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Uric Acid Effects on Endothelium and Oxydative Stress

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03395977
Recruitment Status : Recruiting
First Posted : January 10, 2018
Last Update Posted : September 30, 2019
Sponsor:
Collaborators:
Fonds Erasme
Fonds National de la Recherche Scientifique
Information provided by (Responsible Party):
Benjamin De Becker, Erasme University Hospital

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. 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 hypertensives then in older participants than in young healthy subjects.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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.

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.

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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebos PO and IV
PO : per os IV : intraveinously
Drug: Placebos
Lactose placebo for pills and saline for perfusion.
Other Name: Placebo

Experimental: Febuxostat PO and Placebo IV
240 mg a day for 3 days
Drug: Placebos
Lactose placebo for pills and saline for perfusion.
Other Name: Placebo

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.
Other Name: Placebo

Drug: Rasburicase
Rasburicase injectable solution.
Other Name: Fasturtec




Primary 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.


Secondary 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 ]
  2. Arterial stiffness [ Time Frame: 24 hours after infusion of Uricase or Placebo ]
    Carotido-femoral and carotido-radial 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 and manually

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

  8. Change in renin-angiotensin activity [ Time Frame: Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo ]
  9. Change in urinary excretion of sodium [ Time Frame: Baseline, 30 minutes and 24 hours after infusion of Uricase or Placebo ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Male or female for phases 2 and 3
Accepts Healthy Volunteers:   Yes
Criteria

Phase 1 :

Inclusion Criteria:

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

Phase 2 :

Inclusion Criteria:

  • 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)

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).

Phase 3 :

Inclusion Criteria:

  • Age between 40 and 65 years
  • History of hypertension for more than 6 months
  • Non smoker or smoke stopped for at least for 6 months

Exclusion Criteria:

  • Acute coronary syndrome
  • Heart failure (LVEJ < 40%)
  • Diabetes
  • Active smoking
  • Gout
  • Chronic kidney disease stage superior to 3a
  • History of cerebrovascular thrombosis
  • Cirrhosis
  • Alcohol consumption more than 3 units/day
  • 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).

The populations of phases 2 and 3 will be enrolled and studied together with subgroups analyses of the results for the status of hypertension, of treatment, age and gender.


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

Locations
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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
Erasme University Hospital
Fonds Erasme
Fonds National de la Recherche Scientifique
Investigators
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Study Director: Philippe van de Borne Erasme Hospital

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Benjamin De Becker, Investigator, Clinical Research, Erasme University Hospital
ClinicalTrials.gov Identifier: NCT03395977    
Other Study ID Numbers: 30309647
First Posted: January 10, 2018    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Benjamin De Becker, Erasme University Hospital:
uric acid
xanthin oxydoreductase
febuxostat
uricase
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Febuxostat
Rasburicase
Uric Acid
Gout Suppressants
Antirheumatic Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs