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    Clinical Trial Results:
    A placebo controlled single centre double blind randomised trial to investigate the efficacy of rifaximin versus placebo in improving systemic inflammation and neutrophil malfunction in patients with cirrhosis and chronic hepatic encephalopathy

    Summary
    EudraCT number
    		 2013-004708-20
    Trial protocol
    		 GB  
    Global end of trial date
    29 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2018
    First version publication date
    05 Dec 2018
    Other versions
    Summary report(s)
    		 FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    RIFSYS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02019784
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Debbie Shawcross, King's College London, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Scientific contact
    Debbie Shawcross, King's College London, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Sponsor organisation name
    King's College Hospital
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE59RS
    Public contact
    Debbie Shawcross, King's College Hospital NHS Foundation Trust, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Scientific contact
    Debbie Shawcross, King's College Hospital NHS Foundation Trust, 44 2032993713, debbie.shawcross@kcl.ac.uk
    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
    29 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test if rifaximin reduces neutrophil spontaneous oxidative burst ex vivo in patients with cirrhosis and chronic hepatic encephalopathy after 30 days.
    Protection of trial subjects
    Participants eligible for this study with cirrhosis and hepatic encephalopathy may be unable to provide informed consent due to cognitive impairment arising from hepatic encephalopathy or pharmacologic sedation. In this situation where the potential participant is unable to consent, an appropriate legal representative will be sought. The legal representative will most often be a close personal contact of the potential participant e.g. the patient’s next of kin. They will be suitable to act as the legal representative by the virtue of their relationship, availability and their willingness to do so. In the process of considering inclusion into the study, the patient’s wishes and feelings will be assessed and written information will be provided in the form of a ‘legal representative information sheet’. After an appropriate time period (minimum 24 hours) and the opportunity to ask any questions, the legal representative will sign a ‘legal representative consent form’.
    Background therapy
    		 None
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 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
    United Kingdom: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from one centre in London UK.

    Pre-assignment
    Screening details
    		 Patients with established cirrhosis complicated by hepatic encephalopathy will be recruited to this study. For the purposes of this study a patient will be considered to have cirrhosis if they fulfil two out of the three diagnostic criteria of confirmatory liver histology, biochemistry and/or radiologic findings consistent with cirrhosis/portal hy

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The double-blind supplies of Rifaximin-α (TARGAXAN *, manufactured by Alfa-Wasserman, Bologna, Italy) will be in blister packs each containing 14 tablets of 550mg. Matching placebo (manufactured by Alfa-Wasserman, Bologna, Italy) will also be supplied in blister packs each containing 14 tablets with accompanying stability data of appropriate standard. In order to maintain blinding, the study drug and placebo will be packaged in an identical anonymised fashion.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A - Active
    Arm description
    		 Rifaximin-α 550mg BID
    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
    Rifaximin-α 550mg BID for 90 days

    Arm title
    		 Group B - Placebo
    Arm description
    		 Placebo BID for 90 days
    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 BID for 90 days orally.

    Number of subjects in period 1
    		Group A - Active Group B - Placebo
    Started
    19
    19
    Completed
    13
    13
    Not completed
    6
    6
         Death due to disease progression
    2
    3
         Consent withdrawn by subject
    2
    1
         Patient underwent transplant
    1
    -
         Lost to follow-up
    1
    2

    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
    		 38 38
    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)
    		 34 34
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 27 27

    End points

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    End points reporting groups
    Reporting group title
    Group A - Active
    Reporting group description
    		 Rifaximin-α 550mg BID

    Reporting group title
    Group B - Placebo
    Reporting group description
    		 Placebo BID for 90 days

    Primary: Clinical Endpoint

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    End point title
    		 Clinical Endpoint [1]
    End point description
    A reduction in spontaneous neutrophil oxidative burst of 50% compared to baseline (as measured by the Burstest which measures the spontaneous production of reactive oxygen species) 30 days following the start of rifaximin-α/placebo therapy.
    End point type
    Primary
    End point timeframe
    30 days following start of IMP
    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: Please see attached documents for results.
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Secondary: Systemic Inflammation Reduction

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    End point title
    		 Systemic Inflammation Reduction
    End point description
    A reduction in systemic inflammation as measured by plasma endotoxaemia, bacterial DNA quantification and plasma pro-inflammatory cytokine profile at 90 days.
    End point type
    Secondary
    End point timeframe
    90 days post cmmencement of IMP
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Secondary: Neutrophil

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    End point title
    		 Neutrophil
    End point description
    An improvement in neutrophil bacteriocidal capacity as measured by the Phagotest which utilises opsonised E. coli at 30 and 90 days. An improvement in neutrophil phenotype and function including baseline and LPS-induced toll-like receptor 4 expression and intracellular cytokine production at 30 and 90 days.
    End point type
    Secondary
    End point timeframe
    30 and 90 days post commencement of IMP
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Secondary: Faecal

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    End point title
    		 Faecal
    End point description
    Alterations in faecal microbiota at 90 days. Reduction in intestinal permeability and changes in faecal biomarkers (calprotectin) at 90 days.
    End point type
    Secondary
    End point timeframe
    90 Days post Commencement of IMP
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Secondary: plasma metabonomic profile

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    End point title
    		 plasma metabonomic profile
    End point description
    Changes in urinary and plasma metabonomic profile as measured by proton MR spectroscopy at 90 days.
    End point type
    Secondary
    End point timeframe
    90 days post commencement of IMP
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Secondary: Hepatic Encephalopathy

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    End point title
    		 Hepatic Encephalopathy
    End point description
    Development of recurrent overt hepatic encephalopathy, organ failure and infection during the 90 day follow up. Improvement in Psychometric Hepatic Encephalopathy Score including Trails A and B neuropsychiatric test scores at 30 and 90 days
    End point type
    Secondary
    End point timeframe
    90 days post IMP commencement
    End point values
    		 Group A - Active Group B - Placebo
    Number of subjects analysed
    13
    13
    Units: whole
    13
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until 30 days post final IMP dose for each patient.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Group A - Active
    Reporting group description
    		 -

    Reporting group title
    Group B - Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Group A - Active Group B - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    1
    0
    Gastrointestinal disorders
    Bowel Perforation
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A - Active Group B - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 19 (89.47%)
    19 / 19 (100.00%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Pneumonia
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Ascites
         subjects affected / exposed
    9 / 19 (47.37%)
    17 / 19 (89.47%)
         occurrences all number
    9
    17
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Variceal haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Hepatocellular encephalopathy
         subjects affected / exposed
    0 / 19 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    0
    0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2014
    Change to IMP labels.
    23 Sep 2015
    change to eligibility criteria

    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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