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    Clinical Trial Results:
    A Phase 3, Randomized, Placebo-controlled, Multicenter, Double-blind Study to Evaluate the Safety and Efficacy of Telotristat Etiprate (LX1606) in Patients with Carcinoid Syndrome

    Summary
    EudraCT number
    		 2013-001543-31
    Trial protocol
    		 BE   DE   SE   NL   ES  
    Global end of trial date
    29 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jan 2018
    First version publication date
    27 Jan 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LX1606.1-303-CS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02063659
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, United States, 77381-1160
    Public contact
    Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon Pharmaceuticals, Inc., +1 (908) 360- 4774, plapuerta@lexpharma.com
    Scientific contact
    Pablo Lapuerta, MD, Executive Vice President and Chief Medical Officer, Lexicon Pharmaceuticals, Inc., +1 (908) 360- 4774, plapuerta@lexpharma.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 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study is to evaluate the effect of telotristat etiprate versus placebo on the incidence of treatment-emergent adverse events and on 5-hydroxyindoleacetic acid (5-HIAA) levels.
    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
    11 Mar 2014
    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
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    76
    EEA total number of subjects
    44
    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)
    41
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 31 investigative sites in Australia, Belgium, Canada, France, Germany, Israel, Netherlands, Spain, Sweden, United Kingdom, and the United States from 11 Mar 2014 to 29 Mar 2016.

    Pre-assignment
    Screening details
    		 Participants with Carcinoid Syndrome not adequately controlled by somatostatin analog (SSA) therapy were randomly assigned in a 1:1:1 ratio to receive placebo, 250 mg or 500 mg telotristat etiprate (LX1606) in the double-blind treatment period and were eligible to receive 500 mg telotristat etiprate in the open-label extension period.

    Period 1
    Period 1 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat eptiprate tablets administered three times daily for 12 weeks, followed by a 36 week open-label extension 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
    After a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat eptiprate tablets administered three times daily for 12 weeks.

    Arm title
    		 250 mg Telotristat Etiprate
    Arm description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks, followed by a 36 week open-label extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks.

    Investigational medicinal product name
    Telotristat etiprate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After a 3 to 4-week run-in period, participants were randomized to receive one telotristat etiprate (250 mg) tablet.

    Arm title
    		 500 mg Telotristat Etiprate
    Arm description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks in the 12 Week double-blind treatment period, followed by a 36 week open-label extension period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo-matching telotristat etiprate tablet administered three times daily for one week.

    Investigational medicinal product name
    Telotristat etiprate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After a 3 to 4-week run-in period, participants were randomized to receive one telotristat etiprate (250 mg) tablet administered three times daily for one week, followed by two telotristat etiprate (250 mg) tablets administered three times daily for 11 weeks.

    Number of subjects in period 1
    		Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Started
    26
    25
    25
    Completed
    24
    22
    22
    Not completed
    2
    3
    3
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    1
    2
    -
         Withdrawal of consent
    -
    1
    3
    Period 2
    Period 2 title
    Open-Label Extension Period (OLE)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Telotristat Etiprate Open-Label Extension
    Arm description
    		 Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were adminstered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo-matching telotristat etiprate tablet administered three times daily for one week.

    Investigational medicinal product name
    Telotristat etiprate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One telotristat etiprate (250) mg administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily in a 36-week open-label extension period.

    Number of subjects in period 2 [1]
    		Telotristat Etiprate Open-Label Extension
    Started
    67
    Completed
    47
    Not completed
    20
         Physician decision
    1
         Adverse event, non-fatal
    7
         Withdrawal of consent
    9
         Reason not specified
    2
         Lack of efficacy
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants who participated in the double-blind treatment period participated in the open-label extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat eptiprate tablets administered three times daily for 12 weeks, followed by a 36 week open-label extension period.

    Reporting group title
    250 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks, followed by a 36 week open-label extension period.

    Reporting group title
    500 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks in the 12 Week double-blind treatment period, followed by a 36 week open-label extension period.

    Reporting group values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate Total
    Number of subjects
    		 26 25 25 76
    Age categorical
    Units: Subjects
        <65 years
    		 12 14 15 41
        ≥65 years
    		 14 11 10 35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ± 10.32 63.6 ± 12.62 62.7 ± 11.97 -
    Gender categorical
    Units: Subjects
        Female
    		 13 11 10 34
        Male
    		 13 14 15 42
    Ethnicity
    Ethnicity data is missing for 1 subject.
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0
        Not Hispanic or Latino
    		 25 25 25 75
        No data
    		 1 0 0 1
    Race
    Race data is not available for 1 subject.
    Units: Subjects
        White
    		 25 25 23 73
        Black or African American
    		 0 0 1 1
        Asian
    		 0 0 0 0
        American Indian or Alaska Native
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Other
    		 0 0 1 1
        No data
    		 1 0 0 1
    Somatostatin Analog (SSA) Therapy Schedule at Study Entry
    Patients who were on a 2-week SSA therapy or receiving SSA therapy via a subcutaneous continuous infusion pump are included in the "4-week" category.
    Units: Subjects
        3-Week
    		 6 7 9 22
        4-Week
    		 20 15 11 46
        Not on SSA
    		 0 3 5 8
    SSA Therapy Name at Study Entry
    Units: Subjects
        Octreotide
    		 12 17 16 45
        Lanreotide
    		 14 5 3 22
        Unknown
    		 0 0 1 1
        Not applicable
    		 0 3 5 8
    Childbearing Potential
    Units: Subjects
        Yes
    		 2 4 1 7
        No
    		 11 7 9 27
        Not Applicable
    		 13 14 15 42
    Urinary 5-HIAA at Randomization
    ULN=upper limit of normal.
    Units: Subjects
        ≤ULN
    		 9 5 8 22
        >ULN
    		 17 18 17 52
        Unknown
    		 0 2 0 2
    Country
    Units: Subjects
        USA
    		 4 5 7 16
        Australia
    		 4 0 3 7
        Belgium
    		 1 2 2 5
        Canada
    		 0 1 1 2
        France
    		 1 0 0 1
        Germany
    		 3 2 2 7
        Israel
    		 2 3 2 7
        Netherlands
    		 3 2 1 6
        Spain
    		 1 5 4 10
        Sweden
    		 0 2 0 2
        United Kingdom
    		 7 3 3 13
    Region
    North America includes USA and Canada; Europe includes Belgium, France, Germany, Netherlands, Spain, Sweden, and United Kingdom; Rest of the World includes Australia and Israel.
    Units: Subjects
        North America
    		 4 6 8 18
        Europe
    		 16 16 12 44
        Rest of the World
    		 6 3 5 14
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 76.38 ± 16.959 74.74 ± 17.839 76.69 ± 26.188 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 169.48 ± 9.765 169.74 ± 10.025 170.08 ± 8.525 -
    Baseline BMI
    BMI=body mass index.
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 26.28 ± 4.364 25.96 ± 5.258 26.21 ± 9.213 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat eptiprate tablets administered three times daily for 12 weeks, followed by a 36 week open-label extension period.

    Reporting group title
    250 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks, followed by a 36 week open-label extension period.

    Reporting group title
    500 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks in the 12 Week double-blind treatment period, followed by a 36 week open-label extension period.
    Reporting group title
    Telotristat Etiprate Open-Label Extension
    Reporting group description
    		 Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were adminstered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.

    Primary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Period [1]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE was an AE reported after the first dose of randomized treatment on Day 1. Safety population, defined as all participants who received at least one dose of study drug, was used for analysis.
    End point type
    Primary
    End point timeframe
    First dose of study drug to within 30 days of last dose of study drug in the Double-Blind Period (Up to 17.1 Weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is reported for this endpoint.
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    26
    25
    25
    Units: participants
    21
    25
    22
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels

