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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-27018966 in the Treatment of Patients with Diarrhea-Predominant Irritable Bowel Syndrome

    Summary
    EudraCT number
    		 2012-001600-38
    Trial protocol
    		 GB  
    Global end of trial date
    29 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2018
    First version publication date
    30 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    27018966IBS3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01553591
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan Pharmaceutical International Ltd
    Sponsor organisation address
    Clonshaugh Business & Technology Park, Coolock, Dublin,, Ireland, D17 E400
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area Head, Allergan plc, 001 862-261-7000, IR-CTRegistration@Allergan.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
    29 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study was to evaluate the clinical response of participants with irritable bowel syndrome, diarrhea predominant (IBS-d) to eluxadoline, relative to placebo and evaluation of the overall safety and tolerability of eluxadoline in the treatment of IBS-d for up to 52 weeks.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2012
    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
    United Kingdom: 43
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    United States: 1214
    Worldwide total number of subjects
    1282
    EEA total number of subjects
    43
    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)
    1167
    From 65 to 84 years
    115
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 2832 participants were entered into the screening phase of the study. Out of these, 158 participants were never screened at sites that never randomised a patient; 2674 participants were screened at sites that randomised at least one participant. A total 1282 participants were enrolled into the study.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eluxadoline 75 mg
    Arm description
    		 Eluxadoline 75 mg tablets, orally, twice daily for up to 52 weeks period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eluxadoline
    Investigational medicinal product code
    Other name
    JNJ-27018966
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eluxadoline tablets, orally, twice daily for up to 52 weeks period.

    Arm title
    		 Eluxadoline 100 mg
    Arm description
    		 Eluxadoline 100 mg tablets, orally, twice daily for up to 52 weeks period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eluxadoline
    Investigational medicinal product code
    Other name
    JNJ-27018966
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eluxadoline tablets, orally, twice daily for up to 52 weeks period.

    Arm title
    		 Placebo
    Arm description
    		 Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period.

    Number of subjects in period 1
    		Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Started
    429
    426
    427
    Randomized
    428
    426
    427
    Attended Week 12 visit
    341
    330
    342
    Attended Week 26 visit
    289
    291
    290
    Completed
    257
    257
    269
    Not completed
    172
    169
    158
         Voluntarily withdrew
    94
    79
    96
         Physician decision: other
    11
    14
    16
         Physician decision: lack of efficacy
    2
    3
    7
         Lost to follow-up
    25
    23
    16
         Sponsor decision
    1
    -
    3
         Adverse Event or SAE
    36
    45
    16
         Randomised and never dispensed drug
    -
    1
    -
         Protocol deviation
    3
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eluxadoline 75 mg
    Reporting group description
    		 Eluxadoline 75 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Eluxadoline 100 mg
    Reporting group description
    		 Eluxadoline 100 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Placebo
    Reporting group description
    		 Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period.

    Reporting group values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo Total
    Number of subjects
    		 429 426 427 1282
    Age, Customized
    Units: Subjects
        18-40 years
    		 173 166 159 498
        41-64 years
    		 227 225 217 669
        ≥65 years
    		 29 35 51 115
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.5 ± 13.18 44.4 ± 13.91 45.8 ± 14.10 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 278 283 277 838
        Male
    		 151 143 150 444
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 374 368 370 1112
        Black
    		 46 48 46 140
        Asian
    		 3 3 4 10
        American Indian or Alaska Native
    		 1 2 1 4
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Other
    		 5 4 6 15
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 119 117 125 361
        Not Hispanic or Latino
    		 310 309 302 921
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 30.70 ± 7.421 31.22 ± 7.858 30.63 ± 7.253 -

    End points

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    End points reporting groups
    Reporting group title
    Eluxadoline 75 mg
    Reporting group description
    		 Eluxadoline 75 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Eluxadoline 100 mg
    Reporting group description
    		 Eluxadoline 100 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Placebo
    Reporting group description
    		 Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period.

    Primary: Percentage of Participants who were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores

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    End point title
    		 Percentage of Participants who were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores
    End point description
    Composite responders:participant who met daily response criteria for at least 50% of days with diary entries during the interval of interest. A participant must have met following criteria on given day to be daily responder:1) Daily pain response: worst abdominal pain scores in past 24 hours improved by ≥30% compared to baseline. 2) Daily stool consistency response: Bristol Stool Scale (BSS) score <5 or absence of a bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain. BSS was defined as 7-point Scale in which score of 1 = separate hard lumps, 2 = sausage shaped but lumpy, 3 = sausage-like with cracks on the surface, 4 = sausage-like but smooth and soft, 5 = soft blobs with clear cut edges, 6 = fluffy pieces with ragged edges, 7 = watery with no solid pieces. Intent to Treat (ITT) analysis set included all participants who were randomised into treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Primary
    End point timeframe
    Up to 26 Weeks
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
        number (not applicable)
    23.4
    29.3
    19.0
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The composite responder was analyzed using the CMH (Chi-square) test. The family-wise error rate was controlled by Bonferroni adjustment for each active dose versus placebo.
    Comparison groups
    Eluxadoline 75 mg v Placebo
    Number of subjects included in analysis
    854
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.112 [1]
    Method
    		 Chi-square test statistic
    Confidence interval
    Notes
    [1] - Chi-square test at 0.025 significance level
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The composite responder was analyzed using the CMH (Chi-square) test. The family-wise error rate was controlled by Bonferroni adjustment for each active dose versus placebo.
    Comparison groups
    Eluxadoline 100 mg v Placebo
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [2]
    Method
    		 Chi-square test statistic
    Confidence interval
    Notes
    [2] - Chi-square test at 0.025 significance level

    Secondary: Percentage of Participants who were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores

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    End point title
    		 Percentage of Participants who were Composite Responders Based on Improvements From Baseline in Daily Worst Abdominal Pain And Daily Stool Consistency Scores
    End point description
    Composite responders: a participant who met daily response criteria for at least 50% of the days with diary entries during the interval of interest. A participant must have met following criteria on given day to be daily responder:1) Daily pain response: worst abdominal pain scores in past 24 hours improved by ≥30% compared to baseline. 2) Daily stool consistency response: Bristol Stool Scale (BSS) score <5 or the absence of a bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain. BSS was defined as 7-point Scale in which a score of 1 = separate hard lumps, 2 = sausage shaped but lumpy, 3 = sausage-like with cracks on the surface, 4 = sausage-like but smooth and soft, 5 = soft blobs with clear cut edges, 6 = fluffy pieces with ragged edges, 7 = watery with no solid pieces. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    Up to 12 Weeks
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
        number (not applicable)
    23.9
    25.1
    17.1
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The composite responder was analyzed using the CMH (Chi-square) test. The family-wise error rate was controlled by Bonferroni adjustment for each active dose versus placebo.
    Comparison groups
    Placebo v Eluxadoline 75 mg
    Number of subjects included in analysis
    854
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.014 [3]
    Method
    		 Chi-square test statistic
    Confidence interval
    Notes
    [3] - Chi-square test at 0.025 significance level
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The composite responder was analyzed using the CMH (Chi-square) test. The family-wise error rate was controlled by Bonferroni adjustment for each active dose versus placebo.
    Comparison groups
    Eluxadoline 100 mg v Placebo
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.004 [4]
    Method
    		 Chi-square test statistic
    Confidence interval
    Notes
    [4] - Chi-square test at 0.025 significance level

    Secondary: Percentage of Participants who were Pain Responders In Daily Worst Abdominal Pain Scores by Intervals

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    End point title
    		 Percentage of Participants who were Pain Responders In Daily Worst Abdominal Pain Scores by Intervals
    End point description
    Pain responders are defined as participants who met the daily pain response criteria (ie, the worst abdominal pain score in the past 24 hours improved by ≥30% compared to baseline) for at least 50% of days with diary entries during each interval. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over the 12-week interval, and a minimum of 110 days of diary entries over the 26-week interval to be a responder. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24)
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
    number (not applicable)
        Responders during Weeks 1-12
    42.4
    43.2
    39.6
        Responders during Weeks 1-26
    45.2
    46.5
    43.3
        Responders during Weeks 1-4
    40.5
    44.4
    37.5
        Responders during Weeks 5-8
    44.5
    47.2
    45.4
        Responders during Weeks 9-12
    44.5
    45.8
    43.8
        Responders during Weeks 13-16
    44.3
    44.1
    45.4
        Responders during Weeks 17-20
    44.7
    43.2
    41.5
        Responders during Weeks 21-24
    44.7
    42.0
    38.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants who were Responders In Daily Stool Consistency Scores by Intervals

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    End point title
    		 Percentage of Participants who were Responders In Daily Stool Consistency Scores by Intervals
    End point description
    Stool consistency responders: participants who met daily stool consistency response criterion (ie,score of 1, 2, 3, or 4 or absence of bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared to baseline pain) for at least 50% of days with diary entries during each interval. BSS was defined as 7-point Scale in which score of 1= separate hard lumps, 2= sausage shaped but lumpy, 3= sausage-like with cracks on the surface, 4= sausage-like but smooth and soft, 5= soft blobs with clear cut edges, 6= fluffy pieces with ragged edges, and 7= watery with no solid pieces. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over 12-week interval, and a minimum of 110 days of diary entries over 26-week interval to be a responder. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24)
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
    number (not applicable)
        Responders during Weeks 1-12
    30.0
    34.3
    22.0
        Responders during Weeks 1-26
    28.1
    34.0
    24.1
        Responders during Weeks 1-4
    28.8
    31.5
    19.0
        Responders during Weeks 5-8
    31.1
    35.2
    24.1
        Responders during Weeks 9-12
    29.0
    35.2
    24.6
        Responders during Weeks 13-16
    27.6
    32.9
    24.4
        Responders during Weeks 17-20
    31.9
    31.5
    23.7
        Responders during Weeks 21-24
    30.2
    30.3
    24.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants who were Responders In Irritable Bowel Syndrome, Diarrhea Predominant (IBS-d) Global Symptom Scale by Intervals

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    End point title
    		 Percentage of Participants who were Responders In Irritable Bowel Syndrome, Diarrhea Predominant (IBS-d) Global Symptom Scale by Intervals
    End point description
    IBS-d global symptom responders are defined as those participants who met the daily IBS-d global symptom response criteria (ie, IBS-d global symptom score of 0 [none] or 1 [mild]; or a daily IBS-d global symptom score improved by ≥2.0 compared to the baseline average) for at least 50% of days with diary entries during each interval. IBS-d Global Symptom Scale is a 5 point scale, score ranging from 0 to 4. 0= no symptoms, 1= mild symptoms, 2= moderate symptoms, 3= severe symptoms and 4 = very severe symptoms. A participant must have had a minimum of 20 days of diary entries over any 4-week interval, a minimum of 60 days of diary entries over the 12-week interval, and a minimum of 110 days of diary entries over the 26-week interval to be a responder. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    12-week interval (Weeks 1-12), 26-week interval (Weeks 1-26), and 4-week interval (Weeks 1-4, 5-8, 9-12, 13-16, 17-20, and 21-24)
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
    number (not applicable)
        Responders during Weeks 1-12
    35.1
    34.7
    28.8
        Responders during Weeks 1-26
    36.3
    37.1
    32.3
        Responders during Weeks 1-4
    32.6
    31.9
    26.9
        Responders during Weeks 5-8
    37.0
    38.7
    32.8
        Responders during Weeks 9-12
    35.6
    36.6
    34.0
        Responders during Weeks 13-16
    35.8
    35.9
    35.4
        Responders during Weeks 17-20
    37.5
    36.4
    33.3
        Responders during Weeks 21-24
    36.8
    35.2
    29.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants who were Responders to the Irritable Bowel Syndrome Quality of Life Measure (IBS-QoL) Scale

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    End point title
    		 Percentage of Participants who were Responders to the Irritable Bowel Syndrome Quality of Life Measure (IBS-QoL) Scale
    End point description
    IBS-QoL responders are defined as participants who achieved at least a 14-point improvement in IBS-QoL total score from baseline to the applicable visit. The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100-point (0= worst; 100=better) scale for ease of interpretation. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 18, 26, 36, 44, and 52 (End of Treatment [EOT])
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
    number (not applicable)
        Responders at Week 4
    42.6
    44.1
    37.0
        Responders at Week 8
    43.8
    49.8
    41.7
        Responders at Week 12
    44.3
    48.1
    44.0
        Responders at Week 18
    44.5
    45.1
    43.3
        Responders at Week 26
    45.4
    45.1
    40.0
        Responders at Week 36
    41.0
    43.2
    39.6
        Responders at Week 44
    39.6
    40.1
    37.5
        Responders at Week 52/EOT
    49.4
    54.9
    47.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Irritable Bowel Syndrome – Adequate Relief (IBS-AR) Scale

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    End point title
    		 Percentage of Participants with Irritable Bowel Syndrome – Adequate Relief (IBS-AR) Scale
    End point description
    Adequate relief of IBS symptoms was assessed once weekly by participants answering the IBS-AR item in the electronic diary. IBS-AR responders are defined as participants with a weekly response of “Yes” to adequate relief of their IBS symptoms for at least 50% of the total weeks during the interval. A participant must have had a positive response on ≥6 weeks for the 12-week interval and ≥13 weeks for the 26-week interval, regardless of diary compliance, to be a responder. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment.
    End point type
    Secondary
    End point timeframe
    12-week interval (Weeks 1-12) and 26-week interval (Weeks 1-26)
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: percentage of participants
    number (not applicable)
        Responders during Weeks 1-12
    52.9
    54.2
    43.8
        Responders during Weeks 1-26
    45.7
    49.5
    40.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Daily Abdominal Discomfort Scores

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    End point title
    		 Change From Baseline in Daily Abdominal Discomfort Scores
    End point description
    Symptoms of abdominal discomfort were recorded on a 0 to 10 scale, where 0 corresponded to no discomfort and 10 corresponded to worst imaginable discomfort. A negative change from Baseline indicates the discomfort decreased. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (n= 392, 381, 401)
    -2.24 ± 2.204
    -2.41 ± 2.326
    -2.01 ± 2.156
        Change at Week 12 (n= 338, 335, 335)
    -2.75 ± 2.534
    -2.97 ± 2.526
    -2.61 ± 2.444
        Change at Week 26 (n= 264, 262, 264)
    -3.27 ± 2.578
    -3.52 ± 2.543
    -3.00 ± 2.579
    No statistical analyses for this end point

    Secondary: Change From Baseline in Daily Abdominal Bloating Scores

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    End point title
    		 Change From Baseline in Daily Abdominal Bloating Scores
    End point description
    Symptoms of abdominal bloating were recorded on a 0 to 10 scale, where 0 corresponded to no bloating and 10 corresponded to worst imaginable bloating. A negative change from Baseline indicates the bloating decreased. ITT analysis set included all participants who were randomized into a treatment group and presents data for participants according to their randomization assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (n= 330, 318, 329)
    -1.84 ± 2.303
    -2.03 ± 2.333
    -1.72 ± 2.303
        Change at Week 12 (n= 277, 272, 274)
    -2.42 ± 2.616
    -2.49 ± 2.533
    -2.16 ± 2.544
        Change at Week 26 n= 209, 210, 210)
    -2.76 ± 2.823
    -2.94 ± 2.576
    -2.47 ± 2.562
    No statistical analyses for this end point

    Secondary: Number of Bowel Movements per Day

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    End point title
    		 Number of Bowel Movements per Day
    End point description
    Participants recorded the number of bowel movements over 24 hours daily throughout the treatment. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: number of bowel movements
    arithmetic mean (standard deviation)
        Week 4 (n= 392, 381, 401)
    3.20 ± 2.090
    3.20 ± 2.236
    3.72 ± 2.100
        Week 12 (n= 338, 335, 335)
    3.12 ± 2.143
    3.09 ± 2.318
    3.44 ± 1.987
        Week 26 (n= 264, 262, 264)
    2.83 ± 2.158
    2.79 ± 2.270
    3.12 ± 1.831
    No statistical analyses for this end point

    Secondary: Number of Bowel Incontinence Episodes

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    End point title
    		 Number of Bowel Incontinence Episodes
    End point description
    Participants recorded the number of incontinence episodes over 24 hours daily throughout the treatment. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: incontinence episodes
    arithmetic mean (standard deviation)
        Week 4 (n= 392, 381, 401)
    0.74 ± 1.603
    0.72 ± 1.534
    0.93 ± 2.140
        Week 12 (n= 338, 335, 335)
    0.63 ± 1.542
    0.71 ± 1.663
    0.94 ± 3.612
        Week 26 (n= 264, 262, 264)
    0.46 ± 1.298
    0.58 ± 1.358
    0.69 ± 1.500
    No statistical analyses for this end point

    Secondary: Number of Bowel Incontinence Free Days

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    End point title
    		 Number of Bowel Incontinence Free Days
    End point description
    An incontinence free day is one where the participant reports zero incontinence episodes. The number of incontinence free days for a participant is assessed each week based on the number of reported days. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: days
    arithmetic mean (standard deviation)
        Week 4 (n= 392, 381, 401)
    4.83 ± 2.745
    4.95 ± 2.618
    4.63 ± 2.741
        Week 12 (n= 338, 335, 335)
    4.96 ± 2.672
    4.79 ± 2.671
    4.64 ± 2.704
        Week 26 (n= 264, 262, 264)
    4.39 ± 2.465
    4.35 ± 2.449
    4.00 ± 2.539
    No statistical analyses for this end point

