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    Clinical Trial Results:
    Faecal microbiota transplantation for relapsing Clostridium difficile infection

    Summary
    EudraCT number
    		 2015-003004-24
    Trial protocol
    		 DK  
    Global end of trial date
    15 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Dec 2020
    First version publication date
    17 Dec 2020
    Other versions
    Summary report(s)
    		 Publication primary

    Trial information

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    Trial identification
    Sponsor protocol code
    2015-003004-24
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02743234
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Christian Lodberg Hvas, Aarhus University Hospital, 0045 78463895, christian.hvas@auh.rm.dk
    Scientific contact
    Christian Lodberg Hvas, Aarhus University Hospital, 0045 78463895, christian.hvas@auh.rm.dk
    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
    18 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare 8-week cure rates from relapsing Clostridium difficile colitis following one of three treatments: 1) capsule vancomycin 125 mg 4 times daily 10 days + faecal microbiota transplantation 2) tablet fidamoxicin 200 mg twice daily 10 days 3) capsule vancomycin 125 mg 4 times daily 10 days
    Protection of trial subjects
    Invidivually tailored treatment and application method. Follow-up with protocolled opportunity for rescue treatment in case of treatment failure.
    Background therapy
    		 FMT was superior to vancomycin in small randomised studies. No study compared FMT with fidaxomicin, a new antibiotics for C difficile.
    Evidence for comparator
    		 Both vancomycin and fidaxomicin are established treatments for C difficile infection. We wishes to compare efficacies of the three in a head-to-head investigator-initiated clinical trial.
    Actual start date of recruitment
    04 Apr 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    32
    From 65 to 84 years
    27
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult patients with mental capacity were recruited from an outpatient clinic in a referral centre for gastroenterology at a public teaching hospital in Denmark. Patients could be referred for treatment from neighbouring hospitals.

    Pre-assignment
    Screening details
    		 Recurrent (< 8 weeks) of C difficile infection, negative tests for other pathogens, no concomitant antibiotics treatment, no pregnancy, ability to speak and understand Danish, no fulminant colitis in which case open label FMT was offered for ethical reasons.

    Period 1
    Period 1 title
    Primary intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    FMT was administered by colonoscopy, and we deemed it unethical to perform placebo colonoscopy. Medical treatment (in experimental and comparator arms) were administered open label using marketed products.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FMTv
    Arm description
    		 4-10 days of vancomycin followed by a single FMT, delivered by colonoscopy or nasojejunal tube
    Arm type
    		 Experimental

    Investigational medicinal product name
    FMT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intestinal use
    Dosage and administration details
    Minimally processed donor faeces, unstandardised, derived from 50 grams of donor faeces. Delivered by colonoscopy or nasojejunal tube.

    Arm title
    		 Fidaxomicin
    Arm description
    		 Tablet fidaxomixin (Dificlir(R)) 200 mg BID for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fidaxomixin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet 200 mg BID, oral intake

    Arm title
    		 Vancomycin
    Arm description
    		 Capsule vamcomycin 125 mg QDS for 10 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vancomycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet, 125 mg four times daily, oral intake for 10 days

    Number of subjects in period 1
    		FMTv Fidaxomicin Vancomycin
    Started
    24
    24
    16
    8 weeks global resolution (clinical+PCR)
    24
    24
    16
    Completed
    24
    24
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FMTv
    Reporting group description
    		 4-10 days of vancomycin followed by a single FMT, delivered by colonoscopy or nasojejunal tube

    Reporting group title
    Fidaxomicin
    Reporting group description
    		 Tablet fidaxomixin (Dificlir(R)) 200 mg BID for 10 days

    Reporting group title
    Vancomycin
    Reporting group description
    		 Capsule vamcomycin 125 mg QDS for 10 days

    Reporting group values
    		 FMTv Fidaxomicin Vancomycin Total
    Number of subjects
    		 24 24 16 64
    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
    Age
    Units: years
        median (full range (min-max))
    		 68 (22 to 90) 64 (24 to 87) 72 (21 to 92) -
    Gender categorical
    Units: Subjects
        Female
    		 20 13 11 44
        Male
    		 4 11 5 20

    End points

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    End points reporting groups
    Reporting group title
    FMTv
    Reporting group description
    		 4-10 days of vancomycin followed by a single FMT, delivered by colonoscopy or nasojejunal tube

    Reporting group title
    Fidaxomicin
    Reporting group description
    		 Tablet fidaxomixin (Dificlir(R)) 200 mg BID for 10 days

    Reporting group title
    Vancomycin
    Reporting group description
    		 Capsule vamcomycin 125 mg QDS for 10 days

    Primary: Global resolution (clinical + PCR)

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    End point title
    		 Global resolution (clinical + PCR)
    End point description
    Clinical resolution (normalisation of bowel habits) AND negative C difficile toxin test by PCR
    End point type
    Primary
    End point timeframe
    8 weeks
    End point values
    		 FMTv Fidaxomicin Vancomycin
    Number of subjects analysed
    24
    24
    16
    Units: yes/no
        No
    7
    16
    13
        Yes
    17
    8
    3
    Statistical analysis title
    		 FMVv vs fidaxomicin
    Comparison groups
    FMTv v Fidaxomicin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 FMTv vs vancomycin
    Comparison groups
    FMTv v Vancomycin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Clinical resolution

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    End point title
    		 Clinical resolution
    End point description
    Clinical resolution
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 FMTv Fidaxomicin Vancomycin
    Number of subjects analysed
    24
    24
    16
    Units: Yes or no
        No
    2
    14
    13
        Yes
    22
    10
    3
    Statistical analysis title
    		 FMTv vs fidaxomicin
    Statistical analysis description
    Chi-square analysis of primary endpoint, bivariate comparisons
    Comparison groups
    FMTv v Fidaxomicin
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 FMTV vs vancomycin
    Comparison groups
    FMTv v Vancomycin
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    8 weeks
    Adverse event reporting additional description
    Adverse events that occurred more than 2 days and up to 8 weeks after finalising primary treatment were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    FMTv
    Reporting group description
    		 Randomisation group 1, faecal microbiota transplantation preceded by vancomycin

    Reporting group title
    Fidaxomicin
    Reporting group description
    		 Randomisation group 2, fidaxomicin mono therapy

    Reporting group title
    Vancomycin
    Reporting group description
    		 Randomisation group 3, vancomycin monotherapy

    Serious adverse events
    		 FMTv Fidaxomicin Vancomycin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 12 (41.67%)
    6 / 9 (66.67%)
    4 / 8 (50.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Hospitalisation
    Additional description: Hospitalisation (any cause) within 8 weeks after finalising primary treatment
         subjects affected / exposed
    5 / 12 (41.67%)
    6 / 9 (66.67%)
    4 / 8 (50.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 FMTv Fidaxomicin Vancomycin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    3 / 9 (33.33%)
    4 / 8 (50.00%)
    General disorders and administration site conditions
    Other AE, possibly related
    Additional description: Headache, dizziness, shivering, blurred vision, weight loss, weight gain
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
         occurrences all number
    3
    2
    1
    Other AE unrelated
    Additional description: Alcohol intoxication, hoarseness, cerebral commotion,
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
         occurrences all number
    4
    3
    3
    Gastrointestinal disorders
    GI symptoms, no treatment, probably related
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    4
    3
    2
    GI symptoms, treatment, probably related
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    3
    0
    Infections and infestations
    Non-GI infections
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
         occurrences all number
    4
    2
    2

    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.
    Longterm follow-up was not included in the primary analysis. Very few patients with subtype CD027 C difficile were included, and our results may not be generalisable to these patients.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30610862
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