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    End point title
    		 Percent Change from Baseline in Urinary 5-hydroxyindoleacetic Acid (u5-HIAA) Levels
    End point description
    u5-HIAA is a standard test used in clinical practice to assess neuroendocrine tumor (NET) activity and is collected as a 24-hour urine specimen. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    22
    17
    19
    Units: mg/24 hours
        arithmetic mean (standard deviation)
    97.721 ± 397.0107
    -33.164 ± 58.4754
    -76.466 ± 17.3714
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the u5-HIAA at randomization. Mean difference is calculated as LX1606-Placebo.
    Comparison groups
    Placebo v 250 mg Telotristat Etiprate
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon rank sum
    Parameter type
    		 Hodges-Lehman estimator of difference
    Point estimate
    -53.955
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -84.955
         upper limit
    		 -25.119
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The primary analysis used a blocked 2-sample Wilcoxon rank sum statistic stratified by the u5-HIAA at randomization. Mean difference is calculated as LX1606-Placebo.
    Comparison groups
    Placebo v 500 mg Telotristat Etiprate
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon rank sum
    Parameter type
    		 Hodges-Lehman estimator of difference
    Point estimate
    -89.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -113.104
         upper limit
    		 -63.863

    Primary: Number of Participants with TEAEs in the Open-Label Extension Period

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    End point title
    		 Number of Participants with TEAEs in the Open-Label Extension Period [2]
    End point description
    End point type
    Primary
    End point timeframe
    First dose of study drug to within 30 days of last dose of study drug in the Open-Label Extension Period (Up to 52.6 Weeks)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is reported for this endpoint.
    End point values
    		 Telotristat Etiprate Open-Label Extension
    Number of subjects analysed
    67
    Units: participants
    61
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Number of Bowel Movements (BMs) per Day Averaged over 12 Weeks

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    End point title
    		 Change from Baseline in the Number of Bowel Movements (BMs) per Day Averaged over 12 Weeks
    End point description
    Participants recorded the number of bowel movements per day in a daily diary. The total number of BMs per day were averaged over the 12-week period. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    25
    25
    25
    Units: counts/day
        arithmetic mean (standard deviation)
    0.05 ± 0.3263
    -0.452 ± 0.694
    -0.595 ± 0.724
    No statistical analyses for this end point

    Secondary: Change from Baseline in Stool Form/Consistency Averaged Across all Time-Points

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    End point title
    		 Change from Baseline in Stool Form/Consistency Averaged Across all Time-Points
    End point description
    Participants assessed stool form/consistency of a BM using the Bristol Stool Form Scale where: 1=hard lumps to 7=watery liquid. The daily scores were averaged over the 12-week period. A negative change indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    25
    25
    25
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.006 ± 0.4127
    -0.196 ± 0.7012
    -0.597 ± 0.8605
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across all Time-Points

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    End point title
    		 Change from Baseline in the Number of Daily Cutaneous Flushing Episodes Averaged Across all Time-Points
    End point description
    Participants recorded the number daily flushing episodes per day in a daily diary. The total number of flushing episodes per day were averaged over the 12-week period. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    25
    25
    25
    Units: counts/day
        arithmetic mean (standard deviation)
    -0.333 ± 1.2203
    -0.061 ± 0.9754
    0.114 ± 2.0992
    No statistical analyses for this end point

    Secondary: Change from Baseline in Abdominal Pain Averaged Across all Time-Points

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    End point title
    		 Change from Baseline in Abdominal Pain Averaged Across all Time-Points
    End point description
    Participants recorded abdominal pain in a daily diary. Participants evaluated the level of any abdominal pain using an 11-point numeric rating scale, where: 0=no pain to 10=worst pain ever experienced. The average daily abdominal pain was averaged over the 12-week period. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    25
    25
    25
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.063 ± 0.7823
    -0.234 ± 0.9697
    0.025 ± 0.7744
    No statistical analyses for this end point

    Secondary: Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) used to Treat Carcinoid Syndrome Symptoms Averaged Across all Time-Points

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    End point title
    		 Change in the Frequency of Rescue Short-acting, Somatostatin Analog (SSA) used to Treat Carcinoid Syndrome Symptoms Averaged Across all Time-Points
    End point description
    The frequency (the number of times) the participant used rescue with SSA to control symptoms was recorded in a daily diary. The daily number of rescue treatments with SSA was averaged over the 12-week period. A negative change from Baseline (less use of SSA) indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    End point values
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    25
    25
    25
    Units: counts/day
        arithmetic mean (standard deviation)
    -0.013 ± 0.1359
    -0.065 ± 0.3542
    0.006 ± 0.103
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Number of Daily BMs Averaged over the 12- week DBT Period, among Participants who were not Receiving SSA Therapy at Baseline

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    End point title
    		 Change from Baseline in the Number of Daily BMs Averaged over the 12- week DBT Period, among Participants who were not Receiving SSA Therapy at Baseline [3]
    End point description
    Participants recorded the number of bowel movements per day in a daily diary. The total number of BMs per day were averaged over the 12-week period. A negative change from Baseline indicates improvement. Participants from the Intent-to-treat population, all randomized participants, with data available for this endpoint were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 Weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Placebo arm is not included because all participants in the Placebo arm were receiving SSA therapy at Baseline.
    End point values
    		 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate
    Number of subjects analysed
    3
    5
    Units: counts/day
        arithmetic mean (standard deviation)
    -0.906 ± 0.5925
    -0.98 ± 1.154
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to within 30 days of last dose of study drug (Up to 77.7 Weeks)
    Adverse event reporting additional description
    Data for the double-blind treatment period and the open-label extension period were analyzed separately. In the Non-Serious Adverse Event section, a result of "0" for a preferred term means that there are no participants in that arm above the 5% threshold.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 After a 3 to 4-week run-in period, participants were randomized to receive two placebo-matching telotristat eptiprate tablets administered three times daily for 12 weeks.

    Reporting group title
    250 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for 12 Weeks.

    Reporting group title
    500 mg Telotristat Etiprate
    Reporting group description
    		 Following a 3 to 4-week run-in period, participants were randomized to receive one 250 mg telotristat etiprate tablet and one placebo-matching telotristat etiprate tablet administered three times daily for one week, followed by two 250 mg telotristat etiprate tablets administered three times daily for 11 weeks.

    Reporting group title
    Telotristat Etiprate Open-Label Extension
    Reporting group description
    		 Patients previously assigned to 250 mg or 500 mg three times daily of telotristat etiprate were adminstered two 250 mg telotristat etiprate tablets three times daily in a 36 week open-label extension (OLE) period. Patients previously assigned to placebo were administered one 250 mg telotristat etiprate tablet plus one placebo-matching tablet three times daily for one week, followed by two 250 mg telotristat etiprate tablets three times daily for 35 weeks.

