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    Clinical Trial Results:
    An open-label, non-randomized, sequential, multicenter study to evaluate the pharmacokinetics, efficacy and safety of once daily dosing compared to twice daily dosing of Orfadin in patients diagnosed with hereditary tyrosinemia type 1

    Summary
    EudraCT number
    		 2013-004132-29
    Trial protocol
    		 SE   DK   BE  
    Global end of trial date
    21 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2016
    First version publication date
    07 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Sobi.NTBC-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02323529
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swedish Orphan Biovitrum AB
    Sponsor organisation address
    Tomtebodavägen 23a, Stockholm, Sweden, 112 76
    Public contact
    Medical Information, Swedish Orphan Biovitrum AB, +46 86972000, info@sobi.com
    Scientific contact
    Medical Information, Swedish Orphan Biovitrum AB, +46 86972000, info@sobi.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the steady-state exposure to nitisinone during once and twice daily dosing of Orfadin
    Protection of trial subjects
    This study was conducted in compliance with the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), applicable regulatory requirements, and in accordance with the latest revision of the Ethical Principles for Medical Research Involving Human Patients (the Declaration of Helsinki).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 6
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    2
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 6 study centers in 5 European countries participated in the trial. The first patient was enrolled 22 December 2014 and the last patient was enrolled 3 June 2015.

    Pre-assignment
    Screening details
    		 Male and female patients of all ages diagnosed with HT-1, currently well controlled, on twice-daily (or more frequent) dosing with Orfadin.

    Pre-assignment period milestones
    Number of subjects started
    		 19
    Number of subjects completed
    		 18

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Nitisinone
    Arm description
    		 All patients in the study was first put on twice daily dosing of nitisinone for 4 weeks. This was then followed by once daily dosing of nitisinone for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitisinone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Orfadin (nitisinone) capsules are swallowed whole or emptied and mixed with food or drink. The dose of Orfadin in the study was the same as the one prescribed at the completion of the Screening period.

    Number of subjects in period 1 [1]
    		Nitisinone
    Started
    18
    Completed
    18
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 18 patients received drug in this study. The 19th patient withdraw consent before any intervention had occured. All patients were on their normal prescription of nitisinone before study start.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 -

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 2 2
        Children (2-11 years)
    		 5 5
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 6 6
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Twice daily - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Enrolled patients who received at least one dose of IMP

    Subject analysis set title
    Twice daily - Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Enrolled patients who had SA assessment after the 4-weeks twice daily treatment period.

    Subject analysis set title
    Twice daily - Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Enrolled patients who had PK data from the twice daily treatment period and who had no protocol violations potentially affecting the analysis of PK.

    Subject analysis set title
    Once daily - Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least one dose of IMP during the Once daily period

    Subject analysis set title
    Once daily - Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Enrolled patients who had SA assessment after the 4-weeks once-daily treatment period.

    Subject analysis set title
    Once daily - Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Enrolled patients who had PK data from the once daily period and who had no protocol violations potentially affecting the analysis of PK.

    Subject analysis sets values
    		 Twice daily - Safety Set Twice daily - Full analysis set Twice daily - Per protocol set Once daily - Safety set Once daily - Full analysis set Once daily - Per protocol set
    Number of subjects
    18
    18
    17
    18
    18
    17
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    2
    2
    2
    2
    2
    2
        Children (2-11 years)
    5
    5
    5
    5
    5
    5
        Adolescents (12-17 years)
    5
    5
    4
    5
    5
    4
        Adults (18-64 years)
    6
    6
    6
    6
    6
    6
        From 65-84 years
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    9
    9
    8
    9
    9
    8
        Male
    9
    9
    9
    9
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    Nitisinone
    Reporting group description
    		 All patients in the study was first put on twice daily dosing of nitisinone for 4 weeks. This was then followed by once daily dosing of nitisinone for 4 weeks

    Subject analysis set title
    Twice daily - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Enrolled patients who received at least one dose of IMP

    Subject analysis set title
    Twice daily - Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Enrolled patients who had SA assessment after the 4-weeks twice daily treatment period.

    Subject analysis set title
    Twice daily - Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Enrolled patients who had PK data from the twice daily treatment period and who had no protocol violations potentially affecting the analysis of PK.

    Subject analysis set title
    Once daily - Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received at least one dose of IMP during the Once daily period

    Subject analysis set title
    Once daily - Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Enrolled patients who had SA assessment after the 4-weeks once-daily treatment period.

    Subject analysis set title
    Once daily - Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Enrolled patients who had PK data from the once daily period and who had no protocol violations potentially affecting the analysis of PK.

    Primary: C(min) of nitisinone after at least 4 weeks of treatment on each dosing regimen

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    End point title
    		 C(min) of nitisinone after at least 4 weeks of treatment on each dosing regimen [1]
    End point description
    End point type
    Primary
    End point timeframe
    C(min) was measured immidiately before taking a dose of nitisinone after at least 4 weeks of treatment on once- or twice-daily dosing of nitisinone.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The protocol did not stipulate statistical testing for differences rather only the 95% confidence intervals were to be calculated.
    End point values
    		 Twice daily - Per protocol set Once daily - Per protocol set
    Number of subjects analysed
    17
    17
    Units: micromole(s)/litre
        geometric mean (confidence interval 95%)
    24.68 (20.351 to 29.93)
    18.943 (14.586 to 24.602)
    No statistical analyses for this end point

    Secondary: Serum succinylacetone (s-SA) after at least 4 weeks of treatment

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    End point title
    		 Serum succinylacetone (s-SA) after at least 4 weeks of treatment
    End point description
    Efficacy was assessed by the proportion of patients who had SA above the LLOQ after at least 4 weeks of Orfadin once-daily treatment.
    End point type
    Secondary
    End point timeframe
    s-SA was measured at the end of each treatment period.
    End point values
    		 Twice daily - Full analysis set Once daily - Full analysis set
    Number of subjects analysed
    18
    18
    Units: patients
    0
    0
    No statistical analyses for this end point

    Secondary: Serum concentration of nitisinone, Cmin at possible occurrence of s-SA above lower limit of quantification (LLOQ).

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    End point title
    		 Serum concentration of nitisinone, Cmin at possible occurrence of s-SA above lower limit of quantification (LLOQ).
    End point description
    This endpoint was never assesed as no patients had measurable SA levels above LLOQ.
    End point type
    Secondary
    End point timeframe
    C(min) was measured immidiately before taking a dose of nitisinone after at least 4 weeks of treatment on once- or twice-daily dosing of nitisinone.
    End point values
    		 Twice daily - Full analysis set Once daily - Full analysis set
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: micromole(s)/litre
        number (not applicable)
    Notes
    [2] - No subjects had SA above LLOQ
    [3] - No subjects had SA above LLOQ
    No statistical analyses for this end point

    Secondary: Safety and tolerability assessments

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    End point title
    		 Safety and tolerability assessments
    End point description
    Safety and tolerability assessments; including adverse events (AEs), routine clinical chemistry tests including serum alpha fetoprotein (s-AFP), hepatic and renal function, coagulation, and serum tyrosine.
    End point type
    Secondary
    End point timeframe
    From start of treatment (Visit 2) until 2 weeks after end of treatment (Visit 6)
    End point values
    		 Twice daily - Safety Set Once daily - Safety set
    Number of subjects analysed
    18 [4]
    18 [5]
    Units: patients
    0
    0
    Notes
    [4] - No patient had any clinically significant change in any laboratory parameter during the study.
    [5] - No patient had any clinically significant change in any laboratory parameter during the study.
    No statistical analyses for this end point

    Secondary: C(max) of nitisinone after at least 4 weeks of treatment on each dosing regimen

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    End point title
    		 C(max) of nitisinone after at least 4 weeks of treatment on each dosing regimen
    End point description
    Secondary endpoint related to primary objective.
    End point type
    Secondary
    End point timeframe
    C(max) was measured 3 to 4 hours after taking a dose of nitisinone after at least 4 weeks of treatment on once- or twice-daily dosing of nitisinone.
    End point values
    		 Twice daily - Per protocol set Once daily - Per protocol set
    Number of subjects analysed
    17
    17
    Units: micromole(s)/litre
        geometric mean (confidence interval 95%)
    28.107 (22.09 to 35.763)
    27.187 (22.16 to 33.354)
    No statistical analyses for this end point

    Secondary: C(max)/C(min) ratio after at least 4 weeks of treatment on each dosing regimen

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    End point title
    		 C(max)/C(min) ratio after at least 4 weeks of treatment on each dosing regimen
    End point description
    Secondary endpoint related to primary objective.
    End point type
    Secondary
    End point timeframe
    C(min) was measured immidiately before taking a dose of nitisinone after at least 4 weeks of treatment and C(max) was measured 3-4 hours after taking a dose after at least 4 weeks of treatment on once- or twice-daily dosing of nitisinone.
    End point values
    		 Twice daily - Per protocol set Once daily - Per protocol set
    Number of subjects analysed
    17
    17
    Units: ratio
        geometric mean (confidence interval 95%)
    1.138 (0.998 to 1.299)
    1.436 (1.307 to 1.576)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment (Visit 2) until 2 weeks after end of treatment (Visit 6)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Twice daily - safety set
    Reporting group description
    		 -

    Reporting group title
    Once daily - safety set
    Reporting group description
    		 -

    Serious adverse events
    		 Twice daily - safety set Once daily - safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Twice daily - safety set Once daily - safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    11 / 18 (61.11%)
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Influenza like illness
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal tenderness
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Skin irritation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Acute tonsillitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pyelonephritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Decreased appetite
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1

    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.
    According to the study protocol a minimum of 20 patients were to be enrolled. Due to the absence of eligible patients in the youngest age group it was decided that the study should be terminated with 19 enrolled patients.
    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.

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