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

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT01350388
• Collaborator: Takeda (Industry)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease; Diabetes	Drug: Febuxostat; Drug: Placebo	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Febuxostat 80 mg/day of febuxostat for 24 weeks	Drug: Febuxostat; 80 mg/day of febuxostat for 24 weeks; Other Names: Uloric
Placebo Comparator: Placebo 1 placebo tablet per day for 24 weeks	Drug: Placebo; 1 placebo tablet per day for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks [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

2. Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks [Baseline and 24 weeks]

   The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm

3. Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks [Baseline and 24 weeks]

   The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Secondary Outcome Measures

1. Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 24 Weeks [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

2. Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 24 Weeks [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

3. Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks [Baseline and 24 weeks]

   The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah
• Takeda

Investigators

• Principal Investigator: Srinivasan Beddhu, MD, University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Srinvasan Beddhu, Srinivasan Beddhu, MD Associate Professor of Medicine, University of Utah
• ClinicalTrials.gov Identifier: NCT01350388
• Other Study ID Numbers: IRB_00044016
• First Posted: May 9, 2011
• Last Update Posted: Oct 3, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Srinvasan Beddhu, Srinivasan Beddhu, MD Associate Professor of Medicine, University of Utah: Chronic Kidney Disease; Diabetes; Febuxostat; Inflammation; Hyperuricemia
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Febuxostat

Study Results

Participant Flow

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Period Title: Overall Study
STARTED	40	40
COMPLETED	37	39
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Febuxostat	Placebo	Total
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks	Total of all reporting groups
Overall Participants	40	40	80
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (10)	68 (11)	68 (10)
Sex: Female, Male (Count of Participants)
Female	16 40%	12 30%	28 35%
Male	24 60%	28 70%	52 65%
Plasma Uric Acid Level (milligram per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligram per deciliter]	7.2 (1.5)	7.1 (1.2)	7.2 (1.4)
Estimated Glomerular Filtration Rate (eGFR) (milliliters per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliters per minute]	52.2 (15.3)	54.8 (19.0)	53.5 (17.2)

Outcome Measures

1. Primary Outcome

Title	Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks
Description	The percent difference in thiobarbituric acid reactive substance (TBARS) concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	34.0	44.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Change in Adiponectin Concentration in Adipose Tissue From Baseline to 24 Weeks
Description	The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	2.3	-4.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	ANCOVA
	Comments

3. Primary Outcome

Title	Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks
Description	The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	29.8	10.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change in Tumor Necrosis Factor-α (TNF-α) Concentration in Plasma From Baseline to 24 Weeks
Description	The percent difference in plasma TNF-α concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	-9.9	-7.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change in Interleukin-6 (IL-6) Concentration in Plasma From Baseline to 24 Weeks
Description	The percent difference in plasma IL-6 concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	-24.0	-9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks
Description	The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Febuxostat	Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks	Placebo: 1 placebo tablet per day for 24 weeks
Measure Participants	37	39
Geometric Mean (95% Confidence Interval) [percent difference in geometric mean]	12.2	-7.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	24 Weeks
Adverse Event Reporting Description	Details of adverse events experienced, particularly hospitalizations and emergency department visits obtained at each scheduled follow-up visit through week 24.
Arm/Group Title	Febuxostat		Placebo
Arm/Group Description	Febuxostat: 80 mg/day of febuxostat for 24 weeks		Placebo: 1 placebo tablet per day for 24 weeks
All Cause Mortality
	Febuxostat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Febuxostat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)		3/40 (7.5%)
Cardiac disorders
Atrial Fibrillation	0/40 (0%)	0	1/40 (2.5%)	1
Aortic Valve Disease	1/40 (2.5%)	1	0/40 (0%)	0
General disorders
Flu-like Symptoms	0/40 (0%)	0	1/40 (2.5%)	1
Hepatobiliary disorders
Cholecystitis	0/40 (0%)	0	1/40 (2.5%)	1
Nervous system disorders
Ischemic Stroke	0/40 (0%)	0	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Febuxostat		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/40 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.