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Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01350388
First Posted: May 9, 2011
Last Update Posted: October 3, 2016
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. Read our disclaimer for details.
Collaborator:
Takeda
Information provided by (Responsible Party):
Srinvasan Beddhu, University of Utah
April 20, 2011
May 9, 2011
June 6, 2016
October 3, 2016
October 3, 2016
May 2011
October 2013   (Final data collection date for primary outcome measure)
  • Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in thiobarbituric acid reactive substance (TBARS) concentration geometric mean values from baseline to 24 weeks was calculated for each arm
  • Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm
  • Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Effects of Febuxostat on TBARS, adiponectin and transforming growth factor [ Time Frame: 6 months ]

To determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 CKD and high serum uric acid levels

  1. decreases adipose tissue concentrations of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress
  2. increases adipose tissue expression and concentrations of adiponectin and
  3. decreases urinary concentrations of transforming growth factor (TGF)- B1.
Complete list of historical versions of study NCT01350388 on ClinicalTrials.gov Archive Site
  • Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in plasma TNF-α concentration geometric mean values from baseline to 24 weeks was calculated for each arm
  • Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in plasma IL-6 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
  • Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks [ Time Frame: Baseline and 24 weeks ]
    The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Effects of Febuxostat on plasma adiponectin, TNF-alpha, IL-6, hsCRP and albumin [ Time Frame: 6 months ]

To determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 CKD and high serum uric acid levels

  1. increases plasma concentrations of adiponectin
  2. decreases adipose tissue expression and concentrations of TNF-alpha and IL-6 and
  3. decreases plasma concentrations of TNF-alpha, IL-6 and high sensitivity C-reactive protein (hsCRP) and
  4. decreases urinary concentrations of albumin
Not Provided
Not Provided
 
Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease
Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

Hyperuricemia is emerging as a risk factor for development of diabetes and metabolic syndrome. Recently, it was shown in in-vitro cell culture experiments that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. By targeting levels of uric acid with febuxostat it is hypothesized that the levels of oxidative stress in adipose tissue (obtained by fat biopsy) will decrease.

Primary aims of the study are to determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 Chronic Kidney Disease (CKD) and high serum uric acid levels

  1. will affect adipose tissue concentrations of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress
  2. will affect adipose tissue expression and concentrations of adiponectin; and
  3. will affect urinary concentrations of transforming growth factor (TGF)- B1.

Hyperuricemia is highly prevalent in the US population and commonly clusters with obesity and metabolic syndrome. It remains controversial whether this reflects an epiphenomenon or connotes a causal role of hyperuricemia in metabolic syndrome. If indeed hyperuricemia plays a causal role in metabolic syndrome, it would be expected that hyperuricemia will impact on the molecular signals that mediate the effects of adiposity on inflammation and insulin resistance.

Adipokines, the protein hormones produced by the adipocytes, serve as the signals for the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis. Adipokines include tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor (PAI-1), leptin, angiotensinogen and adiponectin. In obesity, the production of TNF-α, IL-6, PAI-1, leptin and angiotensinogen increases whereas the production of adiponectin decreases. Increased expression of pro-inflammatory TNF-α and IL-6 and decreased expression of anti-inflammatory adiponectin by adipocytes results in insulin resistance and inflammation.

As oxidative stress in adipose tissue is considered to play a critical role in dysregulation of adipokines production in obesity and that hyperuricemia induces oxidative stress in adipocytes, it is hypothesized that hyperuricemia alters adipose tissue production of adipokines; therefore, febuxostat therapy will decrease hyperuricemia and thereby, have beneficial effects on adipokine production by adipose tissue; the favorable effects on adipokine production by febuxostat therapy will result in decrease in plasma levels of markers of inflammation; and as a result of the above, urinary markers of kidney disease will improve.

Chronic Kidney Disease (CKD) patients with type 2 diabetes will be studies because this population has a high prevalence of hyperuricemia and likely represents a target population which might benefit from reduction of uric acid levels.

This is a placebo-controlled, double-blinded, randomized controlled trial to examine the effects of uric acid lowering with oral febuxostat on adipokines and markers of inflammation.

Interventional
Not Provided
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Chronic Kidney Disease
  • Diabetes
  • Drug: Febuxostat
    80 mg/day of febuxostat for 24 weeks
    Other Name: Uloric
  • Drug: Placebo
    1 placebo tablet per day for 24 weeks
  • Active Comparator: Febuxostat
    80 mg/day of febuxostat for 24 weeks
    Intervention: Drug: Febuxostat
  • Placebo Comparator: Placebo
    1 placebo tablet per day for 24 weeks
    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
80
December 2013
October 2013   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age > 18 years
  • BMI > 25 kg/m2
  • type 2 diabetes
  • serum uric acid ≥ 5.5 mg/dl in men and ≥ 4.6 mg/dl in women
  • eGFR 30-60 mL/min/1.73m2

Exclusion Criteria:

  • History of gout
  • concurrent use of azathioprine, mercaptopurine, theophylline, allopurinol, thiazolidinediones or warfarin
  • concurrent use of metformin
  • current antibiotic therapy
  • pregnant women
  • prisoners
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01350388
IRB_00044016
Yes
Not Provided
Not Provided
Srinvasan Beddhu, University of Utah
University of Utah
Takeda
Principal Investigator: Srinivasan Beddhu, MD University of Utah
University of Utah
August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP