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    Clinical Trial Results:
    A Phase 2, Fixed-Sequence, Open-Label, Switch-Over Study of the Safety and Tolerability of HPN-100 Compared to Sodium Phenylbutyrate in Children 6-17 Years of Age with Urea Cycle Disorders, with a Long-Term Safety Extension

    Summary
    EudraCT number
    		 2014-003246-26
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Aug 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jun 2016
    First version publication date
    09 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HPN-100-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00947544
    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, 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
    01 Mar 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Protocol HPN-100-005 was the first study of HPN-100 in pediatric subjects with urea cycle disorders (UCDs) and was a fixed-sequence, open-label, switch over study of HPN-100 with a long-term (12 month) safety extension designed to assess the safety of HPN-100 and to prospectively assess its ability to control blood ammonia as compared with Sodium Phenylbutyrate (NaPBA). Upon DSMB review of the first ten subjects who completed the switch over part of the study, and with DSMB approval, up to an additional 20 subjects were enrolled into the safety extension part of the study. The extension part of the study was a separate study (HPN-100-005SE). HPN-100 is a triglyceride that has a similar mechanism of action as NaPBA. It is a liquid with minimal taste and odor. Three teaspoons of HPN-100 (~17.4mL) delivers an equivalent amount of PBA to 40 tablets of NaPBA.
    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 participants who met the inclusion criteria and none of the exclusion criteria were enrolled to this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2010
    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: 10
    Country: Number of subjects enrolled
    Canada: 1
    Worldwide total number of subjects
    11
    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)
    0
    Children (2-11 years)
    7
    Adolescents (12-17 years)
    4
    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
    		 -

    Pre-assignment
    Screening details
    		 The study was to assess if HPN-100 could control blood ammonia compared with NaPBA. Subjects received NaPBA three times daily with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week.

    Period 1
    Period 1 title
    Switch-Over Period (2 weeks) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 HPN-100 and NaPBA
    Arm description
    		 1 week of NaPBA treatment followed by 1 week of HPN -100 treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycerol phenylbutyrate
    Investigational medicinal product code
    HPN-100
    Other name
    GT4P, Glyceryl tri-(4-phenylbutyrate)
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    g/mL gram(s) millitre 3 teaspoons of HPN-100 (approximately 17.4mL). Subjects dosed three times daily with meals during the first week and the same PBA mole-equivalent dose of HPN-100 during the second week.

    Investigational medicinal product name
    NaPBA
    Investigational medicinal product code
    sodium phenylbutyrate
    Other name
    AMMONAPS
    Pharmaceutical forms
    Powder and solvent for oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    NaPBA was to be administered as either tablets or powder. The dosing was in grams. Subjects dosed three times daily with meals. The dose level recommended by the investigator for each individual subject was not to exceed 20 g per day as recommended in the approved product labeling.

    Number of subjects in period 1
    		HPN-100 and NaPBA
    Started
    11
    Completed
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HPN-100 and NaPBA
    Reporting group description
    		 1 week of NaPBA treatment followed by 1 week of HPN -100 treatment.

    Reporting group values
    		 HPN-100 and NaPBA Total
    Number of subjects
    		 11 11
    Age Categorical
    Units: participants
        <=18 years
    		 11 11
        Between 18 and 65 years
    		 0 0
        >=65 years
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.2 ( 3.95 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 10 10
        Male
    		 1 1
    Region of Enrollment
    Units: Subjects
        United States
    		 10 10
        Canada
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    HPN-100 and NaPBA
    Reporting group description
    		 1 week of NaPBA treatment followed by 1 week of HPN -100 treatment.

