Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    An international, multicentre, randomised, open-label, no-treatment controlled, parallel group, dose-response study to investigate the effect of once daily nitisinone on 24-hour urinary homogentisic acid excretion in patients with alkaptonuria after 4-weeks treatment.

    Summary
    EudraCT number
    		 2012-005340-24
    Trial protocol
    		 GB  
    Global end of trial date
    13 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2022
    First version publication date
    16 Jul 2022
    Other versions
    Summary report(s)
    		 SONIA 1 Main & Supplementary paper

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SONIA1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01828463
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool & Royal Liverpool University Hospital dom
    Sponsor organisation address
    Prescot St, Liverpool, United Kingdom, L7 8XP
    Public contact
    Principal Investigator, Royal Liverpool Unversity Hospital (RLUH), 0044 1517062000, lrang@liverpool.ac.uk
    Scientific contact
    Principal Investigator, Royal Liverpool Unversity Hospital (RLUH), 0044 1517062000, lrang@liverpool.ac.uk
    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
    10 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of different doses of once daily nitisinone on 24-hour urinary homogentisic acid excretion (u-HGA24) in patients with alkaptonuria after 4-weeks treatment.
    Protection of trial subjects
    Short term study, so no specific protection, warning of ocular toxicity, and to inform study team if such events occured.
    Background therapy
    		 All and any co-coniment medications were allowed, no other background thearpy.
    Evidence for comparator
    		 No treatment (0mg) versus with 1, 2, 4 & 8mg. no comparator medication.
    Actual start date of recruitment
    25 Mar 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
    United Kingdom: 15
    Country: Number of subjects enrolled
    Slovakia: 25
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    37
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Inclusion criteria 1. Diagnosis of AKU verified by documented elevated urinary homogentisic acid excretion. 2. Age ≥18 years. 3. Willing and able to visit the investigational site for study visits. 4. Signed written informed consent given Exclusion criteria The presence of any of the following will exclude a patient from inclusion in the st

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open label, since it is not feasible to blind a study with HGA-lowering treatment in AKU. One of the cardinal signs of AKU is urine darkening on standing as HGA is oxidised. Patients could therefore easily know whether they were on nitisinone or not. Furthermore, any personnel involved at the investigative sites who were involved in the processing of urine samples would also be able to see this difference.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Untreated
    Arm description
    		 No treatment provided
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 1 mg
    Arm description
    		 1mg of nitisinone over 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nitisinone
    Investigational medicinal product code
    Other name
    Orfadin
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Suspension - oral 4 mg/mL dosage 1 mg (0.25 mL) Once daily

    Arm title
    		 2mg nitisinone
    Arm description
    		 2mg nitisinone daily over 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nitisinone
    Investigational medicinal product code
    Other name
    Orfadin
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Suspension - oral 4 mg/mL dosage 2 mg (0.50 mL) Once daily

    Arm title
    		 4mg nitisinone
    Arm description
    		 4mg of nitisinone daily over 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nitisinone
    Investigational medicinal product code
    Other name
    Orfadin
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Suspension - oral 4 mg/mL dosage 4 mg (1.0 mL) Once daily

    Arm title
    		 8mg nitisinone
    Arm description
    		 8mg of nitisinone daily over 4 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nitisinone
    Investigational medicinal product code
    Other name
    Orfadin
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Suspension - oral 4 mg/mL dosage 8 mg (2.0 mL) Once daily

    Number of subjects in period 1
    		Untreated 1 mg 2mg nitisinone 4mg nitisinone 8mg nitisinone
    Started
    8
    8
    8
    8
    8
    Completed
    8
    8
    8
    8
    8

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Untreated
    Reporting group description
    		 No treatment provided

    Reporting group title
    1 mg
    Reporting group description
    		 1mg of nitisinone over 4 weeks

    Reporting group title
    2mg nitisinone
    Reporting group description
    		 2mg nitisinone daily over 4 weeks

    Reporting group title
    4mg nitisinone
    Reporting group description
    		 4mg of nitisinone daily over 4 weeks

    Reporting group title
    8mg nitisinone
    Reporting group description
    		 8mg of nitisinone daily over 4 weeks

    Reporting group values
    		 Untreated 1 mg 2mg nitisinone 4mg nitisinone 8mg nitisinone Total
    Number of subjects
    		 8 8 8 8 8 40
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (standard deviation)
    		 45.9 ( 11.5 ) 44.4 ( 10.9 ) 43.9 ( 13.7 ) 47.3 ( 10.7 ) 54.4 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 1 3 3 2 13
        Male
    		 4 7 5 5 6 27

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Untreated
    Reporting group description
    		 No treatment provided

    Reporting group title
    1 mg
    Reporting group description
    		 1mg of nitisinone over 4 weeks

    Reporting group title
    2mg nitisinone
    Reporting group description
    		 2mg nitisinone daily over 4 weeks

    Reporting group title
    4mg nitisinone
    Reporting group description
    		 4mg of nitisinone daily over 4 weeks

    Reporting group title
    8mg nitisinone
    Reporting group description
    		 8mg of nitisinone daily over 4 weeks

    Primary: u-HGA24 in patients with AKU after 4 weeks of nitisinone treatment

    		 Close Top of page
    End point title
    		 u-HGA24 in patients with AKU after 4 weeks of nitisinone treatment
    End point description
    24-hour urinary homogentisic acid excretion (u-HGA24) in patients with alkaptonuria after 4 weeks of treatment with nitisinone daily
    End point type
    Primary
    End point timeframe
    Baseline to 4 weeks
    End point values
    		 Untreated 1 mg 2mg nitisinone 4mg nitisinone 8mg nitisinone
    Number of subjects analysed
    8
    8
    8
    8
    8
    Units: mmol
        median (standard deviation)
    31.0 ( 4.6 )
    3.9 ( 1.7 )
    1.6 ( 0.8 )
    0.7 ( 0.4 )
    0.1 ( 0.05 )
    Statistical analysis title
    		 u-HGA24 at Week 4
    Statistical analysis description
    The primary variable, u-HGA24 at Week 4, was analysed using a mixed model for repeated measures (MMRM). The model included the study site, treatment group, visit, and the interaction between treatment group and visit as fixed factors and the baseline u-HGA24 as a covariate.
    Comparison groups
    Untreated v 1 mg v 2mg nitisinone v 4mg nitisinone v 8mg nitisinone
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.523
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Serum HGA after 4 weeks of treatment with nitisinone

    		 Close Top of page
    End point title
    		 Serum HGA after 4 weeks of treatment with nitisinone
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 4
    End point values
    		 Untreated 1 mg 2mg nitisinone 4mg nitisinone 8mg nitisinone
    Number of subjects analysed
    8
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    Units: mmol
        median (standard deviation)
    30.5 ( 12.4 )
    ( )
    ( )
    ( )
    ( )
    Notes
    [1] - Results not determined for this group.
    [2] - Results not determined for this group.
    [3] - Results not determined for this group.
    [4] - Results not determined for this group.
    No statistical analyses for this end point

    Secondary: Serum tyrosine after 4 weeks of treatment with nitisinone

    		 Close Top of page
    End point title
    		 Serum tyrosine after 4 weeks of treatment with nitisinone
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 4
    End point values
    		 Untreated 1 mg 2mg nitisinone 4mg nitisinone 8mg nitisinone
    Number of subjects analysed
    8
    8
    8
    8
    8
    Units: mmol/L
        median (standard deviation)
    56 ( 15 )
    653 ( 106 )
    715 ( 171 )
    803 ( 155 )
    813 ( 145 )
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The period for recording adverse events, begins from the time the subject has signed the informed consent until 28 days past the last dose of IMP
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 -

    Serious adverse events
    		 All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 32 (34.38%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    General disorders and administration site conditions
    Dizziness
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Haemoglobin decreased
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Foreign body sensation in eyes
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Vitreous floaters
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Pain of skin
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back injury
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Muscle injury
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences all number
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2013
    Following advice from the MHRA the following changes were made to the Protocol; Addition of slit-lamp eye assessment Addition of Demographics, Inclusion/exclusion criteria and slit lamp eye assessment and removal of standardized meals from Schedule of Events Change of visit 2 from home visit to hospital attendance Addition of information regarding rescue procedure Clarification of clinically significant abnormalities being reporting as adverse events in the Laboratory safety assessment section Changes to PIS/ICF; Change of visit 2 from home visit to hospital attendance Addition of eye examination to overview of study procedures

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25475116
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sun Apr 28 05:58:30 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA