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    Clinical Trial Results:
    Double blind, Randomised, Placebo Controlled Clinical Trial Investigating the Efficacy and Safety of Somatuline Depot (Lanreotide) Injection in the Treatment of Carcinoid Syndrome

    Summary
    EudraCT number
    		 2010-019066-92
    Trial protocol
    		 CZ   LV   PL  
    Global end of trial date
    15 Dec 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2-55-52030-730
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00774930
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 TR321: TR321
    Sponsors
    Sponsor organisation name
    Ipsen Pharma SAS
    Sponsor organisation address
    65 quai Georges Gorse, Boulogne Billancourt Cedex, France, 92100
    Public contact
    Medical Director, Oncology, Ipsen Pharma SAS, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Oncology, Ipsen Pharma SAS, clinical.trials@ipsen.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
    15 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lanreotide Autogel (Somatuline Depot) subcutaneous (s.c.) injections administered every 4 weeks (± 3 days) for the control of symptoms associated with carcinoid syndrome (diarrhoea and/or flushing) as compared to placebo, measured by the usage of subcutaneous octreotide as rescue medication to control symptoms.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, and in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice. All national and local regulatory requirements were also adhered to.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 40
    Country: Number of subjects enrolled
    Latvia: 2
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Ukraine: 25
    Country: Number of subjects enrolled
    Czech Republic: 3
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    India: 8
    Country: Number of subjects enrolled
    Brazil: 18
    Worldwide total number of subjects
    115
    EEA total number of subjects
    6
    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)
    78
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with a history of carcinoid syndrome were enrolled into this multi-site, 3 phase study from 26 May 2009. There was a 16 week double-blind phase, a 32 week open-label phase, and long-term open-label extension. The last patient completed the double-blind phase on 6 May 2013, and the open-label extension on 15 December 2015.

    Pre-assignment
    Screening details
    		 153 patients were screened, and 115 patients met all inclusion criteria and none of the exclusion criteria to be randomised to the double-blind phase.

    Period 1
    Period 1 title
    Double-blind phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lanreotide Autogel
    Arm description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Somatuline Depot
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered lanreotide Autogel 120 mg deep s.c. injection every 4 weeks if randomised to receive this treatment in the double-blind phase, in the initial open-label phase and in the long-term open-label extension.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered placebo deep s.c. injection every 4 weeks during the double-blind phase. Placebo consisted of 0.9% saline solution administered in a similar volume to the lanreotide Autogel injection.

    Number of subjects in period 1
    		Lanreotide Autogel Placebo
    Started
    59
    56
    Completed
    45
    34
    Not completed
    14
    22
         Patient decision
    1
    5
         Disease progression
    1
    1
         Adverse event, non-fatal
    1
    2
         Early rollover to open-label phase
    11
    12
         Sponsor decision
    -
    1
         Started non-protocol radiation therapy
    -
    1
    Period 2
    Period 2 title
    Initial open-label phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lanreotide Autogel
    Arm description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Somatuline Depot
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered lanreotide Autogel 120 mg deep s.c. injection every 4 weeks if randomised to receive this treatment in the double-blind phase, in the initial open-label phase and in the long-term open-label extension.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Somatuline Depot
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered lanreotide Autogel 120 mg deep s.c. injection every 4 weeks if randomised to receive this treatment in the double-blind phase, in the initial open-label phase and in the long-term open-label extension.

    Number of subjects in period 2 [1]
    		Lanreotide Autogel Placebo
    Started
    45
    33
    Completed
    43
    37
    Not completed
    13
    8
         Patient decision
    4
    3
         Disease progression
    2
    1
         Adverse event, non-fatal
    1
    1
         Not specified
    1
    -
         Peptide Receptor Radionuclide Therapy
    -
    1
         Investigator decision
    3
    2
         Sponsor decision
    1
    -
         Patient consumed prohibited medication
    1
    -
    Joined
    11
    12
         Early rollover to open-label phase
    11
    12
    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: One patient in the placebo arm completed the double-blind treatment phase but did not enter the initial open-label phase.
    Period 3
    Period 3 title
    Long-term open-label extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lanreotide Autogel
    Arm description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Somatuline Depot
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered lanreotide Autogel 120 mg deep s.c. injection every 4 weeks if randomised to receive this treatment in the double-blind phase, in the initial open-label phase and in the long-term open-label extension.

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Lanreotide Autogel
    Investigational medicinal product code
    Lanreotide Autogel 120 mg
    Other name
    Somatuline Depot
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered lanreotide Autogel 120 mg deep s.c. injection every 4 weeks if randomised to receive this treatment in the double-blind phase, in the initial open-label phase and in the long-term open-label extension.

    Number of subjects in period 3 [2]
    		Lanreotide Autogel Placebo
    Started
    32
    25
    Completed
    17
    8
    Not completed
    15
    17
         Patient decision
    -
    5
         Disease progression
    2
    5
         Adverse event, non-fatal
    7
    3
         Proton Pump Inhibitor Dose Adjusted
    -
    1
         Tumour Progression of Hepatic Metastases
    -
    1
         Investigator decision
    4
    1
         Sponsor decision
    2
    1
    Notes
    [2] - 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: The long-term open-label extension allowed for the continued provision of lanreotide Autogel to eligible patients in which lanreotide Autogel was not yet approved, as such not all patients who completed the initial open-label phase entered the long-term open-label extension.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lanreotide Autogel
    Reporting group description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Reporting group values
    		 Lanreotide Autogel Placebo Total
    Number of subjects
    		 59 56 115
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 43 35 78
        From 65-84 years
    		 16 20 36
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ( 10.6 ) 59.3 ( 11.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 32 35 67
        Male
    		 27 21 48
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 6 3 9
        Black/African American
    		 2 3 5
        White
    		 44 44 88
        Multi-race
    		 7 6 13

    End points

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    End points reporting groups
    Reporting group title
    Lanreotide Autogel
    Reporting group description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Reporting group title
    Lanreotide Autogel
    Reporting group description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.
    Reporting group title
    Lanreotide Autogel
    Reporting group description
    		 Patients were randomised to receive lanreotide Autogel 120 milligrams (mg) deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks). Eligible patients then entered the initial open-label phase in which they received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. In the long-term open-label extension, patients continued to receive lanroetide Autogel 120 mg deep s.c. every 4 weeks.

    Subject analysis set title
    Lanreotide (Double-blind phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients were randomised to receive lanreotide Autogel 120 mg deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks).

    Subject analysis set title
    Placebo (Double-blind phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks).

    Subject analysis set title
    Lanreotide (Initial Open-label phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All eligible patients who continued into the initial open-label phase received lanreotide Autogel 120 mg deep s.c. every 4 weeks for 32 weeks. Analysis set includes patients who were randomised to either lanreotide or placebo in the double-blind phase.

    Subject analysis set title
    Lanreotide (Long-term Open-label extension)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In the long-term open-label extension, eligible patients continued to receive lanreotide Autogel 120 mg deep s.c. every 4 weeks. Analysis set includes patients who were randomised to either lanreotide or placebo in the double-blind phase.

    Primary: Percentage of days with s.c. octreotide as rescue medication during the double-blind phase

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    End point title
    		 Percentage of days with s.c. octreotide as rescue medication during the double-blind phase
    End point description
    Patients were required to record daily, using the Interactive Voice Response System/ Interactive Web Response System (IVRS/IWRS), the number of diarrhoea and/or flushing events per day as well as the use and dose of s.c. octreotide, if any, as rescue medication. The number of days in which s.c. octreotide was used as a rescue medication during the double-blind phase to control symptoms associated with carcinoid syndrome was determined as a measure of lanreotide efficacy. The least squares (LS) mean percentage of days with s.c. octreotide as rescue medication during the 16 week double-blind phase is presented. The Intention-to-Treat (ITT) population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group.
    End point type
    Primary
    End point timeframe
    Day 1 (Week 0) to end of Week 16.
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    59
    56
    Units: percentage of days
        least squares mean (confidence interval 95%)
    33.72 (25.02 to 42.42)
    48.49 (39.57 to 57.40)
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An Analysis of Covariance (ANCOVA) model was used to test whether there was a difference between the placebo and treatment groups in the usage of s.c. ocreotide required to control symptoms associated with carcinoid syndrome. The ANCOVA model used 2 stratification variables at randomisation (study site, and prior somatostatin analogue therapy), and 2 baseline covariates (baseline average daily frequency of diarrhoea and flushing events).
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0165
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -14.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.78
         upper limit
    		 -2.75

    Secondary: Average daily frequency of diarrhoea events during the double-blind phase

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    End point title
    		 Average daily frequency of diarrhoea events during the double-blind phase
    End point description
    The mean frequency of diarrhoea events (per day) during the 16 week double-blind phase based on patient IVRS/IWRS diary records is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Week 0) to end of Week 16.
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    59
    56
    Units: number of events
        arithmetic mean (standard deviation)
    1.56 ( 1.83 )
    1.35 ( 1.45 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline average daily frequency of diarrhoea was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2544
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.15

    Secondary: Average daily frequency of flushing events during the double-blind phase

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    End point title
    		 Average daily frequency of flushing events during the double-blind phase
    End point description
    The mean frequency of flushing events (per day) during the 16 week double-blind phase based on patient IVRS/IWRS diary records is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Week 0) to end of Week 16.
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    59
    56
    Units: number of events
        arithmetic mean (standard deviation)
    0.92 ( 1.45 )
    1.75 ( 2.26 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline average daily frequency of flushing events was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0229
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 -0.06

    Secondary: Percentage of days of use of other rescue medication during the double-blind phase

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    End point title
    		 Percentage of days of use of other rescue medication during the double-blind phase
    End point description
    Patients were required to record daily, using the IVRS/IWRS, the number of diarrhoea and/or flushing events per day as well as the use and dose of s.c. octreotide, if any, as well as the use of other concomitant rescue medications. The number of days in which rescue medications other than s.c. ocreotide were used during the double-blind phase to control symptoms associated with carcinoid syndrome was determined as a measure of lanreotide efficacy. The mean percentage of days with other rescue medication use during the 16 week double-blind phase is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Week 0) to end of Week 16.
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    59
    56
    Units: Percentage of days
        arithmetic mean (standard deviation)
    8.86 ( 19.34 )
    6.25 ( 17.48 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model including baseline usage of other rescue medications and baseline average daily frequencies of diarrhoea and flushing events.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8627
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.68
         upper limit
    		 5.57

    Secondary: Percentage of patients who rolled over into the initial open-label phase before completing the double-blind phase.

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    End point title
    		 Percentage of patients who rolled over into the initial open-label phase before completing the double-blind phase.
    End point description
    The percentage of patients with an early rollover (ERO) into the initial open-label phase before completion of the 16 week double-blind phase is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 (Week 0) to end of Week 16.
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    59
    56
    Units: Percentage of patients
        number (not applicable)
    18.6
    21.4
    Statistical analysis title
    		 Proportion of ERO patients
    Statistical analysis description
    Odds Ratio (reference: Placebo) adjusted for stratification factors was based on a Logistic Regression model.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 2.1

    Secondary: Change from baseline in Global Health Status/Quality of Life Score at Week 12 of the double-blind phase using the European Organisation for the Research and Treatment of Cancer Quality of life Questionnaire (EORTC QLQ)-C30 Module

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    End point title
    		 Change from baseline in Global Health Status/Quality of Life Score at Week 12 of the double-blind phase using the European Organisation for the Research and Treatment of Cancer Quality of life Questionnaire (EORTC QLQ)-C30 Module
    End point description
    The EORTC QLQ-C30 Module was used to measure the Global Health Status/Quality of Life score at baseline and every 12 weeks during the double-blind phase and initial open-label phase, and then every 24 weeks during the long-term open-label extension. The Global Health Status/Quality of Life dimension of the EORTC QLQ-C30 score (based on Items 29 and 30) ranged from 1 (very poor) to 7 (excellent), and the responses were transformed to range from 0 (worst) to 100 (best) according to the EORTC scoring instructions. The mean change from baseline at Week 12 of the double-blind phase in the Global Health Status/Quality of Life dimension score is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group. Only patients with no missing data are included.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Baseline) and 4 (Week 12).
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    48
    34
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4.17 ( 14.18 )
    -1.72 ( 18.21 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline Global Health Status/Quality of Life score was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1931
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    4.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.09
         upper limit
    		 10.2

    Secondary: Change from baseline in the Gastrointestinal (GI) Symptoms Subscore at Week 12 of the double-blind phase using the EORTC QLQ Carcinoid/Neuroendocrine tumours (GI.NET21) Module

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    End point title
    		 Change from baseline in the Gastrointestinal (GI) Symptoms Subscore at Week 12 of the double-blind phase using the EORTC QLQ Carcinoid/Neuroendocrine tumours (GI.NET21) Module
    End point description
    The EORTC QLQ-GI.NET21 Module was used to measure the GI symptoms subscore at baseline and every 12 weeks during the double-blind phase and initial open-label phase, and then every 24 weeks during the long-term open-label extension. The EORTC QLQ-GI.NET21 questionnaire contains 21 items (Items 31 to 51), each with a response ranging from 1 (worst) to 4 (best) for the extent to which the patient has experienced the detailed problem/symptom in the past week. Responses were transformed to range from 0 (worst) to 100 (best) according to the EORTC scoring instructions. The mean change from baseline at Week 12 of the double-blind phase in the GI symptoms subscore (based on items Q34 - Q38 only) is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group. Only patients with no missing data are included.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Baseline) and 4 (Week 12).
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    48
    33
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -4.06 ( 12.80 )
    0.10 ( 13.83 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline EORTC QLQ-GI.NET21 GI subscore was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0632
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -4.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.63
         upper limit
    		 0.26

