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    Clinical Trial Results:
    An Open-Label, Single-Center, Nonrandomized Study to Compare the Therapeutic Efficacy of To Be Marketed (TBM) Cholic Acid Capsules with that of the Currently Used (CU) Formulation of Cholic Acid Capsules Used to Treat Children with Inborn Errors of Bile Acid Synthesis

    Summary
    EudraCT number
    		 2011-004491-10
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    23 Aug 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Aug 2016
    First version publication date
    05 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAC-001-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01115582
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CCHMC Clinical Equivalence Study: CAC-001-01
    Sponsors
    Sponsor organisation name
    Retrophin, Inc.
    Sponsor organisation address
    12255 El Camino Real, Suite 250, San Diego, United States, CA 92130
    Public contact
    Retrophin Medical Information, Retrophin, Inc., +1 877659 5518, medinfo@retrophin.com
    Scientific contact
    Retrophin Medical Information, Retrophin, Inc., +1 877659 5518, medinfo@retrophin.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000651-PIP01-09
    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
    23 Aug 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Aug 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the therapeutic efficacy of TBM cholic acid capsules compared with the effect of the CU formulation of cholic acid prepared in the CCHMC Pharmacy.
    Protection of trial subjects
    Not specified
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Apr 2010
    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
    United States: 16
    Worldwide total number of subjects
    16
    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)
    1
    Children (2-11 years)
    13
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 16 patients were enrolled. The first patient was enrolled on 28 Apr 2010 and the last patient was enrolled on 24 May 2010.

    Pre-assignment
    Screening details
    		 Patients with inborn defects of bile acid synthesis who were currently receiving cholic acid capsules prepared by the Cincinnati Children’s Hospital Medical Center (CCHMC) under IND 45,470. The study planned to include 25 patients; however, only 16 patients fulfilled the eligibility criteria and were willing to travel to the CCHMC.

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

    Arms
    Arm title
    		 Cholic acid
    Arm description
    		 All patients entered and treated
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cholic Acid 50 mg and 250 mg Capsules
    Investigational medicinal product code
    Other name
    Kolbam®, Cholbam®
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 10-15 mg/kg body weight, administered once daily or in divided doses at the discretion of the investigator. Dose adjustment on a patient-by-patient basis was possible based on changes in serum liver function test parameters and changes atypical bile acid metabolites in urine.

    Number of subjects in period 1
    		Cholic acid
    Started
    16
    Completed
    16

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 16 16
    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)
    		 1 1
        Children (2-11 years)
    		 13 13
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.8 ( 4.6 ) -
    Gender categorical
    Units: Subjects
        Male
    		 11 11
        Female
    		 5 5
    Subject analysis sets

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients entered and treated

    Subject analysis sets values
    		 All patients
    Number of subjects
    16
    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)
    1
        Children (2-11 years)
    13
        Adolescents (12-17 years)
    1
        Adults (18-64 years)
    1
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.8 ( 4.6 )
    Gender categorical
    Units: Subjects
        Male
        Female

    End points

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    End points reporting groups
    Reporting group title
    Cholic acid
    Reporting group description
    		 All patients entered and treated

    Subject analysis set title
    All patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients entered and treated

    Primary: Serum transaminases

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    End point title
    		 Serum transaminases [1]
    End point description
    Concentration of serum alanine transaminase (ALT) and aspartate transaminase (AST)
    End point type
    Primary
    End point timeframe
    At baseline and after 30 days of treatment
    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: This Primary endpoint was analysed using descriptive statistics only. No inferential testing was applied. A p-value was not defined.
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: U/L
    arithmetic mean (standard deviation)
        ALT, baseline
    31.4 ( 21.9 )
        ALT, Day 30
    30.9 ( 24 )
        AST, baseline
    62.7 ( 27.1 )
        AST, Day 30
    65 ( 39 )
    No statistical analyses for this end point

