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    Clinical Trial Results:
    A Phase 2 Randomised, Double Blind, Placebo Controlled, Parallel Group, Multicentre Study to Evaluate the Safety and Efficacy of Repeated Oral Doses of Blautix™ in Adult Subjects with Irritable Bowel Syndrome (IBS) Subtypes IBS-C and IBS-D

    Summary
    EudraCT number
    		 2018-001203-36
    Trial protocol
    		 IE   GB   PL  
    Global end of trial date
    13 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Sep 2021
    First version publication date
    24 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BHT-II-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03721107
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    4D Pharma Plc
    Sponsor organisation address
    9 Bond Court, Leeds, United Kingdom, LS1 2JZ
    Public contact
    Clinical Trials Department, 4D Pharma Plc, 44 0113895 0130, clinicaltrials@4dpharmaplc.com
    Scientific contact
    Clinical Trials Department, 4D Pharma Plc, 44 0113895 0130, clinicaltrials@4dpharmaplc.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 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the efficacy of repeated twice daily doses of Blautix > 1*10^10 most probable number (MPN) for 8 weeks in adult subjects with either IBS-C (Cohort C) or IBS-D (Cohort D).
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice (GCP) as required by Food and Drug Administration (FDA) regulations, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and standard operating procedures (SOPs) for clinical investigation and documentation provided by the sponsor, Parexel and Synteract. Compliance with these requirements also indicates conformity with the ethical principles that have their origins in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Oct 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: 122
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    United States: 237
    Worldwide total number of subjects
    366
    EEA total number of subjects
    7
    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)
    335
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 366 subjects were randomised across 30 study centers in Ireland, United Kingdom, and United States between 11 October 2018 (first subject enrolled) and 13 May 2020 (last subject completed study).

    Pre-assignment
    Screening details
    		 Subjects who met the eligibility criteria were randomised to receive Blautix or Placebo in either Cohort C or Cohort D depending on classification of IBS subtype by the study doctor.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort C: Blautix
    Arm description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-C (IBS-C) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 most probable number (MPN).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blautix
    Investigational medicinal product code
    MRx1234
    Other name
    Blautia hydrogenotrophica, DSMZ nº14294
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects diagnosed with IBS-C received two capsules of Blautix orally, twice daily for 8 weeks.

    Arm title
    		 Cohort C: Placebo
    Arm description
    		 Subjects diagnosed with IBS-C received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects diagnosed with IBS-C received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Arm title
    		 Cohort D: Blautix
    Arm description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-D (IBS-D) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 MPN.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Blautix
    Investigational medicinal product code
    MRx1234
    Other name
    Blautia hydrogenotrophica, DSMZ nº14294
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects diagnosed with IBS-D received two capsules of Blautix orally, twice daily for 8 weeks.

    Arm title
    		 Cohort D: Placebo
    Arm description
    		 Subjects diagnosed with IBS-D received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects diagnosed with IBS-D received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Number of subjects in period 1 [1]
    		Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Started
    80
    84
    97
    104
    Completed
    75
    81
    83
    92
    Not completed
    5
    3
    14
    12
         Consent withdrawn by subject
    1
    1
    5
    5
         Physician decision
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    6
    5
         Unspecified
    1
    -
    -
    1
         Lost to follow-up
    2
    -
    3
    -
         Inclusion/Exclusion Criteria not Met
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 366 subjects were enrolled, out of which 365 subjects were treated and presented in subject disposition and baseline characteristics.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort C: Blautix
    Reporting group description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-C (IBS-C) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 most probable number (MPN).

    Reporting group title
    Cohort C: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-C received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Reporting group title
    Cohort D: Blautix
    Reporting group description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-D (IBS-D) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 MPN.

    Reporting group title
    Cohort D: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-D received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Reporting group values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo Total
    Number of subjects
    		 80 84 97 104 365
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ± 13.04 45.3 ± 13.41 43.1 ± 13.65 44.9 ± 14.40 -
    Gender categorical
    Units: Subjects
        Female
    		 67 69 60 73 269
        Male
    		 13 15 37 31 96
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 20 21 10 10 61
        Not Hispanic or Latino
    		 60 63 87 94 304
        Unknown or Not Reported
    		 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 2 0 2
        Asian
    		 1 0 2 1 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 30 33 7 11 81
        White
    		 48 50 86 90 274
        More than one race
    		 0 0 0 1 1
        Unknown or Not Reported
    		 1 1 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    Cohort C: Blautix
    Reporting group description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-C (IBS-C) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 most probable number (MPN).

    Reporting group title
    Cohort C: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-C received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Reporting group title
    Cohort D: Blautix
    Reporting group description
    		 Subjects diagnosed with Irritable Bowel Syndrome Subtype-D (IBS-D) received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 MPN.

    Reporting group title
    Cohort D: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-D received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Primary: Percentage of Subjects With Overall Response

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    End point title
    		 Percentage of Subjects With Overall Response
    End point description
    Overall responder was a subject who has at least 7 evaluable weeks of data and has reported an improvement in their weekly symptoms (abdominal pain intensity [API] and stool frequency [SF] or consistency [SC]) for greater than or equal to (>=) 50 percent (%) of the treatment period. API: decrease in weekly average of worst abdominal pain in the past 24 hours score of at least 30% compared with baseline for Cohort C and D; SF: increase of 1 or more CSBM per week compared with baseline for Cohort C; SC: decrease at least 50% in the proportion of days per week with at least one stool that has a consistency of Type 6 or 7 compared with baseline for Cohort D. Subjects with <4 weeks available were considered non-responders. Full Analysis Set (FAS): all subjects in the safety analysis set who were appropriately randomized into the study. Here, “Number of subjects analysed” signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 8
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    76
    82
    94
    101
    Units: Percentage of subjects
        number (not applicable)
    25.0
    17.1
    23.4
    17.8
    Statistical analysis title
    		 Cohort C: Blautix, Cohort C: Placebo
    Comparison groups
    Cohort C: Placebo v Cohort C: Blautix
    Number of subjects included in analysis
    158
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.152 [1]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Difference in Percentage
    Point estimate
    7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 21.9
    Notes
    [1] - P-value is from a 1-sided Pearson chi-square test with Yates’ correction with null hypothesis that the difference in proportions Blautix – placebo <=0 versus the difference is >0. The significance level for rejection of the null hypotheses is 0.10.
    Statistical analysis title
    		 Cohort D: Blautix, Cohort D: Placebo
    Comparison groups
    Cohort D: Blautix v Cohort D: Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.216 [2]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Difference in Percentage
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 18
    Notes
    [2] - P-value is from a 1-sided Pearson chi-square test with Yates’ correction with null hypothesis that the difference in proportions Blautix - placebo <=0 versus the difference is >0. The significance level for rejection of the null hypotheses is 0.10.

    Secondary: Number of Subjects With Treatment-Related Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-Related Treatment Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject administered study medication and which does not necessarily have a causal relationship with this treatment. TEAE was defined as an AE that started or worsened in severity on or after the start date of the study treatment and includes all AEs recorded through the follow-up visit. A treatment-related TEAE is a TEAE possibly related to the study treatment. Safety analysis set (SAF) included all subjects randomised into the study who received at least one dose of Blautix or Placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow-up visit (up to Week 14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    80
    84
    97
    104
    Units: Subjects
    5
    4
    16
    14
    No statistical analyses for this end point

    Secondary: Number of Subjects With Response to Subject Global Assessment of Relief

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    End point title
    		 Number of Subjects With Response to Subject Global Assessment of Relief
    End point description
    The Subject Global Assessment of Relief was collected weekly through the electronic clinical outcome assessment (eCOA) system. It was a comparison of how the subject has felt over the past week with regards to their IBS to the way they felt before entering the study. It was measured on a 5-point Likert scale with the following responses: Completely relieved; considerably relieved; somewhat relieved; unchanged; worse. The total score ranged from 0-20, where higher scores indicated worsening of condition. FAS included all subjects in the safety analysis set who were appropriately randomised into the study. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 1, 4, 8, follow-up visit (Week 12, 13 and 14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    66
    70
    84
    86
    Units: Subjects
        Week 1: Completely Relieved
    0
    2
    2
    0
        Week 1: Considerably Relieved
    1
    3
    1
    0
        Week 1: Somewhat Relieved
    6
    6
    3
    8
        Week 1: Unchanged
    58
    56
    72
    76
        Week 1: Worse
    1
    3
    6
    2
        Week 4: Completely Relieved
    1
    1
    2
    1
        Week 4: Considerably Relieved
    13
    7
    13
    14
        Week 4: Somewhat Relieved
    31
    31
    26
    24
        Week 4: Unchanged
    17
    19
    28
    28
        Week 4: Worse
    1
    5
    4
    4
        Week 8: Completely Relieved
    2
    3
    5
    3
        Week 8: Considerably Relieved
    20
    13
    14
    16
        Week 8: Somewhat Relieved
    24
    23
    22
    26
        Week 8: Unchanged
    18
    19
    21
    20
        Week 8: Worse
    1
    2
    6
    5
        Week 12: Completely Relieved
    5
    5
    5
    2
        Week 12: Considerably Relieved
    6
    11
    10
    5
        Week 12: Somewhat Relieved
    13
    17
    14
    16
        Week 12: Unchanged
    14
    16
    19
    24
        Week 12: Worse
    2
    3
    2
    5
        Week 13: Completely Relieved
    4
    4
    4
    3
        Week 13: Considerably Relieved
    9
    12
    4
    3
        Week 13: Somewhat Relieved
    12
    9
    12
    14
        Week 13: Unchanged
    7
    12
    15
    18
        Week 13: Worse
    1
    4
    5
    4
        Week 14: Completely Relieved
    2
    0
    0
    1
        Week 14: Considerably Relieved
    2
    2
    0
    1
        Week 14: Somewhat Relieved
    2
    1
    3
    1
        Week 14: Unchanged
    0
    5
    8
    4
        Week 14: Worse
    0
    0
    0
    3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Stool Consistency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)

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    End point title
    		 Change From Baseline in Stool Consistency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)
    End point description
    Stool consistency of each bowel movement was assessed by subjects using the 7-point BSFS from 1 to 7 where Type 1 = separate hard lumps, like nuts (hard to pass), Type 2 = sausage-shaped but lumpy, Type 3 = like a sausage but with cracks on the surface, Type 4 = like a sausage or snake, smooth and soft, Type 5 = soft blobs with clear-cut edges (passed easily), Type 6 = fluffy pieces with ragged edges, a mushy stool, Type 7 = watery, no solid pieces; entirely liquid. A score of 1 or 2 indicates constipation and a score of 6 or 7 indicates diarrhea. FAS included all subjects in the safety analysis set who were appropriately randomised into the study. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint and “n=number analysed” signifies subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, 4, 8, follow-up visit (Week 12, 13 and 14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    64
    73
    83
    94
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n=64, 73, 83, 94)
    0.13 ± 22.859
    3.38 ± 24.412
    -25.67 ± 28.078
    -23.70 ± 30.730
        Change at Week 4 (n=57, 63, 74, 76)
    -4.23 ± 24.470
    -1.99 ± 24.077
    -32.43 ± 33.627
    -33.73 ± 33.615
        Change at Week 8 (n=53, 56, 67, 70)
    -5.93 ± 26.705
    -0.10 ± 22.852
    -40.36 ± 37.595
    -36.91 ± 35.753
        Change at Week 12 (n=33, 46, 51, 57)
    -5.66 ± 23.063
    1.06 ± 27.027
    -34.09 ± 41.128
    -42.13 ± 31.500
        Change at Week 13 (n=7, 15, 17, 25)
    10.88 ± 26.517
    -5.16 ± 19.868
    -29.38 ± 35.002
    -32.21 ± 39.679
        Change at Week 14 (n=2, 2, 4, 6)
    -15.48 ± 1.684
    -2.98 ± 15.994
    -40.00 ± 36.216
    -38.10 ± 36.608
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Stool Consistency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)

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    End point title
    		 Percent Change From Baseline in Stool Consistency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)
    End point description
    Stool consistency of each bowel movement was assessed by subjects using the 7-point BSFS from 1 to 7 where Type 1 = separate hard lumps, like nuts (hard to pass), Type 2 = sausage-shaped but lumpy, Type 3 = like a sausage but with cracks on the surface, Type 4 = like a sausage or snake, smooth and soft, Type 5 = soft blobs with clear-cut edges (passed easily), Type 6 = fluffy pieces with ragged edges, a mushy stool, Type 7 = watery, no solid pieces; entirely liquid. A score of 1 or 2 indicates constipation and a score of 6 or 7 indicates diarrhea. Lower numbers represented more formed stools and higher numbers represented less formed stools. FAS included all subjects in the safety analysis set who were appropriately randomised into the study. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint and “n=number analysed” signifies subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, 4, 8, follow-up visit (Week 12, 13 and 14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    63
    70
    83
    94
    Units: Percent Change
    arithmetic mean (standard deviation)
        Percent Change at Week 1 (n=63, 70, 83, 94)
    15.05 ± 126.940
    27.65 ± 129.217
    -32.30 ± 36.887
    -27.27 ± 38.590
        Percent Change at Week 4 (n=57, 61, 74, 76)
    -6.36 ± 122.165
    -7.18 ± 112.425
    -40.14 ± 42.757
    -40.60 ± 40.128
        Percent Change at Week 8 (n=52, 54, 67, 70)
    -12.00 ± 145.174
    -4.64 ± 103.202
    -49.32 ± 45.798
    -42.64 ± 39.801
        Percent Change at Week 12 (n=33, 44, 51, 57)
    -7.45 ± 125.537
    14.75 ± 144.064
    -36.96 ± 50.023
    -49.94 ± 34.638
        Percent Change at Week 13 (n=7, 14, 17, 25)
    41.07 ± 143.017
    -40.31 ± 89.914
    -33.29 ± 40.067
    -35.91 ± 44.635
        Percent Change at Week 14 (n=2, 2, 4, 6)
    -100.00 ± 0.000
    -25.00 ± 106.066
    -52.50 ± 49.319
    -43.53 ± 44.353
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Average Stool Frequency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)

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    End point title
    		 Change From Baseline in Weekly Average Stool Frequency Assessed by Bristol Stool Form Scale (BSFS) at Week 1, 4, 8, Follow-up Visit (Week 12, 13 and 14)
    End point description
    Stool frequency was defined as a sum of weekly CSBMs. Stool types were assessed using the 7-point BSFS where 1 = separate hard lumps, like nuts, 2 = sausage-shaped but lumpy, 3 = like a sausage but with cracks on the surface, 4 = like a sausage or snake, smooth and soft, 5 = soft blobs with clear-cut edges, 6 = fluffy pieces with ragged edges, a mushy stool, 7 = watery, no solid pieces; entirely liquid. Score of 1 or 2 indicates constipation and 6 or 7 indicates diarrhea. Weekly stool frequency based on the daily stool frequency (DSF) which was calculated as follows: if there was 1 or more entry for BSC, the number of BSC entries was summed up. If on that day laxative was used, daily stool frequency was set to 0. If an answer to CSBMs, but no BSC entry was provided, the DSF was set to 0 on that day. FAS Analysis. “Number of subjects analysed” signifies subjects were evaluable for this endpoint; “n=number analysed” signifies subjects were evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, 4, 8, follow-up visit (Week 12, 13 and 14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    64
    73
    83
    94
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Change at Week 1 (n=64, 73, 83, 94)
    1.33 ± 2.202
    1.61 ± 2.416
    -1.07 ± 2.441
    -1.02 ± 3.119
        Change at Week 4 (n=57, 63, 74, 76)
    2.14 ± 2.348
    1.87 ± 2.809
    -1.60 ± 2.543
    -1.83 ± 3.389
        Change at Week 8 (n=53, 56, 67, 70)
    2.00 ± 2.289
    2.42 ± 2.751
    -2.59 ± 3.012
    -1.97 ± 3.048
        Change at Week 12 (n=33, 46, 51, 57)
    1.76 ± 2.547
    2.18 ± 2.762
    -2.29 ± 2.599
    -2.43 ± 3.299
        Change at Week 13 (n=7, 15, 17, 25)
    2.09 ± 2.489
    1.98 ± 2.539
    -2.05 ± 3.242
    -1.77 ± 2.804
        Change at Week 14 (n=2, 2, 4, 6)
    2.56 ± 0.507
    1.19 ± 0.860
    -4.71 ± 2.626
    -3.54 ± 4.063
    No statistical analyses for this end point

