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Trial record 8 of 14 for:    cardiovascular febuxostat

Uric Acid Effects on Endothelium and Oxydative Stress

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ClinicalTrials.gov Identifier: NCT03395977
Recruitment Status : Recruiting
First Posted : January 10, 2018
Last Update Posted : April 17, 2018
Sponsor:
Collaborator:
Erasme Fund
Information provided by (Responsible Party):
Benjamin De Becker, MD, Fonds National de la Recherche Scientifique

Brief Summary:

Cardiovascular disease is the leading cause of mortality worldwide. Endothelial dysfunction (ED) is the main mechanism which leads to atherosclerosis, where the balance between pro and antioxidant factors results in a decreased nitric oxide (NO) bioavailability. Xanthine OxidoReductase (XOR) is one of the main generators of reactive oxygen species (ROS). Uric acid (UA), a major antioxidant in human plasma and end product of purine metabolism, is associated with cardiovascular diseases since many years; however the precise mechanisms which relate UA to ED are still not well understood.

The purpose of this study is to unravel the XOR and UA pathways involved in ED. Two groups of male participants (healthy and with metabolic syndrome) will be exposed to febuxostat (a strong and selective XOR inhibitor), or recombinant uricase (which oxidizes UA into allantoin) to vary UA levels and concomitantly control for confounding changes in XOR activity. Oxidative stress will be estimated by several markers. Endothelial function will be assessed by a laser Doppler imager in the presence of hyperthermia and endothelium stimulators. This study is specifically designed to untie the respective effects of UA and XOR pathways on oxidative stress and endothelial function in humans.

The investigators will test the following hypothesis:

  1. An extremely low level of uric acid after uricase administration induces endothelial dysfunction and oxydative stress,
  2. A specific XO inhibitor limits unfavourable effects of the serum UA reduction elicited by uricase administration,
  3. Endothelial function and oxydative stress are further improved with febuxostat as compared to placebo,
  4. All these observations are more marked in metabolic syndrome subjects with an impaired endothelial function than in healthy subjects.

Condition or disease Intervention/treatment Phase
Oxidative Stress Endothelial Function Cardiovascular System Metabolic Syndrome Drug: Placebos Drug: Febuxostat Drug: Rasburicase Not Applicable

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

This is a prospective, randomized, placebo-controlled, double-blinded and 3 ways cross-over study. Two groups : healthy subjects and metabolic syndrome subjects (21 participants in each group).

For 5 subjects in each group, we will perform a fourth session with Placebo PO and Rasburicase IV. That session will be non-randomized and blinded only for the subject.

Masking: Double (Participant, Investigator)
Masking Description: Febuxostat and Rasburicase will be prepared by an independant pharmacist.
Primary Purpose: Basic Science
Official Title: Differential Effects of Uric Acid and Xanthine Oxidoreductase on Endothelial Function and Oxydative Stress
Actual Study Start Date : January 3, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Placebo Comparator: Placebos PO and IV
PO : per os IV : intraveinously
Drug: Placebos
Lactose placebo for pills and saline for perfusion.
Experimental: Febuxostat PO and Placebo IV
240 mg a day for 3 days
Drug: Placebos
Lactose placebo for pills and saline for perfusion.
Drug: Febuxostat
Febuxostat tablet.
Other Name: Adenuric
Experimental: Febuxostat PO And Rasburicase IV
Febuxostat : 240 mg a day for 3 days. Uricase : 3 mg once.
Drug: Febuxostat
Febuxostat tablet.
Other Name: Adenuric
Drug: Rasburicase
Rasburicase injectable solution.
Other Name: Fasturtec
Experimental: Placebo PO And Rasburicase IV
Placebo : for 3 days. Uricase : 3 mg once.
Drug: Placebos
Lactose placebo for pills and saline for perfusion.
Drug: Rasburicase
Rasburicase injectable solution.
Other Name: Fasturtec



