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    Clinical Trial Results:
    A Switch-Over, Open-Label Study of the Safety, Pharmacokinetics, and Efficacy of HPN-100, Followed by Long-Term Treatment with HPN-100, in Pediatric Subjects under 6 Years of Age with Urea Cycle Disorders (UCDs)

    Summary
    EudraCT number
    2014-003249-82
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    04 Apr 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    06 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HPN-100-012
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01347073
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Horizon Therapeutics Inc.
    Sponsor organisation address
    150 S. Saunders Road, Lake Forest, United States, 60045
    Public contact
    Elizabeth Robinson, Horizon Therapeutics Inc., clinicaltrials@horizonpharma.com
    Scientific contact
    Tom Vescio, MD, Horizon Therapeutics Inc., clinicaltrials@horizonpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000297-PIP02-12
    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
    04 Apr 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This non-randomized, open-label study was approximately one year in duration and consisted of a short term 10-day sodium phenylbutyrate (NaPBA) to glycerol phenylbutyrate (HPN-100) switch-over part (EudraCT #2014-003248-12) involving two overnight stays followed by a 12-month long term treatment period (EudraCT #2014-003249-82) involving monthly visits. The objectives of this study were to assess safety, pharmacokinetics, and ammonia control during treatment with HPN-100 in pediatric subjects (aged 29 days to < 6 years) with UCDs.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to an Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. The study was conducted in accordance with legal and regulatory requirements including Guidance for Good Clinical Practice (International Conference on Harmonization [ICH] 1996), and the Declaration of Helsinki (World Medical Association 2008). Only subjects who met the inclusion criteria and none of the exclusion criteria were enrolled to this study. Written informed consent was to be obtained from the subject’s legally acceptable representative and assent by the minor subject, as applicable, before screening or baseline assessments. Instructions were given to the subject's legally acceptable representative in case of emergency or other questions.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Sep 2011
    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 States: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    0
    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)
    7
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study Locations: Houston, TX; Minneapolis, MN; Washington, DC; New York, NY; Cleveland, OH; Portland, ME; Portland, OR Study Initiation Date: September 9, 2011 Study Completion Date: April 4, 2013

    Pre-assignment
    Screening details
    The first part of this open-label study consisted of a switch-over period during which subjects were switched from the current medication (NaPBA) to HPN-100. All subjects in the switch-over were enrolled into the 12-month long-term treatment phase.

    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
    HPN-100
    Arm description
    12-month long-term treatment with HPN-100.
    Arm type
    Experimental

    Investigational medicinal product name
    glycerol phenylbutyrate
    Investigational medicinal product code
    HPN-100
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    HPN-100 was to be administered just prior to breastfeeding or administration of formula or food. The maximum recommended dose of HPN-100 in subjects weighing less than 20 kg is 0.52 mL/kg/day (equivalent to 600 mg/kg/day of NaPBA), and is 11.48 mL/m2/day in heavier subjects (equivalent to 13 g/m2/day of NaPBA). The maximum total daily HPN-100 dose allowed is 17.4 mL/day, which is approximately equivalent to 20 g/day of NaPBA.

    Number of subjects in period 1
    HPN-100
    Started
    23
    Completed
    21
    Not completed
    2
         Adverse event, non-fatal
    1
         Liver Transplant
    1

    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
    23 23
    Age Categorical
    Units: participants
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    2.7 ( 1.845 ) -
    Gender, Male/Female
    Units: participants
        Female
    12 12
        Male
    11 11

    End points

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    End points reporting groups
    Reporting group title
    HPN-100
    Reporting group description
    12-month long-term treatment with HPN-100.

    Subject analysis set title
    Pre-enrollment
    Subject analysis set type
    Full analysis
    Subject analysis set description
    12-months preceding the study

    Subject analysis set title
    Long-term Phase
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The second part of this open-label study consisted of a 12-month long-term treatment phase with HPN-100. All subjects in the switch-over were enrolled into the long-term treatment phase.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events [1]
    End point description
    Number of subjects with treatment-emergent adverse events during the safety extension portion of the protocol.
    End point type
    Primary
    End point timeframe
    12 months
    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: Data are summarized for this endpoint per protocol.
    End point values
    HPN-100
    Number of subjects analysed
    23
    Units: subjects
        number (not applicable)
    23
    No statistical analyses for this end point

    Secondary: Mean and Maximum Ammonia Levels During the Pre-enrollment Period and During Long-term HPN-100 Treatment

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    End point title
    Mean and Maximum Ammonia Levels During the Pre-enrollment Period and During Long-term HPN-100 Treatment
    End point description
    Ammonia values were normalized based on a standard ULN of 35 μmol/L. All available values were included (including those obtained during hyperammonemic crises).
    End point type
    Secondary
    End point timeframe
    12 months pre-enrollment, 12 months
    End point values
    Pre-enrollment Long-term Phase
    Number of subjects analysed
    23
    23
    Units: umol/L*hours
    arithmetic mean (standard deviation)
        Maximum Ammonia
    192.35 ( 218.687 )
    154.37 ( 250.558 )
        Average Ammonia
    56.43 ( 39.256 )
    38.72 ( 27.202 )
    No statistical analyses for this end point

    Secondary: Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) During the 12 Months Preceding the Study and During the Long-term Treatment Phase

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    End point title
    Frequency of Ammonia Levels Greater Than the Upper Limit of Normal (ULN) During the 12 Months Preceding the Study and During the Long-term Treatment Phase
    End point description
    Ammonia values were converted to SI units (umol/L) and normalized to a standard ULN of 35 umol/L prior to analysis.
    End point type
    Secondary
    End point timeframe
    12 months pre-enrollment, 12 months
    End point values
    Pre-enrollment Long-term Phase
    Number of subjects analysed
    23 [2]
    23 [3]
    Units: ammonia values > ULN
    146
    35
    Notes
    [2] - number of ammonia values analyzed=362
    [3] - number of ammonia values analyzed=180
    No statistical analyses for this end point

    Secondary: Number of Hyperammonemic Crises (HAC)

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    End point title
    Number of Hyperammonemic Crises (HAC)
    End point description
    Number of HACs during pre-enrollment on NaPBA compared with HACs during HPN-100 treatment.
    End point type
    Secondary
    End point timeframe
    12 months pre-enrollment, 12 months
    End point values
    Pre-enrollment Long-term Phase
    Number of subjects analysed
    23
    23
    Units: number of crises
        number (not applicable)
    29
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the Long-Term Treatment Phase: from approximately 2 weeks (end of switch-over period) through 12 months of long-term treatment, plus 30 days after study completion.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    HPN-100
    Reporting group description
    12-month long-term treatment with HPN-100.

    Serious adverse events
    HPN-100
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 23 (47.83%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Chemical burn of skin
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperammonemia
         subjects affected / exposed
    7 / 23 (30.43%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Hypophagia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    HPN-100
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Blood bicarbonate decreased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Nervous system disorders
    Hyporeflexia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Neutropenia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 23 (39.13%)
         occurrences all number
    13
    Gastrointestinal disorders
    Gastroesophageal reflux disease
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Diarrhea
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    11 / 23 (47.83%)
         occurrences all number
    19
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    10
    Rhinorrhea
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Skin odor abnormal
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Ear infection
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Otitis media
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 23 (60.87%)
         occurrences all number
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4

    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.
    The protocol was designed to capture information important for evaluating safety, pharmacokinetics, and efficacy while recognizing sampling limitations in young children and current standard of care.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24144944
    http://www.ncbi.nlm.nih.gov/pubmed/23324524
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