    Secondary: Number of Urgency Episodes per Day

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    End point title
    		 Number of Urgency Episodes per Day
    End point description
    Participants recorded the number of urgency episodes over 24 hours daily throughout the treatment. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 26
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: episode
    arithmetic mean (standard deviation)
        Week 4 (n= 392, 381, 401)
    1.75 ± 1.840
    1.74 ± 1.879
    2.19 ± 2.082
        Week 12 (n= 338, 335, 335)
    1.55 ± 1.777
    1.60 ± 1.995
    1.81 ± 1.883
        Week 26 (n= 264, 262, 264)
    1.25 ± 1.773
    1.45 ± 2.113
    1.55 ± 1.853
    No statistical analyses for this end point

    Secondary: IBS-QoL Total Scores

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    End point title
    		 IBS-QoL Total Scores
    End point description
    The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100- point scale (0=worst; 100=better) for ease of interpretation. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 18, 26, 36, 44, and 52 (EOT)
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: score on a scale
    arithmetic mean (standard deviation)
        Responders at Week 4 (n= 384, 371, 392)
    62.37 ± 23.747
    64.34 ± 24.049
    57.13 ± 24.318
        Responders at Week 8 (n= 354, 354, 360)
    66.22 ± 23.919
    67.73 ± 23.421
    59.46 ± 24.323
        Responders at Week 12 (n= 339, 330, 342)
    66.80 ± 24.131
    68.93 ± 23.938
    61.72 ± 25.545
        Responders at Week 18 (n= 315, 312, 315)
    68.75 ± 23.902
    70.05 ± 23.662
    63.60 ± 24.618
        Responders at Week 26 (n= 288, 291 , 290)
    70.74 ± 23.312
    71.34 ± 23.106
    64.83 ± 24.380
        Responders at Week 36 (n= 277, 272, 278)
    70.53 ± 23.043
    72.37 ± 23.246
    66.47 ± 24.034
        Responders at Week 44 (n= 267, 261, 271)
    70.30 ± 24.408
    72.15 ± 24.398
    65.59 ± 25.045
        Responders at Week 52/EOT (n= 351, 353, 362)
    68.85 ± 24.754
    71.02 ± 24.294
    63.93 ± 26.359
    No statistical analyses for this end point

    Secondary: Change From Baseline in IBS-QoL Total Scores

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    End point title
    		 Change From Baseline in IBS-QoL Total Scores
    End point description
    The IBS-QoL consists of 34 items each with a 5-point response scale, where 1 generally represents better responses on items and 5 represents worse responses. The individual responses to the answered items were summed and standardized for a total score and then transformed to a 0- to 100- point scale (0=worst; 100=better) for ease of interpretation. A positive change from Baseline indicates that quality of life improved. ITT analysis set included all participants who were randomised into a treatment group and presents data for participants according to their randomisation assignment. Here, “n” indicates the number of participants who were evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 18, 26, 36, 44, and 52/EOT
    End point values
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Number of subjects analysed
    427
    426
    427
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 4 (n= 382, 371, 392)
    16.49 ± 20.693
    17.86 ± 20.191
    13.25 ± 18.475
        Change at Week 8 (n= 353, 354 , 360)
    19.88 ± 21.855
    21.08 ± 21.347
    15.76 ± 19.398
        Change at Week 12 (n= 337, 330, 342)
    20.26 ± 23.412
    22.76 ± 22.592
    17.76 ± 21.523
        Change at Week 18 (n= 313, 312, 315)
    23.09 ± 23.846
    24.18 ± 23.025
    19.80 ± 22.368
        Change at Week 26 (n= 288, 291, 290)
    25.28 ± 23.679
    25.80 ± 23.998
    20.62 ± 22.306
        Change at Week 36 (n= 277, 272, 278)
    25.37 ± 24.603
    27.18 ± 24.201
    22.64 ± 23.414
        Change at Week 44 (n= 267, 261, 271)
    25.13 ± 24.948
    26.64 ± 25.017
    21.77 ± 23.977
        Change at Week 52/EOT (n= 349, 353, 362)
    23.30 ± 23.959
    25.86 ± 23.854
    20.66 ± 23.956
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 54 weeks
    Adverse event reporting additional description
    Safety Analysis Set included participants who were enrolled in the study and received at least one dose of study drug and presents data for participants according to the actual treatment received. The number of participants in the 100-mg eluxadoline group was more than the participants who started this group due to the systematic misallocations.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Eluxadoline 75 mg
    Reporting group description
    		 Eluxadoline 75 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Eluxadoline 100 mg
    Reporting group description
    		 Eluxadoline 100 mg tablets, orally, twice daily for up to 52 weeks period.

    Reporting group title
    Placebo
    Reporting group description
    		 Eluxadoline placebo matching tablets, orally, twice daily for up to 52 weeks period.

    Serious adverse events
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 428 (5.84%)
    27 / 479 (5.64%)
    16 / 427 (3.75%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid neoplasm
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liposarcoma
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hematoma
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneousa
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 428 (0.00%)
    2 / 479 (0.42%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 428 (0.23%)
    2 / 479 (0.42%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural hematoma
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 428 (0.23%)
    2 / 479 (0.42%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Primary progressive multiple sclerosis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope vasovagal
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 428 (0.23%)
    3 / 479 (0.63%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal hemorrhagic
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemorrhoids
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 428 (0.23%)
    2 / 479 (0.42%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 428 (0.47%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 428 (0.47%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 428 (0.47%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 479 (0.00%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 479 (0.21%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 479 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eluxadoline 75 mg Eluxadoline 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 428 (19.63%)
    89 / 479 (18.58%)
    47 / 427 (11.01%)
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    27 / 428 (6.31%)
    44 / 479 (9.19%)
    12 / 427 (2.81%)
         occurrences all number
    31
    53
    12
    Nausea
         subjects affected / exposed
    34 / 428 (7.94%)
    31 / 479 (6.47%)
    19 / 427 (4.45%)
         occurrences all number
    36
    42
    21
    Vomiting
         subjects affected / exposed
    22 / 428 (5.14%)
    19 / 479 (3.97%)
    7 / 427 (1.64%)
         occurrences all number
    22
    21
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 428 (3.27%)
    25 / 479 (5.22%)
    15 / 427 (3.51%)
         occurrences all number
    17
    32
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2012
    • Duration of electronic diary collection from 12 weeks to 26 weeks was changed • Duration of electronic diary notifications for constipation, excess rescue medication usage, and participants compliance from 12 weeks to 26 weeks was changed • Daily assessment of abdominal discomfort to electronic diary collection was added • Clinic visits were scheduled for Weeks 20 and 28 to Weeks 18 and 26, respectively • Exclusion criteria for lactose intolerance and gastrointestinal infection was added • Triglycerides evaluation at Baseline was added and clarified lipase and triglyceride evaluations should be completed for any participant with confirmed or suspected pancreatitis • Clarification for use of rescue medication (loperamide extended from 12 weeks to 26 weeks), prohibited medications (added tramadol to the list), and concomitant medications (extended prohibition of concomitant medications that could interfere with the study from 12 weeks to 26 weeks)
    24 Aug 2012
    • Eligibility criteria was updated and microscopic colitis as an example of an excluded inflammatory bowel disease was added • The pregnancy reporting requirement from the start of the study to the time of the first dose of study drug was changed to be consistent with the inclusion criteria
    30 Oct 2012
    • Eligibility criteria was clarified • Clarification that the electronic diary determines whether a participant met the study entry criteria for diary compliance, loperamide rescue medication use, and averages of worst abdominal pain, BSS, and IBS-d global symptoms, but does not send a notification of eligibility to the sites • Investigators must re-verify the participants meets all inclusion/exclusion criteria at the time of randomisation • Instructions for participants to take their last dose of study drug the day before the end-of-treatment visit were added • Guidance in the event of elevation in liver enzymes, including the timing of repeat labs and the criteria for withdrawal from the study was added
    04 Dec 2013
    • Clarified that to support a potential Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA), composite responder status over 26 weeks should be considered the primary efficacy endpoint rather than the previously designated co-primary endpoints of pain responder status and global symptom responder status • Clarified that an extraction of data would occur once all participants had completed at least 26 weeks of treatment and at least 100 participants had completed 52 weeks of treatment. The protocol previously specified that an initial extraction of efficacy data would be conducted once all participants completed 12 weeks of treatment and an additional extraction of efficacy and safety data would occur when 100 participants completed 52 weeks of treatment. This change was made to minimize the number of data extractions and to eliminate any extraction prior to completion of all diary data collection in the study

    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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