Clinical trial NCT00423280: Effect of 6R-BH4 Treatment in Coronary Artery Disease (OXBIO Study)
Official title: A Randomised, Placebo-Controlled Study of Two Doses of Oral 6R-BH4 on Vascular Function in Subjects With Coronary Artery Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Coronary Artery Disease
Keywords: Endothelium
Nitric Oxide
Magnetic Resonance Imaging
Tetrahydrobiopterin
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: BioMarin Pharmaceutical
First posted: 2007-01-18
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the effect of 6R-BH4 on vascular function in patients with coronary artery disease. We hypothesize that 6R-BH4 will improve vascular function in these patients.

Detailed description: Decreased production of nitric oxide (NO) from the endothelium (the layer of cells that forms the lining of all blood vessels) has been shown to contribute to atherosclerosis. NO has multiple beneficial effects on vascular function. Endothelial function can be measured in humans via a number of methods, and endothelial dysfunction has been shown to be a strong adverse predictor of cardiovascular events and mortality.

Tetrahydrobiopterin (BH4) is essential for the production of NO in endothelial cells. 6R-BH4 is a synthetic version of naturally occurring BH4. We aim to investigate the effects of oral 6R-BH4 supplementation on endothelial function in patients with coronary artery disease.

Eligibility criteria: Inclusion Criteria:

* Multi-vessel coronary artery disease scheduled for coronary artery bypass surgery (CABG)

Exclusion Criteria:

* Inability to provide informed consent
* Female subject who is pregnant, lactating or planning pregnancy during course of study
* Prior clinical diagnosis of heart failure requiring diuretic therapy with evidence of severe left ventricular dysfunction
* Recent acute coronary event (\<4 weeks)
* Emergency CABG
* Newly diagnosed diabetes mellitus (\<1 month)
* Body weight \>130kg
* Impaired renal function (creatinine \>180umol/l)
* Elevated liver function tests (ALT \>50umol/l or AST \>2x normal)
* Pacemakers, ICDs or metallic implants not compatible with MRI scanning
* Subjects receiving experimental medications or participating in another study
* Terminally ill subjects
* Known hypersensitivity to 6R-BH4
* Concomitant treatment with methotrexate, levodopa, PDE-3 or PDE-5 inhibitors

Primary outcomes:
measure: Vascular function using non-invasive magnetic resonance imaging (MRI).
timeFrame: Pre- and post- treatment with 6R-BH4 or placebo
Secondary outcomes:
measure: Laboratory measures of vascular function.
timeFrame: At time of CABG surgery
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: Department of Cardiovascular Medicine, University of Oxford
Study officials:
affiliation: University of Oxford
name: Keith M Channon, MD FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R, Crabtree MJ, Francis JM, Sayeed R, Ratnatunga C, Pillai R, Choudhury RP, Neubauer S, Channon KM. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation. 2012 Mar 20;125(11):1356-66. doi: 10.1161/CIRCULATIONAHA.111.038919. Epub 2012 Feb 7.
citation: Cunnington C, Channon KM. Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology. Heart. 2010 Dec;96(23):1872-7. doi: 10.1136/hrt.2009.180430. Epub 2010 Sep 13.