Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion

• Sponsor: Landspitali University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02752633
• Collaborator: Mayo Clinic (Other), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This exploratory pilot study was an open-label, crossover, single-center and non-randomized clinical trial designed to compare the effect of the standardly employed doses of allopurinol (400 mg/day) and febuxostat (80 mg/day) on the urinary 2,8-dihydroxyadenine (DHA) excretion in patients with adenine phosphoribosyltransferase (APRT) deficiency.

Condition or Disease	Intervention/Treatment	Phase
Adenine Phosphoribosyltransferase Deficiency	Drug: Allopurinol; Drug: Febuxostat	Phase 4

Detailed Description

This exploratory pilot study was an open-label, crossover, single-center and non-randomized clinical trial designed to compare the effect of the standardly employed doses of allopurinol (400 mg/day) and febuxostat (80 mg/day) on the urinary DHA excretion in patients with APRT deficiency. The study was conducted between May 2013 and May 2015 as participants were enrolled at different times. The only study site was Landspitali - The National University Hospital of Iceland in Reykjavik, Iceland. The Data (Observational) Safety Monitoring Board (D/OSMB) constituted by the National Institutes of Health had oversight responsibility of the Data Safety Monitoring Plan for this clinical trial. The monitoring board reviewed accrual, patterns and frequencies of all adverse events, and protocol compliance every 6-12 months. All study subjects gave a written informed consent for their participation.

Study participants were recruited from a group of patients with confirmed APRT deficiency enrolled in the National Institutes of Health supported APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC, http://www.rarekidneystones.org/). Confirmation of APRT deficiency was based upon the determination of known biallelic pathogenic APRT mutations or absent APRT enzyme activity. Participants were eligible for inclusion if they a) were currently receiving allopurinol therapy (the currently recommended treatment for patients with APRT deficiency); b) were willing to interrupt their allopurinol treatment for a total of 3 weeks as outlined below and c) were at least 18 years of age. There were no other exclusion criteria if the above inclusions criteria were met.

Study interventions After a 7-day washout period, all consenting subjects were prescribed 400 mg of allopurinol in a single daily dose for 14 days. After a second 7-day washout period, all subjects were prescribed 80 mg febuxostat in a single daily dose for another 14 days. Twenty-four hour and first morning urine samples were collected at the end of the first washout period, and at the end of allopurinol and febuxostat treatment periods, respectively (days 7, 21 and 42). To minimize the potential adverse effect of dietary purine intake on the results, participants were asked to keep a food record while they collected the first 24 hr urine sample and adhere to the same diet when they collected the other two 24 hr urine samples. No further measures were taken to control dietary purine intake during the study period. At the end of the study, all patients were advised to return to their regular allopurinol dosing regimens.

Measurements Urinary DHA was measured using a rapid and robust ultra high power liquid chromatography - electrospray tandem mass spectrometry (UPLC-MS/MS)), recently developed by our group. The 24-hour urinary DHA excretion (mg/24-hours) was measured and the urinary DHA-to-creatinine ratio (mg/mmol) in first morning urine samples was calculated. Urine and serum creatinine concentrations were measured with an isotope dilution mass spectrometry (IDMS) standardized laboratory method.

Outcome measures The primary trial endpoint is the 24 hr urinary DHA excretion and in patients taking the two study drugs, allopurinol (daily dose 400 mg) and febuxostat (daily dose 80 mg), evaluated at the conclusion of each 14 day drug treatment period.

Statistical Analysis Data are presented as urinary DHA excretion (mg/day) for timed collections and urinary DHA-to-creatinine ratio in first morning urine samples. Data for the whole group are presented as a median (range). Differences in the median urinary DHA excretion and the urinary DHA-to-creatinine ratio, off pharmacotherapy and on the two study drugs, febuxostat and allopurinol, were compared with a paired t-test.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Novel Assay for the Determination of Urinary 2,8-Dihydroxyadenine and Other Key Urinary Purine Metabolites: Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion in APRT Deficient Patients
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Study subjects Following a 7 day washout period all patients receive allopurinol (400 mg/day) as a single daily dose for 2 weeks. Following another 7 day washout period all participants receive febuxostat, 80 mg/day as a single daily dose, for 2 weeks.

Drug: Allopurinol; This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.; Other Names: Apurin ATC Code M04AA01 ; Drug: Febuxostat; This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.; Other Names: Uloric ATC Code M04AA03

Outcome Measures

Primary Outcome Measures

1. Urinary 2,8-dihydroxyadenine Excretion [0, 14 and 28 days]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• All patients 18 year and older who are enrolled in the APRT Deficiency Registry of The Rare Kidney Stone Consortium.

Exclusion Criteria:

• Patients do not want to interrupt drug (allopurinol) treatment for a total of two weeks as requested in protocol. No other exclusion criteria if inclusion criteria are met.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Landspitali - The National University Hospital of Iceland	Reykjavik		Iceland	101

Sponsors and Collaborators

• Landspitali University Hospital
• Mayo Clinic
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Vidar O Edvardsson, MD, Landspitali - The National University Hospital of Iceland, Reykjavik

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Official website of the Rare Kidney Stone Consortium

Publications

None provided.

• Responsible Party: Landspitali University Hospital
• ClinicalTrials.gov Identifier: NCT02752633
• Other Study ID Numbers: RDCRN Protocol #6412; 2013-000975-33; U54DK083908
• First Posted: Apr 27, 2016
• Last Update Posted: Dec 27, 2017
• Last Verified: Dec 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Landspitali University Hospital: Xanthine dehydrogenase inhibitor treatment, pharmacotherapy
• Additional relevant MeSH terms: Allopurinol; Febuxostat

Study Results

Participant Flow

Arm/Group Title	Allopurinol/Febuxostat Treatment
Arm/Group Description	This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.
Period Title: Overall Study
STARTED	9
COMPLETED	8
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Allopurinol/Febuxostat Treatment
Arm/Group Description	This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.
Overall Participants	9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 88.9%
>=65 years	1 11.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	5 55.6%
Male	4 44.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	9 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Iceland	9 100%

Outcome Measures

1. Primary Outcome

Title	Urinary 2,8-dihydroxyadenine Excretion
Time Frame	0, 14 and 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Allopurinol/Febuxostat Treatment
Arm/Group Description	Following a 7 day washout period all patients receive allopurinol (400 mg/day) as a single daily dose for 2 weeks. Following another 7 day washout period all participants receive febuxostat, 80 mg/day as a single daily dose, for 2 weeks. Allopurinol: This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency. Febuxostat: This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.
Measure Participants	8
Baseline	116
On allopurinol treatment	45
On febuxostat treatment	13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Allopurinol/Febuxostat Treatment
	Comments	Data are presented as the urinary DHA excretion (mg/24 hr) and as the DHA-to-creatinine ratio (mg/mmol) in first morning void urine samples. Data are presented as a median (range). Differences in the median urinary DHA excretion and the urinary DHA-to-creatinine ratio between periods off pharmacotherapy and on the two study drugs, febuxostat and allopurinol, were assessed using the Wilcoxon signed rank test.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	Throughout the study, 42 days.
Arm/Group Title	Allopurinol/Febuxostat Treatment
Arm/Group Description	This is a clinical trial comparing the effect of 80 mg/day of febuxostat to 400 mg/day of allopurinol on the urinary excretion of 2,8-dihydroxyadenine in patients with APRT deficiency.
All Cause Mortality
	Allopurinol/Febuxostat Treatment
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Allopurinol/Febuxostat Treatment
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Allopurinol/Febuxostat Treatment
	Affected / at Risk (%)	# Events
Total	0/9 (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.