Clinical trial NCT02752633: Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Adenine Phosphoribosyltransferase Deficiency
Keywords: Xanthine dehydrogenase inhibitor treatment, pharmacotherapy
Lead sponsor: Landspitali University Hospital
Sponsor class: OTHER
Collaborators: name: Mayo Clinic
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2016-04-27
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Urinary 2,8-dihydroxyadenine Excretion
timeFrame: 7, 21 and 42 days
Secondary outcomes:
Other outcomes:
Locations:
city: Reykjavik
country: Iceland
facility: Landspitali - The National University Hospital of Iceland
Study officials:
affiliation: Landspitali - The National University Hospital of Iceland, Reykjavik
name: Vidar O Edvardsson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Runolfsdottir HL, Palsson R, Agustsdottir IM, Indridason OS, Edvardsson VO. Kidney Disease in Adenine Phosphoribosyltransferase Deficiency. Am J Kidney Dis. 2016 Mar;67(3):431-8. doi: 10.1053/j.ajkd.2015.10.023. Epub 2015 Dec 25.