Uric Acid Reduction as a Novel Treatment for Pediatric Chronic Kidney Disease

• Sponsor: Virginia Commonwealth University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03865407
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 2
• Actual Duration (Months): 19
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Aim 1. To determine the effect of Allopurinol treatment on renal function (glomerular filtration rate, GFR) in pediatric chronic kidney disease (CKD) patients with high uric acid levels (hyperuricemia).

Aim 2. Establish whether Allopurinol treatment reduces Nlrp3 inflammasome and renal injury biomarkers.

Condition or Disease	Intervention/Treatment	Phase
Hyperuricemia; Chronic Kidney Diseases	Drug: Allopurinol	Phase 2

Detailed Description

Uric acid levels often rise when kidney function declines. Historically, high uric acid has not been treated unless the uric acid crystallizes in the joint space and causes clinical gout disease, more typically seen in adults. However, new research has shown that high uric acid levels are associated with the development of hypertension, inflammation, and both acute and chronic kidney injury. Adult patients on renal dialysis who have hyperuricemia also have higher mortality rates. In several adult and in one pediatric clinical trial of uric acid lowering therapy (with Allopurinol or Febuxostat), treatment has demonstrated a slower rate of renal function decline and improved blood pressure compared to placebo. The pediatric trial was a 4-month placebo controlled trial of Allopurinol, and showed positive improvement in renal function and blood pressure, but did not adequately control for potential confounders in the outcome. Two known confounders that influence renal function (glomerular filitration rate, GFR) in pediatric CKD are race and glomerular or non-glomerular disease etiology. This study is designed to control for these confounders and establish whether Allopurinol for 6 months of treatment to a goal range of 3-5 mg/dL will improve renal function compared to standard of care. The secondary outcome is to determine whether blood pressure is affected by the treatment and the magnitude of change of serum uric acid. This study will also explore whether Allopurinol treatment alters activation of the Nlrp3 inflammasome or renal injury biomarkers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Uric Acid Reduction as a Novel Treatment for Pediatric Chronic Kidney Disease
• Actual Study Start Date: Mar 10, 2019
• Actual Primary Completion Date: Oct 7, 2020
• Actual Study Completion Date: Oct 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Allopurinol Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial.	Drug: Allopurinol; Allopurinol dosed to target uric acid levels of 3-5 mg/dL.
No Intervention: Standard of Care Control The treatment arm will be compared to a standard of care arm.

Outcome Measures

Primary Outcome Measures

1. eGFR Change [The difference in Cystatin C eGFR between baseline and 6 months will be measured]

   Change in Cys-C eGFR over time

2. eGFR Change [The difference in Creatinine eGFR between baseline and 6 months will be measured]

   Change in Creatinine eGFR over time

Secondary Outcome Measures

1. Serum Uric Acid Change [The difference in Serum Uric Acid between baseline and 6 months will be measured]

   Change in Serum Uric Acid

2. Systolic Blood Pressure [The difference in clinic systolic blood pressure between baseline and 6 months will be measured]

   Change in systolic blood pressure

3. Diastolic Blood Pressure [The difference in clinic diastolic blood pressure between baseline and 6 months will be measured]

   Change in diastolic blood pressure

Other Outcome Measures

1. Serum High Sensitivity C-reactive Protein (Hs-CRP) [Serum hs-CRP will be measured at baseline and 6 months]

   Compare the mean difference of serum hs-CRP from baseline to 6 months between groups

2. Interleukin 18 [Serum interleukin 18 will be measured at baseline, 3 months, and 6 months]

   Change in interleukin 18

3. Serum Nlrp3 [Serum Nlrp3 will be measured at baseline, 3 months, and 6 months]

   Change in serum Nlrp3

4. Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Urine NGAL will be measured at baseline, 3 months, and 6 months]

   Change in urine NGAL

5. Urine Endothelin-1 (ET-1) [Urine ET-1 will be measured at baseline, 3 months, and 6 months]

   Change in urine ET-1

6. Urine Kidney Injury Molecule-1 (KIM-1) [Urine KIM-1 will be measured at baseline, 3 months, and 6 months]

   Change in urine KIM-1

7. Urine N-acetyl-Beta-D-Glucosaminidase (NAG) [Urine NAG will be measured at baseline, 3 months, and 6 months]

   Change in urine NAG

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronic Kidney Disease stage 1-5

• Hyperuricemic (UA >= 5.5 mg/dL)

Exclusion Criteria:

• Contraindication to Allopurinol

• Elevated baseline liver function tests

• Receiving acute or chronic dialysis

• Primary metabolic disorder

• Sickle cell disease

• Autosomal Dominant Polycystic Kidney Disease

• Cystinosis

• Bartter or Gitelman Disease

• Pregnant or nursing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia Commonwealth University	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• Virginia Commonwealth University

Investigators

• Principal Investigator: Cristin Kaspar, MD, Virginia Commonwealth University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 25, 2019

More Information

Publications

None provided.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT03865407
• Other Study ID Numbers: HM20014698
• First Posted: Mar 6, 2019
• Last Update Posted: May 27, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperuricemia; Allopurinol

Study Results

Participant Flow

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Period Title: Overall Study
STARTED	10	7
COMPLETED	7	7
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Allopurinol	Standard of Care Control	Total
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.	Total of all reporting groups
Overall Participants	7	7	14
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.29 (2.5)	13.86 (2.61)	14.07 (2.46)
Sex: Female, Male (Count of Participants)
Female	1 14.3%	3 42.9%	4 28.6%
Male	6 85.7%	4 57.1%	10 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%	0 0%	1 7.1%
Not Hispanic or Latino	6 85.7%	7 100%	13 92.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 14.3%	1 7.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 71.4%	3 42.9%	8 57.1%
White	2 28.6%	3 42.9%	5 35.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	7 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	eGFR Change
Description	Change in Cys-C eGFR over time
Time Frame	The difference in Cystatin C eGFR between baseline and 6 months will be measured

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	7	7
Mean (Standard Deviation) [ml/min/1.73m^2]	3.14 (3.716)	-0.29 (5.251)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1839
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	eGFR Change
Description	Change in Creatinine eGFR over time
Time Frame	The difference in Creatinine eGFR between baseline and 6 months will be measured

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	7	7
Mean (Standard Deviation) [ml/min/1.73m^2]	3.86 (7.798)	0 (3.857)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3036
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Serum Uric Acid Change
Description	Change in Serum Uric Acid
Time Frame	The difference in Serum Uric Acid between baseline and 6 months will be measured

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	7	7
Mean (Standard Deviation) [mg/dl]	-3.33 (0.996)	-0.46 (0.964)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Systolic Blood Pressure
Description	Change in systolic blood pressure
Time Frame	The difference in clinic systolic blood pressure between baseline and 6 months will be measured

Outcome Measure Data

Analysis Population Description

Follow up blood pressure data was not collected from one participant in the treatment group

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	6	7
Mean (Standard Deviation) [mmHg]	-6.5 (13.126)	2.29 (6.264)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1421
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Diastolic Blood Pressure
Description	Change in diastolic blood pressure
Time Frame	The difference in clinic diastolic blood pressure between baseline and 6 months will be measured

Outcome Measure Data

Analysis Population Description

Follow up blood pressure data was not collected from one participant in the treatment group

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	6	7
Mean (Standard Deviation) [mmHg]	-7.33 (6.29)	3.983 (7.543)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments
	Method	t-test, 2 sided
	Comments

6. Other Pre-specified Outcome

Title	Serum High Sensitivity C-reactive Protein (Hs-CRP)
Description	Compare the mean difference of serum hs-CRP from baseline to 6 months between groups
Time Frame	Serum hs-CRP will be measured at baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Allopurinol	Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.	The treatment arm will be compared to a standard of care arm.
Measure Participants	7	7
Mean (Standard Deviation) [mg/dL]	1.66 (3.724)	-7.64 (18.639)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol, Standard of Care Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3032
	Comments
	Method	t-test, 2 sided
	Comments

7. Other Pre-specified Outcome

Title	Interleukin 18
Description	Change in interleukin 18
Time Frame	Serum interleukin 18 will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Serum Nlrp3
Description	Change in serum Nlrp3
Time Frame	Serum Nlrp3 will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Urine Neutrophil Gelatinase-associated Lipocalin (NGAL)
Description	Change in urine NGAL
Time Frame	Urine NGAL will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Urine Endothelin-1 (ET-1)
Description	Change in urine ET-1
Time Frame	Urine ET-1 will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Urine Kidney Injury Molecule-1 (KIM-1)
Description	Change in urine KIM-1
Time Frame	Urine KIM-1 will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Other Pre-specified Outcome

Title	Urine N-acetyl-Beta-D-Glucosaminidase (NAG)
Description	Change in urine NAG
Time Frame	Urine NAG will be measured at baseline, 3 months, and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Regular investigator assessment, regular laboratory testing
Arm/Group Title	Allopurinol		Standard of Care Control
Arm/Group Description	Allopurinol will be administered to this treatment arm group for 6 months. Participants will receive the lowest FDA recommended dose for weight, and will be titrated upwards to achieve the goal uric acid level of 3-5 mg/dL throughout the trial. Allopurinol: Allopurinol dosed to target uric acid levels of 3-5 mg/dL.		The treatment arm will be compared to a standard of care arm.
All Cause Mortality
	Allopurinol		Standard of Care Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Allopurinol		Standard of Care Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)		0/7 (0%)
Immune system disorders
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome	1/7 (14.3%)	1	0/7 (0%)	0
Other (Not Including Serious) Adverse Events
	Allopurinol		Standard of Care Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.