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    Clinical Trial Results:
    A randomised placebo controlled trial of follow on Rifaximin for the prevention of relapse of Clostridium difficile associated diarrhoea.

    Summary
    EudraCT number
    		 2012-003205-10
    Trial protocol
    		 GB  
    Global end of trial date
    10 Dec 2016

    Results information
    Results version number
    		 v1
    This version publication date
    31 Dec 2018
    First version publication date
    31 Dec 2018
    Other versions
    		 v2 , v3
    Summary report(s)
    		 RAPID trial published in Gut

    Trial information

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    Trial identification
    Sponsor protocol code
    12072
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Kingsmeadow campus, Nottingham, United Kingdom, NG7 2NR
    Public contact
    Spiller, University of Nottingham, 44 01158231090, robin.spiller@nottingham.ac.uk
    Scientific contact
    Spiller, University of Nottingham, 44 01158231090, robin.spiller@nottingham.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
    10 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To look at whether a course of Rifaximin after a patient has been successfully treated for C.difficile diarrhoeal infection with a standard course of antibiotics can reduce the rate of the infection returning (recurrence)
    Protection of trial subjects
    Usual measures Very safe drug so risk small
    Background therapy
    		 None
    Evidence for comparator
    		 Placebo controlled as unclear if intervention was beneficial
    Actual start date of recruitment
    11 Dec 2012
    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
    United Kingdom: 151
    Worldwide total number of subjects
    151
    EEA total number of subjects
    151
    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)
    45
    From 65 to 84 years
    99
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between 11 December 2012 and 7 March 2016. Those eligible for inclusion (see online supplementary file 1) were adults aged 18 years or older with a confirmed case of CDI that was successfully treated with metronidazole or vancomycin. This included primary, recurrent and multiply recurrent CDI episodes.

    Pre-assignment
    Screening details
    		 Participants were recruited between 11 December 2012 and 7 March 2016. Those eligible for inclusion (see online supplementary file 1) were adults aged 18 years or older with a confirmed case of CDI that was successfully treated with metronidazole or vancomycin. This included primary, recurrent and multiply recurrent CDI episodes.

    Pre-assignment period milestones
    Number of subjects started
    		 2157 [1]
    Number of subjects completed
    		 151

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 did not meet eligibility: 736
    Reason: Number of subjects
    		 declined to participate: 460
    Reason: Number of subjects
    		 other: 443
    Reason: Number of subjects
    		 consent unobtainable: 138
    Reason: Number of subjects
    		 unable to contact: 136
    Reason: Number of subjects
    		 unknown: 93
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The numbers in the preassignment period were approached to take part but did not and so were not enrolled
    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Participants were given 126 tablets, containing either rifaximin 200 mg or an identical placebo formulation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Identical tablets to active
    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
    2 tablets t.d.s. for 2 weeks then 1 tablet t.d.s. for 2 weeks

    Arm title
    		 Active
    Arm description
    		 The intended treatment regime was two tablets (400 mg rifaximin) taken three times a day for 14 days, reduced to one tablet (200 mg) three times a day for a further 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    two tablets (400 mg rifaximin) taken three times a day for 14 days, reduced to one tablet (200 mg) three times a day for a further 14 days.

    Number of subjects in period 1
    		Placebo Active
    Started
    74
    77
    Completed
    61
    69
    Not completed
    13
    8
         Consent withdrawn by subject
    8
    7
         death
    5
    1

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Identical tablets to active

    Reporting group title
    Active
    Reporting group description
    		 The intended treatment regime was two tablets (400 mg rifaximin) taken three times a day for 14 days, reduced to one tablet (200 mg) three times a day for a further 14 days.

    Subject analysis set title
    Full set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All analyses were conducted according to allocated group (placebo or rifaximin) regardless of the amount of tablets actually taken.

    Primary: CDI recurrence within 12 weeks of randomisation.

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    End point title
    		 CDI recurrence within 12 weeks of randomisation.
    End point description
    The primary outcome was CDI recurrence within 12 weeks of randomisation. A recurrence was defined as three or more loose stools for two or more days in conjunction with a positive stool toxin assay. The primary outcome was determined by research nurses in each site confirming stool frequency with the study subject by direct questioning, together with the laboratory results.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Placebo Active Full set
    Number of subjects analysed
    61 [1]
    69
    130
    Units: number of patients in whom CDI recurred
        CDI recurrence within 12 weeks
    18
    11
    29
    Notes
    [1] - 8 withdrew 5 died
    Statistical analysis title
    		 generalised estimating equation
    Statistical analysis description
    Analyses were carried out using Stata/SE 13.1. All analyses were conducted according to allocated group (placebo or rifaximin) regardless of the amount of tablets actually taken. The primary analysis estimated the difference in percentage CDI recurrence between rifaximin and placebo groups at 12 weeks without imputation of missing outcome data. A generalised estimating equation was used with binomial family, identity link and an exchangeable correlation matrix to account for randomisation
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -13.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.1
         upper limit
    		 0.7
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    weeks 1-8
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    placebo
    Reporting group description
    		 Placebo arm

    Reporting group title
    rifaximin
    Reporting group description
    		 active treatment arm

    Serious adverse events
    		 placebo rifaximin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 74 (20.27%)
    12 / 77 (15.58%)
         number of deaths (all causes)
    5
    1
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 77 (1.30%)
         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
    Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    haemorhage
    Additional description: GASTROINTESTINAL HAEMORRHAGE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
    Additional description: hip fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 placebo rifaximin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 74 (24.32%)
    21 / 77 (27.27%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    18 / 74 (24.32%)
    21 / 77 (27.27%)
         occurrences all number
    18
    21

    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.
    did not achieve intended recruitment numbers which were 180

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30254135
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