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

Brief Title

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

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.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Urinary 2,8-dihydroxyadenine Excretion


Condition

Adenine Phosphoribosyltransferase Deficiency

Intervention

Allopurinol

Study Arms / Comparison Groups

 Study subjects
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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

9

Start Date

May 2013

Completion Date

May 2015

Primary Completion Date

May 2015

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Vidar O Edvardsson, MD, , 

Location Countries

Iceland

Location Countries

Iceland

Administrative Informations


NCT ID

NCT02752633

Organization ID

RDCRN Protocol #6412

Secondary IDs

2013-000975-33

Responsible Party

Sponsor

Study Sponsor

Landspitali University Hospital

Collaborators

 Mayo Clinic

Study Sponsor

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


Verification Date

December 2017