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    Clinical Trial Results:
    Double-blind, randomized, placebo-controlled, phase II dose-finding study comparing different doses of norursodeoxycholic acid capsules with placebo in the treatment of primary sclerosing cholangitis

    Summary
    EudraCT number
    		 2011-002754-31
    Trial protocol
    		 DE   AT   NL   LT   NO   SE   GB   ES   FI   HU   DK   BE  
    Global end of trial date
    22 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2017
    First version publication date
    07 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NUC-3/PSC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, Germany, D-79108
    Public contact
    Dr. Markus Proels, Dr. Falk Pharma GmbH, +49 7611514-0, zentrale@drfalkpharma.de
    Scientific contact
    Dr. Markus Proels, Dr. Falk Pharma GmbH, +49 7611514-0, zentrale@drfalkpharma.de
    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
    16 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of three doses of norUDCA vs. placebo for the treatment of PSC; To identify efficacious and safe norUDCA dose(s) for the treatment of PSC for further evaluation in phase III
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits every 14 days to guarantee their safety and wellbeing. Prior to recruitment of patients, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 None
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    04 Jan 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
    Netherlands: 9
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Lithuania: 2
    Worldwide total number of subjects
    159
    EEA total number of subjects
    159
    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)
    153
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 222 patients were screened. 159 patients were randomized and received study drug.

    Pre-assignment
    Screening details
    		 Screening Criteria: 1. Signed Informed Consent 2. Aged 18 to 80 years. 3. Verified Primary sclerosing cholangitis .

    Period 1
    Period 1 title
    Treatment Phase (overall trial) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Conducted with the double-blind design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 2 x 250 mg Norursodeoycholic acid + 4 x placebo capsules once daily (OD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Norursodeoxycholic acid 250 mg
    Investigational medicinal product code
    Not applicable
    Other name
    Not applicable
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 250 mg Norursodeoxycholic acid capsules + 4 placebo capsules once daily (OD)

    Arm title
    		 Group B
    Arm description
    		 4 x 250 mg Norursodeoxycholic acid capsules + 2 placebo capsules once daily (OD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Norursodeoxycholic acid 250 mg
    Investigational medicinal product code
    Not applicabe
    Other name
    Not applicable
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 x 250 mg Norursodeoxycholic acid capsules + 2 placebo capsules once daily (OD)

    Arm title
    		 Group C
    Arm description
    		 6 x 250 mg Norursodeoxycholic acid capsules once daily (OD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Norursodeoxycholic acid 250 mg
    Investigational medicinal product code
    Not applicable
    Other name
    Not applicable
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    6 x 250 mg Norursodeoxycholic acid capsules once daily (OD)

    Arm title
    		 Group D
    Arm description
    		 6 x placebo capsules once daily (OD)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Not applicable
    Other name
    Not applicable
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    6 x Placebo capsules once daily (OD)

    Number of subjects in period 1
    		Group A Group B Group C Group D
    Started
    39
    41
    39
    40
    Completed
    39
    41
    39
    40

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Phase (overall trial)
    Reporting group description
    		 A total of 222 patients were screened. 159 patients were randomized and received study drug.

    Reporting group values
    		 Treatment Phase (overall trial) Total
    Number of subjects
    		 159 159
    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)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 153 153
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 109 109

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 2 x 250 mg Norursodeoycholic acid + 4 x placebo capsules once daily (OD)

    Reporting group title
    Group B
    Reporting group description
    		 4 x 250 mg Norursodeoxycholic acid capsules + 2 placebo capsules once daily (OD)

    Reporting group title
    Group C
    Reporting group description
    		 6 x 250 mg Norursodeoxycholic acid capsules once daily (OD)

    Reporting group title
    Group D
    Reporting group description
    		 6 x placebo capsules once daily (OD)

    Primary: Relative change in serum alkaline phosphatase

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    End point title
    		 Relative change in serum alkaline phosphatase
    End point description
    Relative change (%) in serum alkaline phosphatase between baseline visit and EOT visit (LOCF)
    End point type
    Primary
    End point timeframe
    Baseline Visit to EOT visit (LOCF)
    End point values
    		 Group A Group B Group C Group D
    Number of subjects analysed
    39
    41
    39
    40
    Units: percent
        number (not applicable)
    -12.3
    -17.3
    -26
    1.2
    Statistical analysis title
    		 Mean relative change in serum ALP: group A vs D
    Statistical analysis description
    Each of the active treatment groups was compared to the placebo group. In order to adjust for multiplicity a closed testing procedure using Simes intersection tests was applied. As the distribution of relative changes (%) was expected to be skewed, one-sided Wilcoxon rank sum tests were used to test the hypotheses.
    Comparison groups
    Group A v Group D
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029 [1]
    Method
    		 one-sided Wilcoxon rank sum test
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - If the global hypothesis could be rejected, then the pairwise intersection hypotheses H0(i) ∩ H0(j), i, j =1, 2, 3, were tested and rejected if any p(j) ≤ j × α /2, i.e., if p(1) ≤ α/2 or p(2) ≤ α = 0.025.
    Statistical analysis title
    		 Mean relative change in serum ALP: group B vs D
    Statistical analysis description
    Each of the active treatment groups was compared to the placebo group. In order to adjust for multiplicity a closed testing procedure using Simes intersection tests was applied. As the distribution of relative changes (%) was expected to be skewed, one-sided Wilcoxon rank sum tests were used to test the hypotheses.
    Comparison groups
    Group B v Group D
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [2]
    Method
    		 one-sided Wilcoxon rank sum test
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [2] - If the global hypothesis could be rejected, then the pairwise intersection hypotheses H0(i) ∩ H0(j), i, j =1, 2, 3, were tested and rejected if any p(j) ≤ j × α /2, i.e., if p(1) ≤ α/2 or p(2) ≤ α = 0.025.
    Statistical analysis title
    		 Mean relative change in serum ALP: group C vs D
    Statistical analysis description
    Each of the active treatment groups was compared to the placebo group. In order to adjust for multiplicity a closed testing procedure using Simes intersection tests was applied. As the distribution of relative changes (%) was expected to be skewed, one-sided Wilcoxon rank sum tests were used to test the hypotheses.
    Comparison groups
    Group C v Group D
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 one-sided Wilcoxon rank sum test
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - If the global hypothesis could be rejected, then the pairwise intersection hypotheses H0(i) ∩ H0(j), i, j =1, 2, 3, were tested and rejected if any p(j) ≤ j × α /2, i.e., if p(1) ≤ α/2 or p(2) ≤ α = 0.025.

    Secondary: Relative change in ALT

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    End point title
    		 Relative change in ALT
    End point description
    Relative change in ALT (%) from Baseline to EOT (LOCF)
    End point type
    Secondary
    End point timeframe
    Baseline visit to EOT visit (LOCF)
    End point values
    		 Group A Group B Group C Group D
    Number of subjects analysed
    39
    41
    39
    40
    Units: percent
    number (not applicable)
        Relative change in ALT
    -6.2
    -21.9
    -33.1
    7.8
    No statistical analyses for this end point

    Secondary: Relative change in Gamma-GT

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    End point title
    		 Relative change in Gamma-GT
    End point description
    Relative change in Gamma-GT (%) from Baseline to EOT (LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline vsist to EOT (LOCF):
    End point values
    		 Group A Group B Group C Group D
    Number of subjects analysed
    39
    41
    39
    40
    Units: percent
    number (not applicable)
        Relative change in GGT
    -8.9
    -26.1
    -33.9
    0.3
    No statistical analyses for this end point

    Secondary: Relative change in AST

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    End point title
    		 Relative change in AST
    End point description
    Relative change in AST (%) from Baseline to EOT (LOCF)
    End point type
    Secondary
    End point timeframe
    Baseline visit to EOT visit (LOCF):
    End point values
    		 Group A Group B Group C Group D
    Number of subjects analysed
    39
    41
    39
    40
    Units: percent
    number (not applicable)
        Relative change in AST
    9.6
    -15.8
    -20.5
    8.1
    No statistical analyses for this end point

    Secondary: Relative change in total bilirubin

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    End point title
    		 Relative change in total bilirubin
    End point description
    Relative change in total Bilirubin (%) from Baseline to EOT (LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline visit to EOT visit (LOCF).
    End point values
    		 Group A Group B Group C Group D
    Number of subjects analysed
    39
    41
    39
    40
    Units: percent
    number (not applicable)
        Relative change in total Bilirubin
    10.8
    11.1
    2.5
    23.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed at Baseline, all interim Visits (Weeks 2, 4, 6, 8 and 10) and at the Final Visit(Week 12), thus every 2 weeks.
    Adverse event reporting additional description
    Treatment-Emergent Adverse Event
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 2 x 250 mg Norursodeoycholic acid + 4 x placebo capsules once daily (OD)

    Reporting group title
    Group B
    Reporting group description
    		 4 x 250 mg Norursodeoxycholic acid capsules + 2 placebo capsules once daily (OD)

    Reporting group title
    Group C
    Reporting group description
    		 6 x 250 mg Norursodeoxycholic acid capsules once daily (OD)

    Reporting group title
    Group D
    Reporting group description
    		 6 x placebo capsules once daily (OD)

    Serious adverse events
    		 Group A Group B Group C Group D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 39 (7.69%)
    1 / 41 (2.44%)
    1 / 39 (2.56%)
    3 / 40 (7.50%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 41 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Disease progression
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endoscopic retrograde cholangiopancreatography
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 41 (0.00%)
    1 / 39 (2.56%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 41 (0.00%)
    0 / 39 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Meniscus removal
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (0.00%)
    0 / 39 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A Group B Group C Group D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 39 (58.97%)
    30 / 41 (73.17%)
    26 / 39 (66.67%)
    32 / 40 (80.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 41 (2.44%)
    7 / 39 (17.95%)
    3 / 40 (7.50%)
         occurrences all number
    4
    1
    7
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 41 (4.88%)
    5 / 39 (12.82%)
    4 / 40 (10.00%)
         occurrences all number
    2
    2
    5
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 39 (2.56%)
    4 / 41 (9.76%)
    1 / 39 (2.56%)
    5 / 40 (12.50%)
         occurrences all number
    1
    4
    1
    7
    Abdominal pain upper
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 41 (7.32%)
    3 / 39 (7.69%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    3
    3
    Diarrhoea
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
    3 / 39 (7.69%)
    4 / 40 (10.00%)
         occurrences all number
    0
    1
    3
    4
    Nausea
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 41 (4.88%)
    2 / 39 (5.13%)
    3 / 40 (7.50%)
         occurrences all number
    2
    2
    2
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 41 (9.76%)
    6 / 39 (15.38%)
    4 / 40 (10.00%)
         occurrences all number
    4
    5
    11
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (0.00%)
    3 / 39 (7.69%)
    4 / 40 (10.00%)
         occurrences all number
    1
    0
    3
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 39 (15.38%)
    9 / 41 (21.95%)
    8 / 39 (20.51%)
    7 / 40 (17.50%)
         occurrences all number
    7
    11
    10
    8

    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
    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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