    Secondary: Change From Baseline in IBS Quality of Life (IBS-QOL) Questionnaire Subscale and Total Scores at Week 4, 8, and Follow-up Visit (Weeks 12-14)

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    End point title
    		 Change From Baseline in IBS Quality of Life (IBS-QOL) Questionnaire Subscale and Total Scores at Week 4, 8, and Follow-up Visit (Weeks 12-14)
    End point description
    Subjects were asked to complete a QOL questionnaire of 34 items each with an individual 5-point response on an ordinal scale. Responses to these items were summed and averaged for a total score (TS) and then transformed to a 100-point scale for ease of interpretation. Sub-scales included dysphoria score (DS [8 items]), interference of activity (IAS [7items]), body image (BIS [4 items]), health worry (HWS [3 items]), food avoidance (FAS [3 items]), social reaction (SRS [4 items]), sexual (SS [2 items]) and relationship (RS [3 items]) were numbered as 1-5 with: 1 = not at all, 2 = slightly, 3 = moderately, 4 = quite a bit, 5 = extremely or a great deal. IBS-QOL was measured on a scale range of 0-100 with (0=worst; 100=better). Higher scores indicates better IBS-specific quality of life. FAS analysis population. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint; “n=number analysed” signifies subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, follow-up visit (Week 12-14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    41
    41
    47
    64
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Change at Week 4: TS (n=41, 41, 45, 64)
    5.67 ± 16.858
    5.79 ± 21.908
    5.62 ± 18.087
    5.93 ± 13.113
        Change at Week 4: DS (n=41, 41, 45, 64)
    5.95 ± 20.561
    5.34 ± 22.881
    9.17 ± 22.627
    5.81 ± 17.429
        Change at Week 4: IAS (n=41, 41, 45, 64)
    4.79 ± 16.952
    6.71 ± 22.633
    7.54 ± 18.230
    8.26 ± 16.008
        Change at Week 4: BIS (n=41, 41, 45, 64)
    4.88 ± 23.779
    7.62 ± 23.239
    5.83 ± 20.703
    4.10 ± 17.860
        Change at Week 4: HWS (n=41, 41, 45, 64)
    10.98 ± 23.082
    10.57 ± 26.940
    6.85 ± 19.727
    7.55 ± 19.056
        Change at Week 4: FAS (n=41, 41, 45, 64)
    6.50 ± 20.625
    4.88 ± 29.461
    5.56 ± 19.624
    7.55 ± 19.960
        Change at Week 4: SRS (n=41, 41, 45, 64)
    4.12 ± 16.922
    2.44 ± 24.402
    0.42 ± 23.963
    6.64 ± 14.935
        Change at Week 4: SS (n=41, 41, 45, 64)
    7.32 ± 29.445
    1.52 ± 24.716
    -0.56 ± 20.288
    0.39 ± 19.284
        Change at Week 4: RS (n=41, 41, 45, 64)
    2.85 ± 21.214
    5.89 ± 26.170
    1.30 ± 23.500
    2.73 ± 17.509
        Change at Week 8: TS (n=38, 35, 47, 53)
    12.27 ± 20.969
    8.09 ± 18.318
    11.89 ± 20.933
    8.37 ± 18.043
        Change at Week 8: DS (n=38, 35, 47, 53)
    13.40 ± 21.044
    7.59 ± 20.085
    14.23 ± 26.241
    12.21 ± 20.403
        Change at Week 8: IAS (n=38, 35, 47, 53)
    10.15 ± 26.120
    10.31 ± 21.529
    15.12 ± 22.944
    8.96 ± 20.247
        Change at Week 8: BIS (n=38, 35, 47, 53)
    12.83 ± 22.696
    8.93 ± 18.890
    13.70 ± 22.217
    7.43 ± 23.096
        Change at Week 8: HWS (n=38, 35, 47, 53)
    17.32 ± 27.834
    12.38 ± 22.810
    7.80 ± 22.947
    7.23 ± 19.614
        Change at Week 8: FAS (n=38, 35, 47, 53)
    17.54 ± 27.522
    7.38 ± 29.412
    14.01 ± 22.327
    6.60 ± 24.534
        Change at Week 8: SRS (n=38, 35, 47, 53)
    10.69 ± 21.401
    3.21 ± 17.960
    8.78 ± 24.473
    7.55 ± 20.669
        Change at Week 8: SS (n=38, 35, 47, 53)
    10.53 ± 24.406
    3.57 ± 22.600
    3.46 ± 26.797
    3.30 ± 26.420
        Change at Week 8: RS (n=38, 35, 47, 53)
    6.36 ± 19.800
    9.05 ± 22.721
    7.45 ± 21.858
    5.35 ± 20.155
        Change at Follow-up: TS (n=34, 36, 37, 38)
    15.55 ± 21.368
    8.09 ± 16.647
    7.93 ± 23.919
    10.80 ± 19.950
        Change at Follow-up: DS (n=34, 36, 37, 38)
    15.99 ± 23.957
    8.07 ± 17.236
    10.47 ± 30.336
    11.43 ± 21.236
        Change at Follow-up: IAS (n=34, 36, 37, 38)
    14.50 ± 23.195
    12.00 ± 21.278
    9.75 ± 25.417
    14.94 ± 26.243
        Change at Follow-up: BIS (n=34, 36, 37, 38)
    17.10 ± 21.777
    9.38 ± 17.772
    8.95 ± 24.409
    9.38 ± 25.200
        Change at Follow-up: HWS (n=34, 36, 37, 38)
    19.36 ± 28.701
    9.26 ± 23.382
    10.14 ± 23.663
    14.25 ± 18.371
        Change at Follow-up: FAS (n=34, 36, 37, 38)
    16.91 ± 23.524
    9.72 ± 21.776
    7.43 ± 24.594
    9.21 ± 26.408
        Change at Follow-up: SRS (n=34, 36, 37, 38)
    13.79 ± 24.942
    1.04 ± 15.917
    6.59 ± 27.676
    9.38 ± 23.554
        Change at Follow-up: SS (n=34, 36, 37, 38)
    15.07 ± 26.253
    3.13 ± 23.599
    -1.69 ± 27.507
    4.93 ± 25.425
        Change at Follow-up: RS (n=34, 36, 37, 38)
    12.25 ± 22.774
    7.18 ± 22.900
    2.03 ± 24.799
    5.26 ± 22.041
    No statistical analyses for this end point

    Secondary: Change From Baseline in IBS Symptom Severity Score (IBS-SSS) at Week 4, 8 and Follow-up Visit (Weeks 12-14)

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    End point title
    		 Change From Baseline in IBS Symptom Severity Score (IBS-SSS) at Week 4, 8 and Follow-up Visit (Weeks 12-14)
    End point description
    Subjects were asked to complete a questionnaire on the severity of abdominal distension and pain, frequency of abdominal pain, dissatisfaction with bowel habits, and interference of IBS symptoms with daily life. The IBS-SSS was measured on a Visual Analog Scale (VAS scale) in combination with reported numeric values which equated to an overall score. The scale range was from 0 (no symptoms) to 500 (maximum severity). Subjects were categorized as having mild (74-174), moderate (175-299), or severe (greater than [>] 300) IBS symptoms based on symptomology. Higher scores were indicative of greater disease severity (worse outcome). FAS included all subjects in the safety analysis set who were appropriately randomised into the study. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint and “n=number analysed” signifies subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, follow-up visit (Week 12-14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    77
    81
    83
    93
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Change at Week 4 (n=77, 81, 83, 93)
    -128.87 ± 143.885
    -141.30 ± 139.439
    -125.75 ± 135.258
    -100.97 ± 114.939
        Change at Week 8 (n=73, 79, 81, 85)
    -168.46 ± 157.300
    -173.53 ± 155.253
    -143.55 ± 143.781
    -133.63 ± 139.290
        Change at Follow up visit (n=77, 80, 83, 90)
    -142.49 ± 149.678
    -160.66 ± 150.174
    -113.47 ± 135.064
    -104.76 ± 146.447
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hospital Anxiety and Depression (HADS) Total Score at Week 4, 8 and Follow-up Visit (Weeks 12-14)