    Primary: Serum and urine bile acids

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    End point title
    		 Serum and urine bile acids [2]
    End point description
    Concentration of bile acids in serum (S) and urine (U) (abbreviations: chol.=cholenoic; monohydro=monohydroxy; dihydro=dihydroxy)
    End point type
    Primary
    End point timeframe
    At baseline (BL) and after 30 days of treatment (D30)
    Notes
    [2] - 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: This Primary endpoint was analysed using descriptive statistics only. No inferential testing was applied. A p-value was not defined.
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: mmol/L
    arithmetic mean (standard deviation)
        U, BL: 3β,7α-dihydroxy-Δ5 sulfate m/z 469
    12.37 ( 35.31 )
        U, D30: 3β,7α-dihydroxy-Δ5 sulfate m/z 469
    2.762 ( 3.955 )
        U, BL: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485
    14.11 ( 42.78 )
        U, D30: 3β,7α,12α-trihydroxy-Δ5 sulfate m/z 485
    2.011 ( 2.995 )
        U, BL: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526
    159.85 ( 474.52 )
        U, D30: 3β,7α-dihydroxy-Δ5 gluycosulfate m/z 526
    19.958 ( 29.341 )
        U,BL: 3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z 542
    105.43 ( 337.05 )
        U,D30:3β,7α,12α-trihydroxy-Δ5 glycosulfate m/z 542
    5.421 ( 7.633 )
        S, BL: Glyco-3-oxo-7-α,12α-dihydro.-4-chol. m/z460
    0.15 ( 0.07 )
        S,D30:Glyco-3-oxo-7-α,12α-dihydro.-4-chol. m/z 460
    0.055 ( 0.078 )
        S,BL: Glyco-3-oxo-7-α,12α-monohydro.-4-chol.m/z444
    0.14 ( 0.01 )
        S,D30:Glyco-3-oxo-7-α,12α-monohydro.-4-chol.m/z444
    0.14 ( 0.184 )
        S,BL:Tauro-3-oxo-7-α,12α-dihydroxy-4-chol. m/z 510
    0.52 ( 0.23 )
        S,D30:Tauro-3-oxo-7-α,12α-dihydroxy-4-chol. m/z510
    0.49 ( 0.679 )
        S,BL:Tauro-3-oxo-7-α,12α-monohydro.-4-chol. m/z498
    0.05 ( 0.04 )
        S,D30:Tauro-3-oxo-7-α,12α-monohydro.-4-chol.m/z498
    0.02 ( 0.028 )
        U, BL: Total 3β-hydroxy-Δ5 bile acids
    291.77 ( 889.56 )
        U, D30: Total 3β-hydroxy-Δ5 bile acids
    30.148 ( 43.582 )
        S, BL: Total 3-oxo-Δ4 bile acids
    0.84 ( 0.13 )
        S, D30: Total 3-oxo-Δ4 bile acids
    0.705 ( 0.601 )
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    Total number of patients with adverse events
    End point type
    Secondary
    End point timeframe
    From start of treatment through to 30 days after the start of treatment
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: Patients
        Number of patients with adverse events
    9
        Number of patients at risk
    16
    No statistical analyses for this end point

    Secondary: Blood pressure

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    End point title
    		 Blood pressure
    End point description
    Systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    End point type
    Secondary
    End point timeframe
    At baseline and after 30 days of treatment
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: mmHg
    arithmetic mean (standard deviation)
        SBP, baseline
    106.9 ( 10.2 )
        SBP, Day 30
    109.6 ( 6.6 )
        DBP, baseline
    63.9 ( 6.7 )
        DBP, Day 30
    65.4 ( 6.8 )
    No statistical analyses for this end point

    Secondary: Physical examination

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    End point title
    		 Physical examination
    End point description
    Total number of patients with abnormal findings from general physical examination
    End point type
    Secondary
    End point timeframe
    At baseline and after 30 days of treatment
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: Patients
        Baseline, patients with abnormal physical finding
    0
        Baseline, patients at risk
    16
        D30, patients with abnormal physical findings
    0
        D30, patients at risk
    16
    No statistical analyses for this end point

    Secondary: Total bilirubin

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    End point title
    		 Total bilirubin
    End point description
    Concentration of total bilirubin in serum
    End point type
    Secondary
    End point timeframe
    At baseline and after 30 days of treatment
    End point values
    		 Cholic acid
    Number of subjects analysed
    16
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline, total bilirubin
    0.35 ( 0.37 )
        Day 30, total bilirubin
    0.32 ( 0.28 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Total of 30 days, i.e. from the time point the patients entered into the study up to the end of treatment
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Cholic acid
    Reporting group description
    		 All patients entered and treated

    Serious adverse events
    		 Cholic acid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cholic acid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 16 (56.25%)
    Investigations
    ALT increased
    Additional description: In the clinical study Report, this event was counted towards the Body System "Hepatobiliary"
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    AST increased
    Additional description: In the clinical study Report, this event was counted towards the Body System "Hepatobiliary"
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Vascular disorders
    Nosebleed
    Additional description: In the clinical study report, this event was counted towards the Body System "Eye, ear, nose, throat"
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    General disorders and administration site conditions
    Decreased/low 250H/vitamin D
         subjects affected / exposed
    4 / 16 (25.00%)
         occurrences all number
    4
    Decreased vitamin D
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Reflux
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasm
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2010
    Protocol amended to remove the sentence, “For each visit, parents will be compensated $200 to cover lost wages and incidental expenses.” This sentence was inadvertently left in the protocol from a previous version.

    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
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    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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