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

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ClinicalTrials.gov Identifier: NCT02752633
Recruitment Status : Completed
First Posted : April 27, 2016
Results First Posted : December 27, 2017
Last Update Posted : December 27, 2017
Sponsor:
Collaborators:
Mayo Clinic
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Landspitali University Hospital

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
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 2013
Actual Primary Completion Date : May 2015
Actual Study Completion Date : May 2015


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




Primary Outcome Measures :
  1. Urinary 2,8-dihydroxyadenine Excretion [ Time Frame: 0, 14 and 28 days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02752633


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

Additional Information:
Publications of Results:
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Responsible Party: Landspitali University Hospital
ClinicalTrials.gov Identifier: NCT02752633     History of Changes
Other Study ID Numbers: RDCRN Protocol #6412
2013-000975-33 ( EudraCT Number )
U54DK083908 ( U.S. NIH Grant/Contract )
First Posted: April 27, 2016    Key Record Dates
Results First Posted: December 27, 2017
Last Update Posted: December 27, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Published in Eur J Intern Med. 2017 Dec 11, 2017. PMID: 29241594 DOI: 10.1016/j.ejim.2017.10.007
URL: http://www.sciencedirect.com/science/article/pii/S0953620517304156

Keywords provided by Landspitali University Hospital:
Xanthine dehydrogenase inhibitor treatment, pharmacotherapy

Additional relevant MeSH terms:
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Febuxostat
Metabolism, Inborn Errors
Urolithiasis
Genetic Diseases, Inborn
Metabolic Diseases
Urologic Diseases
Allopurinol
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs