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    Clinical Trial Results:
    Clearance of the probiotic strain Escherichia coli Nissle 1917 in the gastrointestinal tract of healthy volunteers

    Summary
    EudraCT number
    		 2016-001240-19
    Trial protocol
    		 BG  
    Global end of trial date
    19 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2018
    First version publication date
    27 Dec 2018
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL16001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Synlogic Inc
    Sponsor organisation address
    301 Binney Street, Suite 402, Cambridge, United States, 02142
    Public contact
    Marja Puurunen, Synlogic Inc, 508 6657667, marja@synlogictx.com
    Scientific contact
    Marja Puurunen, Synlogic Inc, 508 6657667, marja@synlogictx.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
    13 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the clearance of Escherichia coli strain Nissle 1917 in the gastrointestinal tract after administration of an oral test preparation containing 2.5-25 x 10^9 CFU (Test IMP: Mutaflor® capsules) after single or multiple dose administrations of one capsule three times daily for 28 days (48 volunteers) or for 1 day (10 volunteers) taken together with meals.
    Protection of trial subjects
    standard ICH-GCP guidelines were followed
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 2016
    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
    Bulgaria: 58
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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)
    58
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The recruitment of subjects was performed by the principal investigator from a pool of healthy subjects generally qualified for participation in clinical studies at the clinical center. After receiving a written volunteer information and informed consent form and after all questions were explained by the informing physician, 83 volunteers were aske

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Single Dose Arm
    Arm description
    		 10 subjects received single dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mutaflor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    1 mutalfor capsule 3 times in one day

    Arm title
    		 Multiple Dose Arm
    Arm description
    		 multiple administrations of one capsule of mutalfor three times daily for 48 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mutaflor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    1 mutalfor capsule 3 times a day x 28 days

    Number of subjects in period 1
    		Single Dose Arm Multiple Dose Arm
    Started
    10
    48
    Completed
    10
    48

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Single Dose Arm
    Reporting group description
    		 10 subjects received single dose

    Reporting group title
    Multiple Dose Arm
    Reporting group description
    		 multiple administrations of one capsule of mutalfor three times daily for 48 days

    Primary: a. Percentage of volunteers with a stool sample positive for EcN, 24 weeks after the start of treatment

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    End point title
    		 a. Percentage of volunteers with a stool sample positive for EcN, 24 weeks after the start of treatment
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks after start of treatment
    End point values
    		 Single Dose Arm Multiple Dose Arm
    Number of subjects analysed
    10
    45
    Units: days
    10
    45
    Statistical analysis title
    		 Clearance
    Comparison groups
    Single Dose Arm v Multiple Dose Arm
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 yes or no
    Point estimate
    1
    Confidence interval
         level
    		 99.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -

    Primary: b. Time to no detection of EcN in the stool (2 consecutively negative fecal samples by qualitative qPCR)

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    End point title
    		 b. Time to no detection of EcN in the stool (2 consecutively negative fecal samples by qualitative qPCR)
    End point description
    End point type
    Primary
    End point timeframe
    2 consecutively negative fecal samples by qPCR within 24 weeks of last dose
    End point values
    		 Single Dose Arm Multiple Dose Arm
    Number of subjects analysed
    10
    45
    Units: negative fecal samples
        number (not applicable)
    10
    45
    Statistical analysis title
    		 qPCR
    Comparison groups
    Single Dose Arm v Multiple Dose Arm
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 yes or no
    Point estimate
    1
    Confidence interval
         level
    		 99.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -
    Notes
    [1] - yes or no

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of observation, the time in which adverse events will be documented, for this study is defined as follows: The time that the informed consent is signed by the subject is designated as start of safety data collection. The data collection period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Non-Serious Adverse Events
    Reporting group description
    		 Non-Serious Adverse Events

    Serious adverse events
    		 Non-Serious Adverse Events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 55 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Non-Serious Adverse Events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 55 (12.73%)
    General disorders and administration site conditions
    Headache
    Additional description: 6 subjects
         subjects affected / exposed
    6 / 55 (10.91%)
         occurrences all number
    6
    Hepatobiliary disorders
    Elevated Liver Enzymes
    Additional description: 1 subject
         subjects affected / exposed
    1 / 55 (1.82%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    a. Original protocol stated that “the multi-dose group will be dosed first. The single dose group will be dosed after the multi-dose have completed dosing on day 28.” As of 45 healthy volunteer subjects in the multi-dose cohort having received Mutaflor with no adverse events after the first day of taking Mutaflor capsules with each meal and for that matter after several days of dosing with Mutalfor, it was determined there was a low safety risk of subjects taking Mutaflor for one day and therefore no reason to wait until all 45 subjects had completed their day 28 dosing before starting the single dose cohort.

    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.
    qPCR assay variability and possibility that subjects had variable/changes in microorganism content in their intestine over time that cross reacted with the probes used in the qPCR assay.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29194983
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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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