Uric Acid Effects on Endothelium and Oxydative Stress

NCT03395977 | Completed DMC

• 1 other identifier: 30309647
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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. Three groups of participants (young (\< 40 y) male healthy participants \[1\] ; male and female helthy participants (40 to 65 y) \[2\] and patients with primary hypertension \[3\]) 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. 1.An extremely low level of uric acid after uricase administration induces endothelial dysfunction and oxydative stress,
2. 2.A specific XO inhibitor limits unfavourable effects of the serum UA reduction elicited by uricase administration,
3. 3.Endothelial function and oxydative stress are further improved with febuxostat as compared to placebo,
4. 4.All these observations are more marked in hypertensives then in older participants than in young healthy subjects.

Conditions

Oxidative Stress; Endothelial Function; Cardiovascular System; Hypertension

Keywords

uric acid; xanthin oxydoreductase; febuxostat; uricase

Outcome Measures

Primary Outcomes (1)

• Cutaneous perfusion by Laser Doppler (perfusion unit)

  Perfusion unit (Laser Doppler Imager + iontophoresis of (ACh and SNP and hyperemia with ou without L-NAME). Assessment of endothelial function.

  24 hours after infusion of Uricase or Placebo

Secondary Outcomes (9)

• Change in Oxydative stress biomarkers from baseline to 30 min or 24 hours after infusion of Uricase or Placebo

  Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo

• Arterial stiffness

  24 hours after infusion of Uricase or Placebo

• Blood pressure (mmHg)

  24 hours after infusion of Uricase or Placebo

• Cardiac output (l-min)

  24 hours after infusion of Uricase or Placebo

• Change in enzymes activity

  30 min and 24 hours after infusion of Uricase or Placebo

Study Arms (4)

Placebos PO and IV

PLACEBO COMPARATOR

PO : per os IV : intraveinously

Drug: Placebos

Febuxostat PO and Placebo IV

EXPERIMENTAL

240 mg a day for 3 days

Drug: Placebos; Drug: Febuxostat

Febuxostat PO And Rasburicase IV

EXPERIMENTAL

Febuxostat : 240 mg a day for 3 days. Uricase : 3 mg once.

Drug: Febuxostat; Drug: Rasburicase

Placebo PO And Rasburicase IV

EXPERIMENTAL

Placebo : for 3 days. Uricase : 3 mg once.

Drug: Placebos; Drug: Rasburicase

Interventions

Placebos DRUG

Lactose placebo for pills and saline for perfusion.

Also known as: Placebo

Febuxostat PO and Placebo IV; Placebo PO And Rasburicase IV; Placebos PO and IV

Febuxostat DRUG

Febuxostat tablet.

Also known as: Adenuric

Febuxostat PO And Rasburicase IV; Febuxostat PO and Placebo IV

Rasburicase DRUG

Rasburicase injectable solution.

Also known as: Fasturtec

Febuxostat PO And Rasburicase IV; Placebo PO And Rasburicase IV

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: Male or female for phases 2 and 3
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 40 years
• Male
• Healthy volunteers
• Non smoker for at least 6 months
• Uric acid level in normal range (normouricemic group)

You may not qualify if:

• 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).
• Phase 2 :
• Age between 40 and 65 years
• Male or female (menopaused)
• Healthy volunteers
• Non smoker for at least 6 months
• Uric acid level in normal range (normouricemic group)
• 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).
• Phase 3 :

Sponsors & Collaborators

• Erasme University Hospital: lead
• Fonds Erasme: collaborator
• Fonds National de la Recherche Scientifique: collaborator

Study Sites (1)

Erasme Hospital

Brussels, Belgique, 1070, Belgium

Location

Related Publications (2)

• De Becker B, Hupkens E, Dewachter L, Coremans C, Delporte C, van Antwerpen P, Franck T, Zouaoui Boudjeltia K, Cullus P, van de Borne P. Acute effects of hypouricemia on endothelium, oxidative stress, and arterial stiffness: A randomized, double-blind, crossover study. Physiol Rep. 2021 Sep;9(17):e15018. doi: 10.14814/phy2.15018.

  PMID: 34435469 DERIVED

• De Becker B, Coremans C, Chaumont M, Delporte C, Van Antwerpen P, Franck T, Rousseau A, Zouaoui Boudjeltia K, Cullus P, van de Borne P. Severe Hypouricemia Impairs Endothelium-Dependent Vasodilatation and Reduces Blood Pressure in Healthy Young Men: A Randomized, Placebo-Controlled, and Crossover Study. J Am Heart Assoc. 2019 Dec 3;8(23):e013130. doi: 10.1161/JAHA.119.013130. Epub 2019 Nov 22.

  PMID: 31752638 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Febuxostat; rasburicase

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Philippe van de Borne

  Erasme University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Febuxostat and Rasburicase will be prepared by an independant pharmacist.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Investigator, Clinical Research

Model Details: This is a prospective, randomized, placebo-controlled, double-blinded and 3 ways cross-over study. Three populations : healthy male subjects under 40 y \[1\] ; healthy male and female participants between 40 and 65 years \[2\] and subjects with hypertension \[3\]. Minimum 15 participants in each group are needed. The populations 2 and 3 will be studied together with subgroups analyses of the results for the status of hypertension, of treatment, age and gender. 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.

Study Record Dates

• First Submitted: December 29, 2017
• First Posted: January 10, 2018
• Study Start: January 3, 2018
• Primary Completion: December 31, 2019
• Study Completion: February 27, 2020
• Last Updated: February 28, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)