Primary Outcome Measures :
  1. Change in Oxydative stress biomarkers from baseline to 30 min or 24 hours after infusion of Uricase or Placebo [ Time Frame: Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo ]
    Among these oxidative stress biomarkers, we will measure F2 isoprostanes and malondialdehyde. F2-isoprostanes constitute the most reliable approach to assess oxidative stress in vivo. Malondialdehyde will be used as marker of cell injury. Due to their roles in the oxidative stress pathway, we will measure myeloperoxidase (MPO), protein-bound 3-chlorotyrosine and homocitrulline; MPO oxidized apolipoprotein A1, oxidized Trp72/Trp72 ratio and oxidized Met112/Met112 ratio; MPO-dependent modified LDL (Mox-LDL) ; angiotensin II (ANG II) and Interleukin-8 (IL-8). To assess the resolution of the oxidative stress and inflammation in vivo, we will measure the followed markers : resolvin D1, docosahexaenoic acid (DHA) and 17R-hydroxydocosahexaenoic acid (17-OHDHA). Superoxide production from cells incubated with plasma from participants. We will also measure blood and urinary allantoïn (the degradation product of uricase).


Secondary Outcome Measures :
  1. Cutaneous perfusion by Laser Doppler (perfusion unit) [ Time Frame: 24 hours after infusion of Uricase or Placebo ]
    Perfusion unit (Laser Doppler Imager + iontophoresis of (ACh and SNP and hyperemia with ou without L-NAME). Assessment of endothelial function.

  2. Arterial stiffness [ Time Frame: 24 hours after infusion of Uricase or Placebo ]
    Carotido-femoral pulse wave velocity and pulse wave analysis

  3. Blood pressure (mmHg) [ Time Frame: 24 hours after infusion of Uricase or Placebo ]
    Beat-to-beat measurements with Finapres

  4. Cardiac output (l-min) [ Time Frame: 24 hours after infusion of Uricase or Placebo ]
    Beat-to-beat measurements with Finapres

  5. Change in enzymes activity [ Time Frame: 30 min and 24 hours after infusion of Uricase or Placebo ]
    Xanthin oxydase activity

  6. Change in enzymes expression [ Time Frame: 30 min and 24 hours after infusion of Uricase or Placebo ]
    eNOS, NOX, XO we will incubate endothelial cells with plasma or serum from subjects. Then we will measure the sus-mentionned enzymes' expression.

  7. Change in proteomic analysis [ Time Frame: 30 min and 24 hours after infusion of Uricase or Placebo ]
    We will perform proteomics analysis directly on serum from participants and also on lysate of endothelial cells pre-incubated with plasma or serum from participants.



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy volunteers
  • Uric acid level in normal range (normouricemic group)
  • Uric acid level more than 6.8 mg/dl (hyperuricemic group)

Exclusion Criteria:

  • Any diseases of one of the following systems: cardiovascular, digestive, hormonal, urinary, pulmonary, rheumatic or immune.
  • Smoker, alcoholic
  • Participants should not take any chronic medicine nor vitamins or other antioxidants.
  • A G6PD deficit will be excluded as this is a contraindication to uricase administration (hemolytic anemia).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03395977


Contacts
Contact: Benjamin De Becker +32474328542 Benjamin.De.Becker@erasme.ulb.ac.be

Locations
Belgium
Erasme Hospital Recruiting
Brussels, Belgique, Belgium, 1070
Contact: Benjamin De Becker    +32474328542    Benjamin.De.Becker@erasme.ulb.ac.be   
Principal Investigator: Benjamin De Becker         
Sponsors and Collaborators
Fonds National de la Recherche Scientifique
Erasme Fund
Investigators
Study Director: Philippe van de Borne Erasme Hospital

Responsible Party: Benjamin De Becker, MD, Investigator, Clinical Research, Fonds National de la Recherche Scientifique
ClinicalTrials.gov Identifier: NCT03395977     History of Changes
Other Study ID Numbers: 30309647
First Posted: January 10, 2018    Key Record Dates
Last Update Posted: April 17, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Benjamin De Becker, MD, Fonds National de la Recherche Scientifique:
uric acid
xanthin oxydoreductase
febuxostat
uricase

Additional relevant MeSH terms:
Febuxostat
Metabolic Syndrome X
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Rasburicase
Uric Acid
Gout Suppressants
Antirheumatic Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs