidant Cocktail: CF Patients		Antioxidant Cocktail: Healthy Controls		Tetrahydrobiopterin (BH4): 5mg		Tetrahydrobiopterin (BH4): 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Antioxidant Cocktail: CF Patients		Antioxidant Cocktail: Healthy Controls		Tetrahydrobiopterin (BH4): 5mg		Tetrahydrobiopterin (BH4): 20mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.