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    End point title
    		 Change From Baseline in Hospital Anxiety and Depression (HADS) Total Score at Week 4, 8 and Follow-up Visit (Weeks 12-14)
    End point description
    Subjects were asked to complete the HADS which was a 14-item scale that generated ordinal data. Seven of the items were related to anxiety and seven were related to depression. Each item on the questionnaire was scored from 0-3 which means that a subject total score (TS) ranges from 0 and 21 each are derived by summing the individual scores under each category for anxiety or depression. Total Scores are interpreted as: 0-7 = Normal, 8-10 = Borderline abnormal and 11-21 = Abnormal. Higher HADS scores were indicative of more severe depression and anxiety. FAS included all subjects in the safety analysis set who were appropriately randomised into the study. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint and “n=number analysed” signifies subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, follow-up visit (Week 12-14)
    End point values
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Number of subjects analysed
    41
    41
    47
    64
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Change at Week 4: Anxiety TS (n=41, 41, 45, 64)
    -0.02 ± 2.612
    0.22 ± 2.954
    0.09 ± 2.827
    -0.27 ± 3.243
        Change at Week 4: Depression TS (n=41, 41, 45, 64)
    0.24 ± 3.527
    -0.29 ± 3.303
    0.22 ± 2.566
    0.00 ± 2.410
        Change at Week 8: Anxiety TS (n=38, 35, 47, 53)
    0.08 ± 2.981
    -0.09 ± 3.320
    -0.32 ± 3.251
    -0.40 ± 3.213
        Change at Week 8: Depression TS (n=38, 35, 47, 53)
    -0.18 ± 3.432
    -0.06 ± 3.556
    0.19 ± 2.787
    -0.36 ± 3.169
        Change at Follow-up: Anxiety TS (n=34, 36, 37, 38)
    -0.53 ± 3.360
    0.06 ± 2.714
    -0.14 ± 3.029
    -0.55 ± 3.375
        Change at Follow-up: Depression TS(n=34,36,37,38)
    -0.85 ± 3.735
    -0.14 ± 2.939
    0.51 ± 3.024
    -0.68 ± 2.886
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to follow-up visit (up to Week 14)
    Adverse event reporting additional description
    SAF included all subjects randomized into the study who received at least one dose of Blautix or Placebo.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort C: Blautix
    Reporting group description
    		 Subjects diagnosed with IBS-C received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to10^11 MPN.

    Reporting group title
    Cohort C: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-C received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Reporting group title
    Cohort D: Blautix
    Reporting group description
    		 Subjects diagnosed with IBS-D received two capsules of Blautix orally, twice daily for 8 weeks. Maximum daily dose of Blautix (strain of Blautia hydrogenotrophica) was 10^10 to 10^11 MPN.

    Reporting group title
    Cohort D: Placebo
    Reporting group description
    		 Subjects diagnosed with IBS-D received two capsules of placebo matched to Blautix orally, twice daily for 8 weeks.

