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    Clinical Trial Results:
    Double-blind, randomised, placebo-controlled, multi-centre phase III clinical study comparing the combination of ursodeoxycholic acid capsules plus budesonide capsules to ursodeoxycholic acid capsules plus placebo in the treatment of primary biliary cirrhosis

    Summary
    EudraCT number
    2007-004040-70
    Trial protocol
    DE   SE   FR   AT   NL   FI   ES   HU   GB   LT   DK   IT   PL  
    Global end of trial date
    19 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Dec 2018
    First version publication date
    23 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BUC-56/PBC
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00746486
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Dr. Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, Germany, 79108
    Public contact
    Project Management, Dr. Falk Pharma GmbH , +49 7611514199, markus.proels@drfalkpharma.de
    Scientific contact
    Project Management, Dr. Falk Pharma GmbH , +49 7611514199, markus.proels@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
    20 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    - To compare the efficacy and tolerability of a combination therapy with ursodeoxycholic acid (12-16 mg/kg body weight/d) plus budesonide (9 mg/d) vs. ursodeoxycholic acid (12-16 mg/kg body weight/d) plus placebo in the treatment of PBC.
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits every 14 days during the first 4 weeks of treatment, every 3 months up to Month 12 and every 6 months up to month 36 to guarantee their safety and wellbeing. Prior to recruitment of patients all relevant documents of the clinical study were submitted and approved 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
    Ursodeoxycholic acid (Ursofalk®250 mg capsules) is registered for the treatment of cholestatic liver diseases including PBC.
    Actual start date of recruitment
    21 Jan 2009
    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
    Israel: 1
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Lithuania: 12
    Worldwide total number of subjects
    62
    EEA total number of subjects
    61
    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)
    54
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 90 patients were enrolled into the study in Austria, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Lithuania, Netherlands, Poland, Spain and Sweden from February 2009 to Oct 2014.

    Pre-assignment
    Screening details
    Screening Criteria: 1. Signed Informed Consent 2. Age ≥ 18 years 3. UDCA treatment for at least 6 months prior to baseline exam. 4. Liver biopsy performed. In total, 90 patients were screened. Thereof 62 patients were randomised and received at least one dose of study medication and were included in the safety set and full analysis set (FAS) .

    Pre-assignment period milestones
    Number of subjects started
    62
    Number of subjects completed
    62

    Period 1
    Period 1 title
    Treatment Phase (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
    Arm A
    Arm description
    9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid
    Arm type
    Experimental

    Investigational medicinal product name
    Budesonide plus ursodeoxycholic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) if adjustment according to disease plus 12-16 mg/kg BW/d ursodeoxycholic acid.

    Arm title
    Arm B
    Arm description
    Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid .
    Arm type
    Placebo

    Investigational medicinal product name
    Budesonide Placebo (one capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Budesonide Placebo (one capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid.

    Number of subjects in period 1
    Arm A Arm B
    Started
    40
    22
    Completed
    40
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Phase (overall period)
    Reporting group description
    90 patients have signed an Informed Consent at Screening. 62 patients were finally randomised in one of the two treatment groups. 28 patients were Screening failures.

    Reporting group values
    Treatment Phase (overall period) Total
    Number of subjects
    62 62
    Age categorical
    90 patients have signed the Informed Consent at Screening. 62 patients were finally randomized.
    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)
    54 54
        From 65-84 years
    8 8
        85 years and over
    0 0
    Gender categorical
    Subjects of both sex were recruited into the trial.
    Units: Subjects
        Female
    60 60
        Male
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid

    Reporting group title
    Arm B
    Reporting group description
    Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid .

    Primary: Number of patients with Improvement of liver histology

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    End point title
    Number of patients with Improvement of liver histology
    End point description
    Number of patients with improvement of liver histology with respect to inflammation and no progression of fibrosis.
    End point type
    Primary
    End point timeframe
    From Baseline to the last individual patient visit
    End point values
    Arm A Arm B
    Number of subjects analysed
    40
    22
    Units: number
    11
    5
    Statistical analysis title
    Cochran-Mantel-Haenszel test
    Statistical analysis description
    For confirmatory hypothesis testing the Cochran-Mantel-Haenszel test for comparing two rates
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.025
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Number of patients presenting with cirrhosis or esophageal varices and/or ascites

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    End point title
    Number of patients presenting with cirrhosis or esophageal varices and/or ascites
    End point description
    Number of patients presenting with cirrhosis or esophageal varices and/or ascites at the end of the treatment.
    End point type
    Secondary
    End point timeframe
    At the end of the treatment (from Baseline to the last individual patient visit).
    End point values
    Arm A Arm B
    Number of subjects analysed
    40
    22
    Units: number
    1
    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 all interim visits (Week 2, Week 4, Month 3, Month 6, Month 9, starting from Month 12 (every 6 months) to final study visit of individual patient or Month 36 respectively.
    Adverse event reporting additional description
    Treatment-Emergent Adverse Events
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    9 mg Budesonide (3 mg capsules TD). 6 mg Budesonide (3 mg capsules BD) are allowed if adjustment according to disease activity is necessary plus 12-16 mg/kg BW/d ursodeoxycholic acid.

    Reporting group title
    Arm B
    Reporting group description
    Budesonide Placebo (one Placebo capsule TD) or BD depending on AST values plus 12-16 mg/kg BW/d ursodeoxycholic acid

    Serious adverse events
    Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 40 (62.50%)
    14 / 22 (63.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gatrointestinal tract adenoma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy liver
    Additional description: Planned hospitalization due to liver biopsy was reported as serious adverse event according to the clinical study protocol in this trial.
         subjects affected / exposed
    22 / 40 (55.00%)
    11 / 22 (50.00%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Tongue cyst
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary cirrhosis primary
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 22 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallblader polyp
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 22 (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
    Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 40 (97.50%)
    21 / 22 (95.45%)
    Investigations
    Blood cortisol
         subjects affected / exposed
    6 / 40 (15.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    0
    Weight increased
         subjects affected / exposed
    5 / 40 (12.50%)
    0 / 22 (0.00%)
         occurrences all number
    5
    0
    Blood glucose increased
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 40 (45.00%)
    9 / 22 (40.91%)
         occurrences all number
    18
    9
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 22 (18.18%)
         occurrences all number
    5
    4
    Nausea
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 22 (18.18%)
         occurrences all number
    4
    4
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 22 (18.18%)
         occurrences all number
    3
    4
    Dyspepsia
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 40 (17.50%)
    4 / 22 (18.18%)
         occurrences all number
    7
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2011
    Amendment was issued based on an advice from the German competent authority and containing the following elements: • Modification of trial population from "patients at risk of disease progression" to "patients with an incomplete response to UDCA treatment" • Modification of the primary endpoint • Modification of the secondary endpoints • Adjustment of sample size due to modified primary endpoint and trial population
    12 Feb 2015
    Termination of recruitment into the study following a recommendation of the Independent Data Monitoring Committee. Patients had to leave the study after at least 1 year of study treatment. The last visit of the last patient who completed the study after at least 1 year of treatment was estimated to occur in August 2015. As a consequence, the number of patient enrolled into the study was 62.

    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.
    Early termination of the trial by the sponsor based on the recommendation of the IDMC. IDMC recommendation was to observe the blinded patients recruited until now for one year more was respected.
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