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    Clinical Trial Results:
    A Prospective, randomised placebo controlled feasibility trial of Faecal Microbiotica Transplantation in cirrhosis

    Summary
    EudraCT number
    2017-003629-13
    Trial protocol
    GB  
    Global end of trial date
    17 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Oct 2020
    First version publication date
    15 Oct 2020
    Other versions
    Summary report(s)
    Clinical Study report

    Trial information

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    Trial identification
    Sponsor protocol code
    PROFIT
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02862249
    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
    Professor Debbie Shawcross, King's College London, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Scientific contact
    Professor Debbie Shawcross, King's College London, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Professor Debbie Shawcross, King's College London, 44 2032993713, debbie.shawcross@kcl.ac.uk
    Scientific contact
    Professor Debbie Shawcross, King's College London, 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
    01 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether stabilising gut dysbiosis with FMT in patients with advanced cirrhosis is both feasible and safe
    Protection of trial subjects
    A trial participant has the liberty to withdraw their consent at any time and for any reason, without penalty or loss of benefits to which the individual would otherwise be entitled. Participants who withdraw consent will discontinue their participation in the trial and no further data will be collected. Prior to giving consent, recipients will be informed that they are able to request the destruction of stored biological samples (e.g. blood/stool) upon withdrawal, and that this will only be possible for samples that have not been tested at the time of withdrawal. Participants will not be able to request the deletion of data generated from tested samples. The DMEC’s role was to ensure safety of trial participants and review the interim data to ensure safety of trial continuation.
    Background therapy
    Patients received 2L of Moviprep®, one litre at 6pm the night before the endoscopy and the second litre at 6am on the morning of the endoscopy. Patients were required to be nil by mouth for 6 hours prior to the endoscopy.
    Evidence for comparator
    -
    Actual start date of recruitment
    23 May 2018
    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: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    15
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Thirty-two patients were recruited from outpatient clinics and the hepatology wards at King’s College Hospital, including two patients who were referred from Kingston Hospital. Subjects were recrited in a 12 month period from 23/05/2018.

    Pre-assignment
    Screening details
    At the screening visit consent forms signed and bloods checked for the MELD score and HIV serology. If the patient met the inclusion criteria, they attended the baseline visit where they were reviewed in the Clinical Research Facility by the research team. Concomitant medications, medical and surgical histories were confirmed.

    Pre-assignment period milestones
    Number of subjects started
    318 [1]
    Number of subjects completed
    23

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 9
    Reason: Number of subjects
    ineligible: 286
    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: Includes screen fails who were not enrolled in the study
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    IMP was delivered out of the patient’s sight, so as not to unblind them to the treatment allocation. All efforts were made to maintain blinding of the treatment allocation to the patient, but the study investigators were not blinded as the placebo and FMT solutions were not matched.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Faecal microbiota transplantation (FMT)
    Arm description
    Faecal microbiota transplantation (FMT) derived from a healthy donor (200mls- less small aliquot for archiving) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep® [PEG-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution 100g, 7.5g, 2.691g, 1.051g, 5.9g, 4.7g
    Arm type
    Experimental

    Investigational medicinal product name
    Faecal Microbiota for Transplantation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gastroenteral liquid
    Routes of administration
    Intraduodenal use
    Dosage and administration details
    190ml administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep® [PEG-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution 100g, 7.5g, 2.691g, 1.051g, 5.9g, 4.7g].

    Arm title
    Placebo
    Arm description
    Placebo solution (200mls 0.9% normal saline and 12.5% glycerol) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep®.
    Arm type
    Placebo

    Investigational medicinal product name
    200mls 0.9% normal saline and 12.5% glycerol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gastroenteral liquid
    Routes of administration
    Intraduodenal use
    Dosage and administration details
    Placebo solution (200mls 0.9% normal saline and 12.5% glycerol) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep®.

    Number of subjects in period 1
    Faecal microbiota transplantation (FMT) Placebo
    Started
    17
    6
    Completed
    15
    6
    Not completed
    2
    0
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faecal microbiota transplantation (FMT)
    Reporting group description
    Faecal microbiota transplantation (FMT) derived from a healthy donor (200mls- less small aliquot for archiving) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep® [PEG-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution 100g, 7.5g, 2.691g, 1.051g, 5.9g, 4.7g

    Reporting group title
    Placebo
    Reporting group description
    Placebo solution (200mls 0.9% normal saline and 12.5% glycerol) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep®.

    Reporting group values
    Faecal microbiota transplantation (FMT) Placebo Total
    Number of subjects
    17 6 23
    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
        arithmetic mean (standard deviation)
    57.3 ± 11.1 56.8 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    4 2 6
        Male
    13 4 17
    Ethnicity
    Units: Subjects
        White
    15 3 18
        Black
    0 1 1
        Asian
    0 2 2
        Mixed
    0 0 0
        Other
    2 0 2
    Smoking Status
    Units: Subjects
        Current
    5 1 6
        Ex-smoker
    5 1 6
        Never smoker
    7 4 11
    Height
    Units: cm
        arithmetic mean (standard deviation)
    170.9 ± 10.6 165.5 ± 11.3 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    86.9 ± 19.7 73.7 ± 20.9 -

    End points

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    End points reporting groups
    Reporting group title
    Faecal microbiota transplantation (FMT)
    Reporting group description
    Faecal microbiota transplantation (FMT) derived from a healthy donor (200mls- less small aliquot for archiving) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep® [PEG-3350, sodium sulphate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution 100g, 7.5g, 2.691g, 1.051g, 5.9g, 4.7g

    Reporting group title
    Placebo
    Reporting group description
    Placebo solution (200mls 0.9% normal saline and 12.5% glycerol) administered via a gastroscope into the duodenum following preparation of the bowel with 2 sachets of MoviPrep®.

    Primary: Assessment of Safety

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    End point title
    Assessment of Safety [1]
    End point description
    Assessment of the safety of FMT: • Incidence of any transmissable bacterial or viral infection that is deemed to have been acquired from the donor including Clostridiodes difficile infection. • The development of any Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected Serious Adverse Reaction (USAR) that is not pre-specified or is a known consequence of disease progression or complication of cirrhosis that:  Results in death  Is life-threatening  Required hospitalisation or prolongation of existing hospitalisation  Results in persistent or significant disability or incapacity
    End point type
    Primary
    End point timeframe
    Day 1 (endoscopy) to Day 90
    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 report for analyses
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: Number of SAEs
        SAE
    8
    1
        SAR
    0
    0
        USAR
    0
    0
        Incidence of any transmissable bacterial or viral
    0
    0
    No statistical analyses for this end point

    Primary: Assess tolerability of FMT e.g reflux rates

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    End point title
    Assess tolerability of FMT e.g reflux rates [2]
    End point description
    End point type
    Primary
    End point timeframe
    Administration to 2 hours
    Notes
    [2] - 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 report for analyses
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: Subjects
        Vomit within 2 hours
    1
    0
        Type 6/7 bowel motion within 2 hours
    3
    0
    No statistical analyses for this end point

    Primary: Assess recruitment rates

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    End point title
    Assess recruitment rates [3]
    End point description
    End point type
    Primary
    End point timeframe
    Randomization to 90 days
    Notes
    [3] - 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 report for analyses
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    17
    6
    Units: Subjects
        Received Intervention
    15
    6
        Completed 7 day FU
    15
    6
        Completed 30 day FU
    15
    6
        Completed 90 day FU
    15
    5
    No statistical analyses for this end point

    Secondary: improvement in global liver synthetic function as assessed by the MELD score

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    End point title
    improvement in global liver synthetic function as assessed by the MELD score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: MELD Score
    arithmetic mean (standard deviation)
        Baseline
    9.7 ± 2.84
    9.76 ± 3.63
        90 Days
    10.20 ± 3.8
    8.92 ± 3.03
        Change (90 days-Baseline)
    -0.58 ± 2.18
    -1.83 ± 1.77
    No statistical analyses for this end point

    Secondary: Development of overt hepatic encephalopathy

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    End point title
    Development of overt hepatic encephalopathy
    End point description
    The development of organ failure (hypotension requiring inotropic support, respiratory failure requiring ventilator support or the development of acute kidney injury requiring renal replacement therapy) and infection
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: Westhaven Criteria >=grade1
        Baseline
    5
    1
        90 days
    7
    1
    No statistical analyses for this end point

    Secondary: The development of any infection

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    End point title
    The development of any infection
    End point description
    The development of any infection during the 90 day follow up including chest, urinary, stool, ascites and blood infection.
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: Number
        7 days
    1
    0
        30 days
    1
    0
        90 days
    0
    0
    No statistical analyses for this end point

    Secondary: The development of organ failure

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    End point title
    The development of organ failure
    End point description
    The development of organ failure (hypotension requiring inotropic support, respiratory failure requiring ventilator support or the development of acute kidney injury requiring renal replacement therapy) and infection
    End point type
    Secondary
    End point timeframe
    Baseline to 90 days
    End point values
    Faecal microbiota transplantation (FMT) Placebo
    Number of subjects analysed
    15
    6
    Units: Number
        by 90 days
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period for AE reporting was from the date of the intervention up until 90 days post intervention.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    FMT- faecal microbiota transplantation
    Reporting group description
    -

    Reporting group title
    PLacebo
    Reporting group description
    -

    Serious adverse events
    FMT- faecal microbiota transplantation PLacebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal bleeding
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    lesion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (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: 0%
    Non-serious adverse events
    FMT- faecal microbiota transplantation PLacebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    6 / 6 (100.00%)
    Nervous system disorders
    neurological disorder
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    General disorders and administration site conditions
    other
         subjects affected / exposed
    13 / 15 (86.67%)
    5 / 6 (83.33%)
         occurrences all number
    29
    5
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 6 (50.00%)
         occurrences all number
    1
    3
    Constipation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    4
    3
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2018
    IMPD updated to change container

    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.
    Mechanistic analyses are in progress and the manuscript is currently being drafted.
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