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    Clinical Trial Results:
    Anti-fibrotic and molecular aspects of rifaximin in alcoholic liver disease: A randomized placebo controlled clinical trial

    Summary
    EudraCT number
    		 2014-001856-51
    Trial protocol
    		 DK  
    Global end of trial date
    27 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jun 2023
    First version publication date
    11 Jun 2023
    Other versions
    Summary report(s)
    		 Israelsen 2023, Lancet Gas Hep

    Trial information

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    Trial identification
    Sponsor protocol code
    12.007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    Kløvervænget 12, Odense, Denmark, 5000
    Public contact
    Mads Israelsen, Dept of Gastroenterology Odense Universityhospital, 0045 20681060, mads_israelsen@hotmail.com
    Scientific contact
    Mads Israelsen, Dept of Gastroenterology Odense Universityhospital, 20681060 20681060, mads_israelsen@hotmail.com
    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
    26 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We hypothesise that the gut microbiota is a major contributor to progression of fibrosis in alcoholic liver disease and that modulating gut flora by rifaximn halter disease progression.
    Protection of trial subjects
    A full version of the protocol is available in the Appendix 2 (Israelsen 2023, Lancet Gas Hep) and a protocol paper has been published. The regional ethical committee approved the study (S-20140078) and all patients provided written informed consent. The trial was conducted according to the principles of the International Conference on Harmonization Good Clinical Practice guidelines and externally monitored by the Good Clinical Practice Unit at Odense University Hospital.
    Background therapy
    		 The mechanism of rifaximin-α has been associated with modulating the gut microbiome and promoting gut barrier repair in decompensated cirrhosis. However, the efficacy in the attenuation of fibrogenesis and its safety in patients with ALD remain unknown.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2014
    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
    Denmark: 136
    Worldwide total number of subjects
    136
    EEA total number of subjects
    136
    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)
    38
    From 65 to 84 years
    98
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial commenced March 23, 2015 and ended November 10, 2021.

    Pre-assignment
    Screening details
    		 During this period, we screened 1,886 consecutive patients with a history of excessive alcohol consumption and identified 413 eligible for inclusion

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The participants as well as sponsor, investigators, and nurses involved in the study were blinded to the outcome of the randomization and the randomization key was only available to designated personnel at the hospital pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rifaximin
    Arm description
    		 tablet rifaximin-α 550 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifaximin-α
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    tablet rifaximin-α 550 mg twice daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		Rifaximin Placebo
    Started
    68
    68
    Completed
    54
    54
    Not completed
    14
    14
         Physician decision
    14
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rifaximin
    Reporting group description
    		 tablet rifaximin-α 550 mg twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Rifaximin Placebo Total
    Number of subjects
    		 68 68 136
    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)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 60 (53 to 64) 60 (54 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 13 9 22
        Male
    		 55 59 114
    Fibrosis stage
    Fibrosis stage according to Kleiner fibrosis score
    Units: Subjects
        Stage 0
    		 3 4 7
        Stage 1
    		 17 20 37
        Stage 2
    		 33 30 63
        Stage 3
    		 11 12 23
        Stage 4
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Rifaximin
    Reporting group description
    		 tablet rifaximin-α 550 mg twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Regression of fibrosis

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    End point title
    		 Regression of fibrosis
    End point description
    The primary outcome was regression of liver fibrosis. This was defined as a between-treatment group comparison of the proportion who had a decrease of at least one fibrosis stage according to the Kleiner histological scoring system.
    End point type
    Primary
    End point timeframe
    18 month
    End point values
    		 Rifaximin Placebo
    Number of subjects analysed
    54 [1]
    54 [2]
    Units: Fibrosis score
        Regression
    14
    15
        no regression
    40
    39
    Notes
    [1] - Per protocol analysis (Modified-intention-to-treat analysis can be found in the full paper)
    [2] - Per protocol analysis (Modified-intention-to-treat analysis can be found in the full paper)
    Statistical analysis title
    		 Fibrosis regression
    Statistical analysis description
    Comparison of binary outcome data are reported as odds ratio (OR) with 95% confidence intervals (CI), and continuous outcome data are reported as estimated mean difference from baseline to 18 months with 95% CI. Unless noted otherwise, results are reported after adjustment for stratification factors (abstinence six months prior to inclusion and baseline fibrosis stage) using logistic and linear regression analysis accordingly.
    Comparison groups
    Rifaximin v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 2.68
    Variability estimate
    Standard deviation
    Dispersion value
    0

    Secondary: Fibrosis progression

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    End point title
    		 Fibrosis progression
    End point description
    Comparison of binary outcome data are reported as odds ratio (OR) with 95% confidence intervals (CI), and continuous outcome data are reported as estimated mean difference from baseline to 18 months with 95% CI. Unless noted otherwise, results are reported after adjustment for stratification factors (abstinence six months prior to inclusion and baseline fibrosis stage) using logistic and linear regression analysis accordingly
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 Rifaximin Placebo
    Number of subjects analysed
    54 [3]
    54 [4]
    Units: Liver fibrosis
        Progression
    13
    23
        no progression
    31
    21
    Notes
    [3] - Per protocol (Modified intention to treat analysis can be found in full paper)
    [4] - Per protocol (Modified intention to treat analysis can be found in full paper)
    Statistical analysis title
    		 Fibrosis progression
    Comparison groups
    Rifaximin v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.98
    Variability estimate
    Standard deviation
    Dispersion value
    0

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Rifaximin
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Rifaximin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 68 (17.65%)
    14 / 68 (20.59%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Serology normal
         subjects affected / exposed
    12 / 68 (17.65%)
    14 / 68 (20.59%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Placebo Rifaximin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 68 (77.94%)
    48 / 68 (70.59%)
    Gastrointestinal disorders
    Pain
         subjects affected / exposed
    53 / 68 (77.94%)
    48 / 68 (70.59%)
         occurrences all number
    53
    48

    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 main limitation is that the primary endpoint, decrease of liver fibrosis, was not met. Preferably, the beneficial effect of rifaximin-α on haltering fibrosis progression should be validated in a multicentre phase III confirmatory efficacy trial.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36893774
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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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