    Subject analysis set title
    HPN-100
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    HPN-100: Subjects treated with HPN-100

    Subject analysis set title
    NaPBA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    NaPBA: Subjects treated with NaPBA

    Primary: Rate of Adverse Events during the switchover part (number of participants showing Adverse Events)

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    End point title
    		 Rate of Adverse Events during the switchover part (number of participants showing Adverse Events) [1]
    End point description
    To evaluate the safety and PK characteristics of HPN-100 compared with sodium phenylbutyrate (NaPBA) in pediatric patients with urea cycle disorders.
    End point type
    Primary
    End point timeframe
    1 week on each treatment for a total of 2 weeks.
    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 NaPBA
    Number of subjects analysed
    11
    11
    Units: participants
        number (not applicable)
    4
    2
    No statistical analyses for this end point

    Secondary: Blood ammonia control

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    End point title
    		 Blood ammonia control
    End point description
    To evaluate control of blood ammonia by HPN-100 compared with NaPBA in pediatric patients with urea cycle disorders. Results are for 24 hour ammonia levels.
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: μmol∙h/L
        arithmetic mean (standard deviation)
    603.83 ( 187.92 )
    814.62 ( 322.36 )
    No statistical analyses for this end point

    Secondary: NH3 Cmax on NaPBA vs. HPN-100 on the last day of treatment with each drug

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    End point title
    		 NH3 Cmax on NaPBA vs. HPN-100 on the last day of treatment with each drug
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: subjects
        arithmetic mean (standard deviation)
    47.77 ( 12.8 )
    55.66 ( 21.61 )
    No statistical analyses for this end point

    Secondary: Rate (percentage) of ammonia values above upper limit of normal (ULN) on NaPBA vs. HPN-100

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    End point title
    		 Rate (percentage) of ammonia values above upper limit of normal (ULN) on NaPBA vs. HPN-100
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100). The percentages are the number of ammonia values above the upper limit of normal/ the total number of ammonia samples (76).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: percentage of sample
        number (not applicable)
    18.4
    31.6
    No statistical analyses for this end point

    Secondary: Average ammonia values on NaPBA vs. HPN-100 on the last day of treatment with each drug (switch over)

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    End point title
    		 Average ammonia values on NaPBA vs. HPN-100 on the last day of treatment with each drug (switch over)
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: µmol/L
        arithmetic mean (standard deviation)
    28.68 ( 14.867 )
    37.75 ( 20.31 )
    No statistical analyses for this end point

    Secondary: Urinary PAGN 24-hour excretion values on NaPBA vs. HPN-100 (switch over)

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    End point title
    		 Urinary PAGN 24-hour excretion values on NaPBA vs. HPN-100 (switch over)
    End point description
    Urinary PAGN (phenylacetylglutamine) 24-hour excretion. Urine was collected during 0-12 hrs and 12-24 hrs.
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: μg
        arithmetic mean (standard deviation)
    12501037 ( 56.9 )
    12512426 ( 51.3 )
    No statistical analyses for this end point

    Secondary: Plasma PAA (phenylacetate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug

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    End point title
    		 Plasma PAA (phenylacetate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: μg•h/mL AUC 0-24
        arithmetic mean (standard deviation)
    964 ( 63.6 )
    773 ( 73.3 )
    No statistical analyses for this end point

    Secondary: Plasma PBA (phenylbutyrate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug

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    End point title
    		 Plasma PBA (phenylbutyrate) AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: µg*h/ml AUC 0-24
        arithmetic mean (standard deviation)
    631 ( 44.9 )
    236 ( 105.2 )
    No statistical analyses for this end point

    Secondary: Plasma PAGN AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug

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    End point title
    		 Plasma PAGN AUC0-24 values on NaPBA vs. HPN-100 on on the last day of treatment with each drug
    End point description
    Blood samples were collected at pre-dose, 4, 8, 12, 16, 20, and 24 hour post dose on both Day 7 (NaPBA) and Day 14 (HPN-100).
    End point type
    Secondary
    End point timeframe
    Day 7 (NaPBA) and Day 14 (HPN-100)
    End point values
    		 HPN-100 NaPBA
    Number of subjects analysed
    11
    11
    Units: μg*h/mL AUC 0-24
        arithmetic mean (standard deviation)
    1378 ( 40.2 )
    1015 ( 44.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All treatment emergent adverse events (TEAE) were defined as an AE that began (or a pre-existing AE that worsened) after receiving study drug on Day 1 and at any time through 7 days after the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    HPN-100 and NaPBA
    Reporting group description
    		 HPN-100: Patient treated with HPN-100

    Serious adverse events
    		 HPN-100 and NaPBA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 HPN-100 and NaPBA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 11 (54.55%)
    Investigations
    Cardiac murmur
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 11 (18.18%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    1 / 11 (9.09%)
         occurrences all number
    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24144944
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