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    Clinical Trial Results:
    Novel Assays for the Determination of Urinary 2,8-Dihydroxyadenine and Other Key Urinary Purine Metabolites - Rare Diseases Clinical Research Network Protocol Version 1

    Summary
    EudraCT number
    		 2013-000975-33
    Trial protocol
    		 IS  
    Global end of trial date
    02 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2021
    First version publication date
    04 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RDCRN_RKSC_6412
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02752633
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Landspitali–The National University Hospital of Iceland
    Sponsor organisation address
    Hringbraut, Reykjavik, Iceland, 101
    Public contact
    Vidar Orn Edvardsson, Landspitali–The National University Hospital of Iceland, 354 8245227, vidare@lsh.is
    Scientific contact
    Vidar Orn Edvardsson, Landspitali–The National University Hospital of Iceland, 354 8245227, vidare@lsh.is
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare 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.
    Protection of trial subjects
    This clinical trial was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and all applicable regulatory requirements. This study will met the NIH definition of “greater than minimal risk” as the research procedures included a) the interruption of drug treatment for 2 weeks; b) substitution of allopurinol with febuxostat for 2 weeks in patients who had not taken febuxostat before the trial started; 3) the introduction of a new study drug, febuxostat (in a standard dose) introduced the minimal risk of adverse effects, different from that of allopurinol, which all participants were taking at study entry for the treatment of APRT deficiency; and 4) possibly an increase in the allopurinol dose, if the cases were taking less than 400 mg/day at study entry. Other than the above, this research did not pose additional risk to the patient beyond the risks for standard diagnosis and treatment of kidney stones and kidney disease. There were no real risks associated with a 24-hour urine collection, random urine collection; and the risks associated with venipuncture are minor. Interruption of drug therapy for two weeks posed minimal risks to participants. There was no physical risk to answering the study questions. There was the potential risk, though extremely unlikely, of loss of privacy. The data collected were anonymous and did not include personal identifiers. The investigators believe that there was no breach in privacy during the study.
    Background therapy
    		 No such therapy was used.
    Evidence for comparator
    		 The xanthine oxidoreductase (XOR) enzyme inhibitor allopurinol is an effective therapy for preventing new kidney stone formation, renal 2,8-dihydroxyadenine (DHA) deposition and progressive crystal nephropathy in individuals with adenine phosphoribosyltransferase deficiency (APRTd). The drug decreases DHA synthesis and urinary DHA excretion/crystalluria.(1, 2) Febuxostat, a selective non-purine XOR inhibitor,(2) has also been reported to decrease urinary DHA excretion/crystalluria in APRTd patients, providing an alternative treatment option for those who are intolerant of allopurinol. Based on our own personal experience some patients with minimal or no crystalluria continue to form stones while others with persistent crystalluria do not develop new stones or evidence of CKD progression. Thus, the dosing of XOR inhibitor (allopurinol and febuxostat) therapy has simply been empiric and has been modified by the degree of DHA crystalluria or by clinical events such as recurrent kidneys stones or progressive CKD. In adults, allopurinol has commonly been prescribed in doses ranging from 200 to 400 mg/day. Recently, our group developed a novel high-throughput ultra-performance liquid chromatography - electrospray tandem mass spectrometry (UPLC-MS/MS) assay for measurement of DHA in urine samples, which has the potential to greatly improve monitoring of pharmacotherapy in patients with APRTd. 1. Edvardsson V, Palsson R, Olafsson I, Hjaltadottir G, Laxdal T. Clinical features and genotype of adenine phosphoribosyltransferase deficiency in iceland. Am J Kidney Dis. 2001;38(3):473-80. 2. Runolfsdottir HL, Palsson R, Agustsdottir IM, Indridason OS, Edvardsson VO. Kidney Disease in Adenine Phosphoribosyltransferase Deficiency. Am J Kidney Dis. 2016;67(3):431-8.
    Actual start date of recruitment
    01 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Iceland: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    8
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study participants were recruited from a group of patients with confirmed adenine phosphoribosyltransferase (APRT) deficiency, who were enrolled in the National Institutes of Health-supported APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC, http://www.rarekidneystones.org/).

    Pre-assignment
    Screening details
    		 Confirmation of adenine phosphoribosyltransferase (APRT) deficiency was based upon the determination of known biallelic pathogenic APRT mutations or absent APRT enzyme activity in red blood cell lysates.

    Pre-assignment period milestones
    Number of subjects started
    		 9
    Number of subjects completed
    		 9

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Washout 1
    Arm description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Allopurinol treatment
    Arm description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allopurinol
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Arm title
    		 Febuxostat treatment
    Arm description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Febuxostat
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Number of subjects in period 1
    		Washout 1 Allopurinol treatment Febuxostat treatment
    Started
    9
    8
    8
    Washout period 1
    8
    8
    8
    Allopurinol treatment
    8
    8
    8
    Febuxostat treatment
    8
    8
    8
    Completed
    8
    8
    8
    Not completed
    1
    0
    0
         Pregnancy
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Washout 1
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Allopurinol treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Febuxostat treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group values
    		 Washout 1 Allopurinol treatment Febuxostat treatment Total
    Number of subjects
    		 9 8 8 25
    Age categorical
    Study participants were recruited from a group of patients with confirmed APRT deficiency, who were enrolled in the 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 activity in red blood cell lysates.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 8 7 7 22
        From 65-84 years
    		 1 1 1 3
        85 years and over
    		 0 0 0 0
    Age continuous
    Study participants were recruited from a group of patients with confirmed APRT deficiency, who were enrolled in the 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 activity in red blood cell lysates.
    Units: years
        median (full range (min-max))
    		 54 (28 to 67) 54 (28 to 67) 54 (28 to 67) -
    Gender categorical
    Study participants were recruited from a group of patients with confirmed APRT deficiency, who were enrolled in the 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 activity in red blood cell lysates.
    Units: Subjects
        Female
    		 5 4 4 13
        Male
    		 4 4 4 12

    End points

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    End points reporting groups
    Reporting group title
    Washout 1
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Allopurinol treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Febuxostat treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Primary: Urinary 2,8-dihydroxyadenine excretion

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    End point title
    		 Urinary 2,8-dihydroxyadenine excretion
    End point 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.
    End point type
    Primary
    End point timeframe
    Urinary 2,8-dihydroxyadenine excretion was evaluated at days 7, 21, and 42
    End point values
    		 Washout 1 Allopurinol treatment Febuxostat treatment
    Number of subjects analysed
    8
    8
    8
    Units: mg
        number (not applicable)
    9
    8
    8
    Attachments
    		 Results_text
    Table 1
    Untitled (Filename: Table 2.pdf)
    Table 3
    Table 4
    Statistical analysis title
    		 Endpoint analysis
    Statistical analysis description
    Differences in the median urinary DHA excretion and the urinary DHA/Cr ratio between periods off pharmacotherapy and on treatment with the two study drugs, allopurinol and febuxostat, were assessed using the Wilcoxon signed-rank test.
    Comparison groups
    Allopurinol treatment v Febuxostat treatment v Washout 1
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Notes
    [1] - 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 (washout period 1) and on the two study drugs, febuxostat and allopurinol, were assessed using the Wilcoxon signed rank test.

    Primary: Urinary DHA-to-creatinine ratio

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    End point title
    		 Urinary DHA-to-creatinine ratio
    End point 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.
    End point type
    Primary
    End point timeframe
    The urinary DHA-to-creatinine ratio was evaluated at days 0, 21 and 42
    End point values
    		 Washout 1 Allopurinol treatment Febuxostat treatment
    Number of subjects analysed
    8
    8
    8
    Units: mg DHA/microg creatinine
        number (not applicable)
    9
    8
    8
    Statistical analysis title
    		 Endpoint analysis
    Comparison groups
    Allopurinol treatment v Febuxostat treatment v Washout 1
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Continuous during the study period.
    Adverse event reporting additional description
    Continuous during the study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Washout 1
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Allopurinol treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Reporting group title
    Febuxostat treatment
    Reporting group description
    		 At baseline, after a 7-day washout period, all participants were prescribed 400 mg of allopurinol in a single daily dose for 14 days. Following a second 7-day washout period, all participants were prescribed 80 mg of febuxostat in a single daily dose for another 14 days.

    Serious adverse events
    		 Washout 1 Allopurinol treatment Febuxostat treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Washout 1 Allopurinol treatment Febuxostat treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The study only had 8 participants. Doses were moderate. Treatment period was short. No adverse events reported by participants.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Limitations inherent in this study include a small number of participants as expected for a rare disease.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29241594
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