    Serious adverse events
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort C: Blautix Cohort C: Placebo Cohort D: Blautix Cohort D: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 80 (21.25%)
    19 / 84 (22.62%)
    41 / 97 (42.27%)
    43 / 104 (41.35%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Hypertension
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Early satiety
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 84 (3.57%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Thirst
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    2 / 97 (2.06%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    2
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    2 / 97 (2.06%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Irritability
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    2 / 104 (1.92%)
         occurrences all number
    0
    0
    0
    2
    Post-traumatic pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Radius fracture
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Wrist fracture
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    4 / 97 (4.12%)
    5 / 104 (4.81%)
         occurrences all number
    1
    2
    4
    5
    Hypoaesthesia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Normocytic anaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    2 / 104 (1.92%)
         occurrences all number
    0
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 84 (1.19%)
    2 / 97 (2.06%)
    3 / 104 (2.88%)
         occurrences all number
    2
    1
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Anal fissure
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Anorectal discomfort
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    1 / 97 (1.03%)
    2 / 104 (1.92%)
         occurrences all number
    0
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    5 / 97 (5.15%)
    2 / 104 (1.92%)
         occurrences all number
    1
    0
    5
    2
    Dyspepsia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    3 / 97 (3.09%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    3
    1
    Flatulence
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 84 (2.38%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    1
    2
    0
    1
    Glossodynia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 84 (2.38%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    2
    0
    1
    Haemorrhoids thrombosed
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    3 / 97 (3.09%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    3
    1
    Nausea
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    2 / 104 (1.92%)
         occurrences all number
    0
    0
    1
    2
    Rectal haemorrhage
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Brachioradial pruritus
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    1
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    2 / 104 (1.92%)
         occurrences all number
    0
    0
    0
    2
    Ear infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    4 / 97 (4.12%)
    4 / 104 (3.85%)
         occurrences all number
    0
    1
    4
    4
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lice infestation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 84 (1.19%)
    5 / 97 (5.15%)
    1 / 104 (0.96%)
         occurrences all number
    2
    1
    5
    1
    Oral herpes
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    0 / 104 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 80 (5.00%)
    3 / 84 (3.57%)
    3 / 97 (3.09%)
    4 / 104 (3.85%)
         occurrences all number
    4
    3
    3
    4
    Urinary tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    1
    1
    1
    Vaginal infection
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Viral rhinitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    1 / 97 (1.03%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    1
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 84 (0.00%)
    0 / 97 (0.00%)
    1 / 104 (0.96%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 84 (1.19%)
    0 / 97 (0.00%)
    0 / 104 (0.00%)
         occurrences all number
    1
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2018
    Protocol Version 1.1: - Amended an administrative error regarding the timing of the dosing by adding approximately 30 minutes to be consistent with other sections of the protocol. - Removal of erythrocyte sedimentation rate and replacement with C-reactive protein [CRP] test within the haematology panel as this is a more accurate measurement for investigator review. - Additional testing for hepatitis B surface antigen, a hepatitis B surface antibody, and a hepatitis core antibody test was added for all subjects at the Screening Visit. - Removal of bile acid analysis of fasting serum from the planned per-protocol assessments.
    31 May 2018
    Protocol Version 2.0: - Changed the primary endpoint responder symptom definition for stool consistency from number of days per week to proportion of days per week. - Changed the timing for the collection of stool samples from within 48 hours before or on the morning of baseline to the night before or the morning of the next clinic visit. - Added a 24-hour window for completion of IBS QOL before the clinic visit. - Re-added hepatitis C to the safety assessment as it was removed in error during the changes to Version 1.1. - Added the requirement for the subject to record stool frequency of up to 10 bowel movements daily to ensure data required to meet the primary endpoint is sufficient.
    13 Feb 2019
    Protocol version 3.0: - Added text to inclusion criterion 4 for clarity: Have a moderate or severe IBS symptom severity score: >175 at the Screening Visit as defined by IBS-SSS. A tolerance of -10% (>= an IBS-SSS score of 157.5) will be allowable at the baseline (Visit 1). - Added a definition for the ranges of mild, moderate, and severe IBS symptom scores.
    31 Mar 2020
    Protocol version 3.1: - Planned futility analysis following the randomisation of approximately 250 subjects was cancelled as the study had stopped enrolment before the interim analysis was reported. - An informal interim analysis was conducted once all recruited subjects had completed the primary efficacy analysis 8-week treatment period. - This interim analysis was planned to enable 4D pharma plc to expedite the clinical development strategy based on the outcome of the interim analysis.

    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
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