    Serious adverse events
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate Telotristat Etiprate Open-Label Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 26 (19.23%)
    1 / 25 (4.00%)
    3 / 25 (12.00%)
    17 / 67 (25.37%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    1 / 25 (4.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    0 / 67 (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
    Neuroendocrine tumour
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Investigations
    Diagnostic procedure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Injury, poisoning and procedural complications
    Femur fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Post procedural bile leak
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Wound secretion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Congenital, familial and genetic disorders
    Atrial septal defect
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Cardiac disorders
    Mitral valve incompetence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Urethral stent insertion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatectomy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal resection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Antibiotic prophylaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Therapeutic embolisation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    3 / 67 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Hiatus hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Ileus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Lower gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Small intestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Infections and infestations
    Escherichia bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Herpes zoster ophthalmic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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
    Metabolism and nutrition disorders
    Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 67 (1.49%)
         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: 5%
    Non-serious adverse events
    		 Placebo 250 mg Telotristat Etiprate 500 mg Telotristat Etiprate Telotristat Etiprate Open-Label Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 26 (80.77%)
    25 / 25 (100.00%)
    22 / 25 (88.00%)
    61 / 67 (91.04%)
    Investigations
    Gamma-glutamyltransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    5
    Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    4
    Vascular disorders
    Flushing
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    9 / 67 (13.43%)
         occurrences all number
    2
    3
    0
    12
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    0 / 67 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    6
    Presyncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    5
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    2 / 25 (8.00%)
    7 / 67 (10.45%)
         occurrences all number
    2
    3
    2
    7
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    7 / 67 (10.45%)
         occurrences all number
    2
    1
    0
    7
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    3
    1
    5
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    6 / 67 (8.96%)
         occurrences all number
    0
    5
    0
    13
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    7
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 26 (15.38%)
    8 / 25 (32.00%)
    1 / 25 (4.00%)
    12 / 67 (17.91%)
         occurrences all number
    5
    11
    1
    15
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 26 (19.23%)
    4 / 25 (16.00%)
    2 / 25 (8.00%)
    9 / 67 (13.43%)
         occurrences all number
    5
    4
    2
    12
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 26 (15.38%)
    3 / 25 (12.00%)
    2 / 25 (8.00%)
    14 / 67 (20.90%)
         occurrences all number
    6
    4
    2
    20
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 25 (16.00%)
    3 / 25 (12.00%)
    8 / 67 (11.94%)
         occurrences all number
    1
    5
    3
    9
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 25 (4.00%)
    2 / 25 (8.00%)
    5 / 67 (7.46%)
         occurrences all number
    3
    2
    2
    6
    Abdominal distension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    1 / 25 (4.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    3
    1
    4
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    7 / 67 (10.45%)
         occurrences all number
    0
    0
    0
    11
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    2
    1
    0
    5
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    4
    Skin and subcutaneous tissue disorders
    Night sweats
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Psychiatric disorders
    Depressed mood
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    8 / 67 (11.94%)
         occurrences all number
    0
    0
    0
    9
    Musculoskeletal and connective tissue disorders
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    1 / 25 (4.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Musculoskeletal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    5
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    4
    Infections and infestations
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    5 / 67 (7.46%)
         occurrences all number
    0
    0
    0
    5
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    6 / 67 (8.96%)
         occurrences all number
    0
    0
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2013
    Amendment 1: 1. Clarified the objectives of the study 2. Removed pharmacokinetic (PK) sampling 3. Modified study design to include dose titrations at Week 1 of the Double-blind Treatment (DBT) Period and at Week 13 of the Open-label Extension (OLE) Period to improve tolerability during the study period transitions 4. Revised study population to clarify eligible patients 5. Revised Inclusion Criterion 4 to clarify stool form/consistency entry requirement 6. Added exclusion criterion to require that patients provide a stool sample for examination for enteric pathogens, pathogenic ova or parasites, or clostridium difficile 7. Removed exclusion criterion 19 8. Added discontinuation for pregnancy to criteria for stopping treatment/study withdrawal 9. Revised criteria for termination of the study to reflect that the data safety monitoring board (DSMB) may have terminated the study if warranted 10. Revised treatment compliance to include criteria for defining a missed dose 11. Added stool sampling to the screening laboratory assessments 12. Revised serious adverse event (SAE) reporting to include an email address in case of fax failure and to remove a duplicate email address for sites outside of North America 13. Revised safety reporting of pregnancy to indicate that any patient who became pregnant during the study was to be discontinued from study drug immediately and followed through delivery or termination of the pregnancy 14. Revised efficacy analyses to reflect changes from baseline in bowel movements (BMs) for the regression models being used
    01 Feb 2014
    Amendment 2: 1. Revised wording of the primary endpoint to correctly reflect that planned analysis was to evaluate individual dose groups versus placebo for a percent change in u5-HIAA from an initial baseline value and incidence of TEAEs 2. Increased the number of study sites anticipated to participate in the study 3. Clarified entry criteria and data disposition of patients who previously failed screening for LX1606.1-301-CS 4. Provided updated information on new, ongoing, and completed studies 5. Removed the requirements of capturing individual missed doses 6. Included Depression and Sleep Assessments at each visit during the DBT Period 7. Included contact information for reporting of SAEs in Israel and Brazil 8. Updated study management to reflect that current guidance documents were to be used to conduct the study 9. Updated statistical methodology to support protocol revisions
    14 Jan 2015
    Amendment 3: 1. Modified the eligibility criteria in order to remove the QTcF exclusion criterion 2. Clarified that patients must have been taking a stable dose of SSA therapy if receiving therapy at study entry 3. Clarified the allocation of tablets and doses given during the blinded transition period to the OLE Period 4. Clarified Adverse Events of Special Interest (AESIs) 5. Clarified the manner in which responses to questions designed to detect early signs of depression were to be managed 6. Clarified definitions of AEs not related to study drug 7. Included a fifth classification for AEs: “unlikely related” 8. Further defined the criteria for reporting hospitalization as a SAE 9. Further defined how the study was to be reported

    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.
    During the open-label extension there was no placebo control, so safety results should be interpreted with caution.
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