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    Clinical Trial Results:
    A Multicenter, Long-term Extension Study to Further Evaluate the Safety and Tolerability of Telotristat Etiprate (LX1606)

    Summary
    EudraCT number
    		 2013-002596-18
    Trial protocol
    		 DE   GB   ES   SE   IT   BE  
    Global end of trial date
    12 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2019
    First version publication date
    01 Mar 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LX1606.1-302-CS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02026063
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, Texas, United States, 73301
    Public contact
    Shanna Jackson, Lexicon Pharmaceuticals, Inc., 001 281 863 3484, sjackson@lexpharma.com
    Scientific contact
    Shanna Jackson, Lexicon Pharmaceuticals, Inc., 001 281 863 3484, sjackson@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
    12 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety and tolerability of orally administered telotristat etiprate.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jan 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
    Netherlands: 9
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Israel: 7
    Worldwide total number of subjects
    124
    EEA total number of subjects
    73
    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)
    65
    From 65 to 84 years
    57
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects whose participation was ongoing in 1 of the following studies [LX1606.1-202-CS (NCT00853047), LX1606.1-203-CS (NCT01104415), LX1606.1-301-CS (NCT01677910), LX1606.1-303-CS (NCT02063659)] were eligible to enrol in this long-term safety study at the same dose received in the previous (parent) study.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Telotristat Etiprate 250 mg
    Arm description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received one telotristat etiprate (250 mg) tablet three times daily (tid) up to an additional 228 weeks in this long-term extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telotristat Etiprate
    Investigational medicinal product code
    Other name
    LX1606
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Telotristat etiprate tablet administered tid orally in this long-term extension study.

    Arm title
    		 Telotristat Etiprate 500 mg
    Arm description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received two telotristat etiprate (250 mg) tablet tid up to an additional 204 weeks in this long-term extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telotristat Etiprate
    Investigational medicinal product code
    Other name
    LX1606
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Telotristat etiprate tablet administered tid orally in this long-term extension study.

    Number of subjects in period 1
    		Telotristat Etiprate 250 mg Telotristat Etiprate 500 mg
    Started
    22
    102
    Completed
    13
    53
    Not completed
    9
    49
         Physician decision
    -
    10
         Adverse event
    5
    20
         Noncompliance with study drug
    1
    1
         Withdrawal of consent
    1
    6
         Reason not specified
    2
    7
         Lost to follow-up
    -
    1
         Lack of efficacy
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Telotristat Etiprate 250 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received one telotristat etiprate (250 mg) tablet three times daily (tid) up to an additional 228 weeks in this long-term extension study.

    Reporting group title
    Telotristat Etiprate 500 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received two telotristat etiprate (250 mg) tablet tid up to an additional 204 weeks in this long-term extension study.

    Reporting group values
    		 Telotristat Etiprate 250 mg Telotristat Etiprate 500 mg Total
    Number of subjects
    		 22 102 124
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 7.60 ) 63.4 ( 10.33 ) -
    Gender categorical
    Units: Subjects
        Female
    		 14 41 55
        Male
    		 8 61 69
    Ethnicity
    Here, Unknown= Ethnicity information not provided.
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 22 100 122
        Unknown
    		 0 1 1
    Race
    Units: Subjects
        White
    		 22 93 115
        Black or African American
    		 0 2 2
        American Indian or Alaska Native
    		 0 1 1
        Other
    		 0 6 6

    End points

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    End points reporting groups
    Reporting group title
    Telotristat Etiprate 250 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received one telotristat etiprate (250 mg) tablet three times daily (tid) up to an additional 228 weeks in this long-term extension study.

    Reporting group title
    Telotristat Etiprate 500 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received two telotristat etiprate (250 mg) tablet tid up to an additional 204 weeks in this long-term extension study.

    Subject analysis set title
    Telotristat Etiprate (All subjects)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Telotristat etiprate (250 or 500 mg) tablet administered tid up to an additional 228 weeks ( 250 mg) and an additional 204 weeks (500 mg) in this long-term extension study.

    Primary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE includes any noxious, pathological, or unintended change in anatomical, physiological, or metabolic functions as indicated by physical signs or symptoms occurring in any phase of the clinical study whether or not considered related to the study medication. Safety Population included all subjects who received any fraction of a dose of telotristat etiprate during the study.
    End point type
    Primary
    End point timeframe
    First dose of study drug (Day 1) up to 15 days post last dose (approximately up to 236 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: Statistical analyses were not planned for this endpoint.
    End point values
    		 Telotristat Etiprate 250 mg Telotristat Etiprate 500 mg
    Number of subjects analysed
    22
    102
    Units: Number of Subjects
    number (not applicable)
        TEAE
    22
    100
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) Score at Each Visit

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) Score at Each Visit
    End point description
    QLQ-C30 is a standardized 30-item scale used to assess HR-QOL and is composed of both multi-item scales and single-item measures. These included 5 functional scales physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning; 3 symptom scales (fatigue, nausea and vomiting, and pain); a global health status (GHS) /quality of life (QOL)scale; and 6 single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). Minimum and maximum values are 0 and 100 respectively. Higher score indicated higher response level. Per-Protocol (PP) population included subjects who received telotristat etiprate and had no major protocol deviations that would interfere with collection or interpretation of efficacy data. “n” is number of subjects with evaluable data at the given time-point. Subjects were combined for efficacy endpoint as the subjects received dose adjustment per investigator’s discretion.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 84
    End point values
    		 Telotristat Etiprate (All subjects)
    Number of subjects analysed
    124
    Units: Score on a scale
    arithmetic mean (standard deviation)
        GHS/QOL, Baseline (n=118)
    60.664 ( 17.4627 )
        GHS/QOL, Change at Week 24 (n=102)
    -0.980 ( 17.9878 )
        GHS/QOL, Change at Week 48 (n=88)
    -4.261 ( 17.3239 )
        GHS/QOL, Change at Week 72 (n=77)
    -1.840 ( 17.0795 )
        GHS/QOL, Change at Week 84 (n=54)
    0.309 ( 14.5660 )
        Physical functioning, Baseline (n=120)
    79.958 ( 20.3109 )
        Physical functioning, Change at Week 24 (n=103)
    -2.670 ( 13.6888 )
        Physical functioning, Change at Week 48 (n=90)
    -2.667 ( 13.2129 )
        Physical functioning, Change at Week 72 (n=78)
    -3.077 ( 14.8758 )
        Physical functioning, Change at Week 84 (n=55)
    -1.939 ( 9.8275 )
        Role functioning, Baseline (n=119)
    73.810 ( 26.9766 )
        Role functioning, Change at Week 24 (n=102)
    -4.248 ( 23.9965 )
        Role functioning, Change at Week 48 (n=89)
    -5.431 ( 27.1518 )
        Role functioning, Change at Week 72 (n=77)
    -4.329 ( 23.9399 )
        Role functioning, Change at Week 84 (n=54)
    -1.543 ( 21.5414 )
        Emotional functioning, Baseline (n=118)
    75.683 ( 21.6630 )
        Emotional functioning, Change at Week 24 (n=102)
    -1.552 ( 17.5010 )
        Emotional functioning, Change at Week 48 (n=88)
    -0.852 ( 17.5549 )
        Emotional functioning, Change at Week 72 (n=77)
    -1.623 ( 19.7313 )
        Emotional functioning, Change at Week 84 (n=54)
    3.858 ( 14.3621 )
        Cognitive functioning, Baseline (n=118)
    78.955 ( 21.7283 )
        Cognitive functioning, Change at Week 24 (n=102)
    0.000 ( 18.1668 )
        Cognitive functioning, Change at Week 48 (n=88)
    -1.515 ( 16.8830 )
        Cognitive functioning, Change at Week 72 (n=77)
    -1.299 ( 22.2568 )
        Cognitive functioning, Change at Week 84 (n=54)
    3.086 ( 18.0478 )
        Social functioning, Baseline (n=118)
    74.011 ( 24.1220 )
        Social functioning, Change at Week 24 (n=102)
    -1.797 ( 21.2258 )
        Social functioning, Change at Week 48 (n=88)
    -4.167 ( 24.5327 )
        Social functioning, Change at Week 72 (n=77)
    -1.732 ( 26.0151 )
        Social functioning, Change at Week 84 (n=54)
    -0.617 ( 20.7215 )
        Fatigue, Baseline (n=120)
    33.981 ( 24.7530 )
        Fatigue, Change at Week 24 (n=103)
    4.800 ( 21.3903 )
        Fatigue, Change at Week 48 (n=90)
    7.284 ( 20.9473 )
        Fatigue, Change at Week 72 (n=78)
    6.054 ( 19.3320 )
        Fatigue, Change at Week 84 (n=55)
    4.444 ( 17.8394 )
        Nausea and vomiting, Baseline (n=119)
    9.104 ( 13.3312 )
        Nausea and vomiting, Change at Week 24 (n=103)
    1.618 ( 15.0371 )
        Nausea and vomiting, Change at Week 48 (n=90)
    0.556 ( 14.8757 )
        Nausea and vomiting, Change at Week 72 (n=78)
    2.137 ( 20.3432 )
        Nausea and vomiting, Change at Week 84 (n=55)
    -1.212 ( 15.3339 )
        Pain, Baseline (n=120)
    26.528 ( 25.0579 )
        Pain, Change at Week 24 (n=103)
    3.722 ( 21.8845 )
        Pain, Change at Week 48 (n=90)
    6.481 ( 22.9930 )
        Pain, Change at Week 72 (n=78)
    1.709 ( 26.5351 )
        Pain, Change at Week 84 (n=55)
    -4.848 ( 22.3774 )
        Dyspnea, Baseline (n=120)
    18.611 ( 24.7474 )
        Dyspnea, Change at Week 24 (n=103)
    1.294 ( 19.7602 )
        Dyspnea, Change at Week 48 (n=89)
    5.618 ( 22.0399 )
        Dyspnea, Change at Week 72 (n=78)
    2.564 ( 21.3331 )
        Dyspnea, Change at Week 84 (n=55)
    6.667 ( 16.2288 )
        Insomnia, Baseline (n=120)
    26.389 ( 28.6307 )
        Insomnia, Change at Week 24 (n=103)
    3.560 ( 26.3679 )
        Insomnia, Change at Week 48 (n=90)
    3.704 ( 27.1144 )
        Insomnia, Change at Week 72 (n=78)
    2.564 ( 24.4827 )
        Insomnia, Change at Week 84 (n=55)
    0.000 ( 21.2762 )
        Appetite loss, Baseline (n=119)
    13.165 ( 21.3563 )
        Appetite loss, Change at Week 24 (n=102)
    3.595 ( 26.0772 )
        Appetite loss, Change at Week 48 (n=89)
    3.745 ( 21.5780 )
        Appetite loss, Change at Week 72 (n=78)
    10.256 ( 27.5543 )
        Appetite loss, Change at Week 84 (n=55)
    4.848 ( 22.6061 )
        Constipation, Baseline (n=118)
    7.345 ( 16.3854 )
        Constipation, Change at Week 24 (n=102)
    3.595 ( 18.7079 )
        Constipation, Change at Week 48 (n=88)
    0.379 ( 17.8645 )
        Constipation, Change at Week 72 (n=77)
    4.762 ( 20.7423 )
        Constipation, Change at Week 84 (n=54)
    3.086 ( 19.7134 )
        Diarrhea, Baseline (n=118)
    42.090 ( 33.3128 )
        Diarrhea, Change at Week 24 (n=102)
    1.961 ( 29.9701 )
        Diarrhea, Change at Week 48 (n=88)
    5.682 ( 34.7300 )
        Diarrhea, Change at Week 72 (n=76)
    3.947 ( 32.1879 )
        Diarrhea, Change at Week 84 (n=53)
    0.000 ( 31.3513 )
        Financial difficulties, Baseline (n=118)
    18.079 ( 28.1240 )
        Financial difficulties, Change at Week 24 (n=102)
    -0.327 ( 15.9034 )
        Financial difficulties, Change at Week 48 (n=87)
    1.533 ( 19.6270 )
        Financial difficulties, Change at Week 72 (n=77)
    0.433 ( 25.0692 )
        Financial difficulties, Change at Week 84 (n=54)
    -1.235 ( 19.3857 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Gastrointestinal Symptoms of Carcinoid Neuroendocrine Tumors (GI.NET21) Score at Each Visit

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    End point title
    		 Change From Baseline in Gastrointestinal Symptoms of Carcinoid Neuroendocrine Tumors (GI.NET21) Score at Each Visit
    End point description
    GI.NET21 is a standardized 21-item scale composed of both multi-item scales and single-item measures. These included 5 functional scales gastrointestinal (GI), endocrine, treatment-related, social functioning, and disease related worries scale (DRWS), and 4 single items (muscle and bone pain symptom (BPS), sexual functioning, communication function (CF), body image and information about the disease). The minimum and maximum values are 1 and 4, respectively. A higher score indicated worst outcome. PP population included the subjects who received telotristat etiprate and had no major protocol deviations that would interfere with the collection or interpretation of the efficacy data. “n” is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 24, 48, 72 and 84
    End point values
    		 Telotristat Etiprate (All subjects)
    Number of subjects analysed
    124
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Endocrine scale, Baseline (n=120)
    25.000 ( 20.6367 )
        Endocrine scale, Change at Week 24 (n=103)
    1.726 ( 15.8483 )
        Endocrine scale, Change at Week 48 (n=90)
    1.111 ( 17.0717 )
        Endocrine scale, Change at Week 72 (n=78)
    1.425 ( 19.8082 )
        Endocrine scale, Change at Week 84 (n=54)
    4.938 ( 21.2213 )
        GI symptoms scale, Baseline (n=120)
    25.014 ( 17.9343 )
        GI symptoms scale, Change at Week 24 (n=103)
    3.576 ( 14.9243 )
        GI symptoms scale, Change at Week 48 (n=90)
    3.759 ( 16.7890 )
        GI symptoms scale , Change at Week 72 (n=78)
    1.581 ( 19.0823 )
        GI symptoms scale, Change at Week 84 (n=54)
    -0.278 ( 17.3137 )
        Treatment scale, Baseline (n=101)
    10.176 ( 14.6370 )
        Treatment scale, Change at Week 24 (n=80)
    -0.486 ( 13.7849 )
        Treatment scale, Change at Week 48 (n=66)
    1.684 ( 14.0873 )
        Treatment scale, Change at Week 72 (n=58)
    0.575 ( 18.8668 )
        Treatment scale, Change at Week 84 (n=35)
    2.063 ( 20.4384 )
        Social function scale, Baseline (n=120)
    32.037 ( 22.8748 )
        Social function scale, Change at Week 24 (n=103)
    3.128 ( 16.4229 )
        Social function scale, Change at Week 48 (n=90)
    2.160 ( 22.4658 )
        Social function scale, Change at Week 72 (n=77)
    1.587 ( 21.3052 )
        Social function scale, Change at Week 84 (n=54)
    0.000 ( 18.4415 )
        DRWS, Baseline (n=120)
    36.713 ( 26.9224 )
        DRWS, Change at Week 24 (n=103)
    1.456 ( 20.4932 )
        DRWS, Change at Week 48 (n=90)
    -1.049 ( 22.5767 )
        DRWS, Change at Week 72 (n=77)
    -0.289 ( 26.5962 )
        DRWS, Change at Week 84 (n=54)
    -3.601 ( 22.4868 )
        Muscle and BPS, Baseline (n=120)
    30.833 ( 27.7250 )
        Muscle and BPS, Change at Week 24 (n=102)
    -3.268 ( 21.7546 )
        Muscle and BPS, Change at Week 48 (n=90)
    7.407 ( 31.9088 )
        Muscle and BPS, Change at Week 72 (n=76)
    -1.316 ( 25.2048 )
        Muscle and BPS, Change at Week 84 (n=54)
    2.469 ( 24.9543 )
        Sexual function, Baseline (n=91)
    30.769 ( 36.5928 )
        Sexual function, Change at Week 24 (n=62)
    2.151 ( 29.4893 )
        Sexual function , Change at Week 48 (n=58)
    -2.299 ( 24.0711 )
        Sexual function, Change at Week 72 (n=51)
    -3.922 ( 24.6280 )
        Sexual function, Change at Week 84 (n=36)
    -1.852 ( 19.4274 )
        Information and CF, Baseline (n=120)
    2.500 ( 9.8186 )
        Information and CF, Change at Week 24 (n=103)
    3.236 ( 17.1591 )
        Information and CF, Change at Week 48 (n=90)
    0.741 ( 13.1995 )
        Information and CF, Change at Week 72 (n=77)
    1.299 ( 13.7241 )
        Information and CF, Change at Week 84 (n=54)
    5.556 ( 25.6978 )
        Body image, Baseline (n=119)
    11.765 ( 21.5187 )
        Body image, Change at Week 24 (n=100)
    6.333 ( 24.4789 )
        Body image, Change at Week 48 (n=89)
    5.618 ( 23.1573 )
        Body image, Change at Week 72 (n=76)
    6.579 ( 28.8134 )
        Body image, Change at Week 84 (n=53)
    3.774 ( 27.4721 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adequate Relief as per Subjective Global Assessment Question

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    End point title
    		 Percentage of Subjects with Adequate Relief as per Subjective Global Assessment Question
    End point description
    Subjects were asked to respond to the following question: “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain, or discomfort? The percentage of subjects reporting adequately (answered Yes) were reported. PP population included the subjects who received telotristat etiprate and had no major protocol deviations that would interfere with the collection or interpretation of the efficacy data. “n” is the number of subjects with evaluable data at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72 and 84
    End point values
    		 Telotristat Etiprate (All subjects)
    Number of subjects analysed
    124
    Units: Percentage of subjects
    number (not applicable)
        Baseline (n=99)
    61.6
        Week 12 (n=106)
    64.2
        Week 24 (n=104)
    52.9
        Week 36 (n=95)
    57.9
        Week 48 (n=95)
    61.1
        Week 60 (n=89)
    55.1
        Week 72 (n=77)
    58.4
        Week 84 (n=55)
    67.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Subjective Global Assessment of Carcinoid Syndrome Symptoms on 11-Point Numeric Scale at Each Visit

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    End point title
    		 Change From Baseline in Subjective Global Assessment of Carcinoid Syndrome Symptoms on 11-Point Numeric Scale at Each Visit
    End point description
    Subjects were asked the following question to assess global symptoms associated with carcinoid syndrome (CS) on an 11-point scale: “Rate the severity of your overall carcinoid symptoms over the past 7 days on a scale from 0 to 10, where 0=no symptoms and 10=worst symptoms ever experienced. A negative change from baseline indicated improvement. PP population included the subjects who received telotristat etiprate and had no major protocol deviations that would interfere with the collection or interpretation of the efficacy data. “n” is the number of subjects with evaluable data at the given time-point. Subjects were combined for efficacy endpoint as the majority of subjects received telotristat etiprate 500 mg.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72 and 84
    End point values
    		 Telotristat Etiprate (All subjects)
    Number of subjects analysed
    124
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=92)
    3.022 ( 1.9214 )
        Change at Week 12 (n=86)
    0.558 ( 2.4428 )
        Change at Week 24 (n=78)
    0.654 ( 2.2553 )
        Change at Week 36 (n=73)
    0.630 ( 2.2944 )
        Change at Week 48 (n=71)
    1.056 ( 2.5684 )
        Change at Week 60 (n=66)
    0.576 ( 1.9773 )
        Change at Week 72 (n=60)
    0.483 ( 2.2661 )
        Change at Week 84 (n=45)
    0.644 ( 2.2172 )
    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 (Day 1) up to 15 days post last dose (approximately up to 236 Weeks)
    Adverse event reporting additional description
    Safety population included all subjects who received any fraction of a dose of telotristat etiprate during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Telotristat Etiprate 250 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received one telotristat etiprate (250 mg) tablet tid up to an additional 228 weeks in this long-term extension study.

    Reporting group title
    Telotristat Etiprate 500 mg
    Reporting group description
    		 Subjects were treated with telotristat etiprate in a previous study for 9 to 46 months. Subjects received two telotristat etiprate (250 mg) tablet tid up to an additional 204 weeks in this long-term extension study.

    Serious adverse events
    		 Telotristat Etiprate 250 mg Telotristat Etiprate 500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 22 (54.55%)
    54 / 102 (52.94%)
         number of deaths (all causes)
    2
    18
         number of deaths resulting from adverse events
    2
    18
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Investigation
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 102 (3.92%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid tumour
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to testicle
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic carcinoid tumour
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Radiotherapy
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileocolectomy
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 22 (9.09%)
    11 / 102 (10.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    General physical health deterioration
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Complication of device insertion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laparoscopy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 102 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Localised intraabdominal fluid collection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute hepatic failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cholangitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoid crisis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondritis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Telotristat Etiprate 250 mg Telotristat Etiprate 500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    100 / 102 (98.04%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroendocrine tumour
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 102 (4.90%)
         occurrences all number
    8
    6
    Vascular disorders
    Flushing
         subjects affected / exposed
    4 / 22 (18.18%)
    13 / 102 (12.75%)
         occurrences all number
    8
    18
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
    13 / 102 (12.75%)
         occurrences all number
    1
    16
    Surgical and medical procedures
    Radiotherapy
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 102 (1.96%)
         occurrences all number
    10
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 22 (18.18%)
    28 / 102 (27.45%)
         occurrences all number
    4
    37
    Pyrexia
         subjects affected / exposed
    1 / 22 (4.55%)
    20 / 102 (19.61%)
         occurrences all number
    1
    25
    Disease progression
         subjects affected / exposed
    2 / 22 (9.09%)
    16 / 102 (15.69%)
         occurrences all number
    2
    21
    Oedema periphera
         subjects affected / exposed
    1 / 22 (4.55%)
    17 / 102 (16.67%)
         occurrences all number
    1
    19
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    15 / 102 (14.71%)
         occurrences all number
    0
    26
    Chest discomfort
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 102 (1.96%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 22 (13.64%)
    11 / 102 (10.78%)
         occurrences all number
    3
    15
    Cough
         subjects affected / exposed
    2 / 22 (9.09%)
    10 / 102 (9.80%)
         occurrences all number
    2
    10
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 22 (9.09%)
    11 / 102 (10.78%)
         occurrences all number
    4
    14
    Depressed mood
         subjects affected / exposed
    0 / 22 (0.00%)
    9 / 102 (8.82%)
         occurrences all number
    0
    15
    Insomnia
         subjects affected / exposed
    1 / 22 (4.55%)
    8 / 102 (7.84%)
         occurrences all number
    1
    8
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 22 (4.55%)
    15 / 102 (14.71%)
         occurrences all number
    1
    18
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 102 (2.94%)
         occurrences all number
    3
    3
    Investigation
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 102 (2.94%)
         occurrences all number
    6
    7
    Blood glucose increased
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 102 (0.98%)
         occurrences all number
    4
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 22 (4.55%)
    10 / 102 (9.80%)
         occurrences all number
    1
    10
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
    10 / 102 (9.80%)
         occurrences all number
    1
    13
    Syncope
         subjects affected / exposed
    1 / 22 (4.55%)
    10 / 102 (9.80%)
         occurrences all number
    1
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 22 (9.09%)
    11 / 102 (10.78%)
         occurrences all number
    2
    17
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 22 (40.91%)
    35 / 102 (34.31%)
         occurrences all number
    16
    73
    Nausea
         subjects affected / exposed
    5 / 22 (22.73%)
    36 / 102 (35.29%)
         occurrences all number
    19
    49
    Abdominal pain
         subjects affected / exposed
    3 / 22 (13.64%)
    37 / 102 (36.27%)
         occurrences all number
    4
    74
    Constipation
         subjects affected / exposed
    3 / 22 (13.64%)
    22 / 102 (21.57%)
         occurrences all number
    6
    30
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    24 / 102 (23.53%)
         occurrences all number
    6
    32
    Abdominal pain upper
         subjects affected / exposed
    2 / 22 (9.09%)
    13 / 102 (12.75%)
         occurrences all number
    2
    18
    Flatulence
         subjects affected / exposed
    1 / 22 (4.55%)
    7 / 102 (6.86%)
         occurrences all number
    1
    7
    Abdominal distension
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    8
    Small intestinal obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    9
    Glossodynia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 102 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    8 / 102 (7.84%)
         occurrences all number
    0
    8
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    8
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 102 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 22 (0.00%)
    17 / 102 (16.67%)
         occurrences all number
    0
    18
    Arthralgia
         subjects affected / exposed
    1 / 22 (4.55%)
    15 / 102 (14.71%)
         occurrences all number
    1
    18
    Musculoskeletal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    8 / 102 (7.84%)
         occurrences all number
    0
    9
    Flank pain
         subjects affected / exposed
    1 / 22 (4.55%)
    6 / 102 (5.88%)
         occurrences all number
    1
    7
    Pain in extremity
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 102 (4.90%)
         occurrences all number
    2
    5
    Neck pain
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 102 (3.92%)
         occurrences all number
    3
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 22 (9.09%)
    9 / 102 (8.82%)
         occurrences all number
    4
    14
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    9 / 102 (8.82%)
         occurrences all number
    2
    10
    Influenza
         subjects affected / exposed
    2 / 22 (9.09%)
    8 / 102 (7.84%)
         occurrences all number
    2
    8
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 22 (13.64%)
    13 / 102 (12.75%)
         occurrences all number
    4
    15
    Dehydration
         subjects affected / exposed
    0 / 22 (0.00%)
    7 / 102 (6.86%)
         occurrences all number
    0
    7
    Hypokalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    8
    Vitamin D deficiency
         subjects affected / exposed
    0 / 22 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2014
    The following changes were made in the protocol amendment 1: 1. Study name modified to remove “symptoms” consistent with the secondary objective. 2. Modified text to specify that up to 100 subjects were expected to participate in this study. 3. Modified Synopsis and Treatments section. 4. Modified the Clinical Trials of TE in Humans section to reflect the most current data. 5. Modified Benefit/Risk section to clarify a reduction in serotonin, decreased the risk of carcinoid heart disease. 6. Modified Criteria for Stopping Treatment/Study Withdrawal section to clarify patient responsibilities. 7. Modified Dose Adjustment section to clarify dose adjustment. 8. Modified the Study Procedures to remove reference to study visits. 9. Modified the Efficacy Assessments section to indicate EORTC QLQ-C30 and GI.NET21 and the subjective global assessment were quality of life (QOL) measurements. 10. Modified Study Procedures, Depression Detection to include parameters for depression. 11. Revise definitions of AEs and SAEs. 12. Modified Ethical Standards, General Instructions section to reflect current guidance documents were used. 13. Modified Schedule of Assessments table to include weight with all physical examinations (including brief symptom oriented examinations); added urine pregnancy test to be conducted for females of childbearing potential at Weeks 12, 24, and 36; and added sleep and depression assessments to be captured at every visit, including the 2-Week Follow-up Visit.
    08 Oct 2014
    The following changes were made in the protocol amendment 2: 1. Modified Duration of Participation section in Synopsis to 86 weeks. 2. Modified Synopsis exclusion criterion (number 1) and Study Populations sections 3. Modified the Clinical Trials of Telotristat Etiprate in Humans section 4. Modified the Phase 1 and Phase 2 Studies section to reflect a recently completed Phase 1 and Phase 2 study. 5. Modified the Benefit/Risk Assessment section. 8. Modified the Study Population, Inclusion Criteria section. 9. Modified Study Population. 10.Modified Treatment – Concomitant Medication section. 11. Modified Study Procedures –Vital Sign Measurements section to remove the requirement to capture blood pressure measurement by using Sponsor-provided equipment. 12. Modified the Safety Reporting, SAE section bullet number 3, to include reference to a new section defining hospitalization as an SAE. 13. Inserted Safety Reporting. 14. Modified Statistical Methodology – Interim analysis section. 15. Modified Schedule of Assessments to show dispensation of LX1606 at Week 48; removal of EOS from Week 48; removal of serum pregnancy testing from the study; added urine pregnancy test to be conducted for females of childbearing potential at all study weeks; added Week 60, Week 72, and Week 84/EOS Visits; and updated the footnote to reflect the new EOS Visit. 16. Modified Appendix B, Amount of Blood to be Collected from Each subject to reflect the estimated volume of blood collected based upon changes in the Schedule of Assessments table.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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