    Secondary: Change from baseline in the Endocrine Symptoms Subscore at Week 12 of the double-blind phase using the EORTC QLQ-GI.NET21 Module

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    End point title
    		 Change from baseline in the Endocrine Symptoms Subscore at Week 12 of the double-blind phase using the EORTC QLQ-GI.NET21 Module
    End point description
    The EORTC QLQ-GI.NET21 Module was used to measure the endocrine symptoms subscore at baseline and every 12 weeks during the double-blind phase and initial open-label phase, and then every 24 weeks during the long-term open-label extension. The EORTC QLQ-GI.NET21 questionnaire contains 21 items, each with a response ranging from 1 (worst) to 4 (best) for the extent to which the patient has experienced the detailed problem/symptom in the past week. Responses were transformed to range from 0 (worst) to 100 (best) according to the EORTC scoring instructions. The mean change from baseline at Week 12 of the double-blind phase in the endocrine symptoms subscore (based on items Q31 - Q33 only) is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group. Only patients with no missing data are included.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Baseline) and 4 (Week 12).
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    48
    33
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -6.83 ( 18.98 )
    -2.69 ( 22.23 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline EORTC QLQ-GI.NET21 endocrine symptoms subscore was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.075
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -7.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 0.73

    Secondary: Absolute change from baseline in plasma Chromogranin A (CgA) at Week 12 during the double-blind phase

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    End point title
    		 Absolute change from baseline in plasma Chromogranin A (CgA) at Week 12 during the double-blind phase
    End point description
    Plasma CgA levels were evaluated as a biochemical marker of NETs. The mean change in plasma CgA level from baseline at Week 12 of the double-blind phase is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group. Only patients with no missing data are included.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Baseline) and 4 (Week 12).
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    41
    28
    Units: micrograms per litre
        arithmetic mean (standard deviation)
    1125.8 ( 12579.4 )
    801.5 ( 2294.0 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline CgA levels was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2695
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -2147.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6574.03
         upper limit
    		 2278.14

    Secondary: Absolute change from baseline in urinary 5-hydroxyindoleacetic acid (5-HIAA) at Week 12 during the double-blind phase

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    End point title
    		 Absolute change from baseline in urinary 5-hydroxyindoleacetic acid (5-HIAA) at Week 12 during the double-blind phase
    End point description
    Urinary 5-HIAA levels were evaluated as a biochemical marker of NETs. The mean change in urinary 5-HIAA level from baseline at Week 12 of the double-blind phase is presented. The ITT population consisted of all randomised patients (regardless of whether the patients received or adhered to the allocated treatment group). Patients from the ITT population were analysed under the randomised treatment group. Only patients with no missing data are included.
    End point type
    Secondary
    End point timeframe
    Visits 1 (Baseline) and 4 (Week 12).
    End point values
    		 Lanreotide Autogel Placebo
    Number of subjects analysed
    39
    27
    Units: micromol per decilitre (micromol/dL)
        arithmetic mean (standard deviation)
    -201.4 ( 1009.9 )
    36.3 ( 142.3 )
    Statistical analysis title
    		 Treatment difference (Lanreotide - Placebo)
    Statistical analysis description
    An ANCOVA model adjusted for stratification factors and baseline 5-HIAA levels was used.
    Comparison groups
    Lanreotide Autogel v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5787
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -39.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -202.28
         upper limit
    		 123.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the time of informed consent until the exit visit (up to 16 weeks for the double-blind phase, 32 weeks for the initial open-label phase and at least 2 years in the long-term open-label phase).
    Adverse event reporting additional description
    The safety population consisted of all randomised patients who received at least 1 injection of study treatment. Subjects were anlysed under the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo (Double-blind phase)
    Reporting group description
    		 Patients were randomised to receive placebo deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks).

    Reporting group title
    Lanreotide (Double-blind phase)
    Reporting group description
    		 Patients were randomised to receive lanreotide Autogel 120 mg deep s.c. injections administered every 4 weeks (±3 days) for a total of 4 injections during the double-blind phase (16 weeks).

    Reporting group title
    Lanreotide (Initial Open-label phase)
    Reporting group description
    		 All patients in the initial open-label phase received lanreotide Autogel 120 mg deep s.c. injections every 4 weeks for 32 weeks. The analysis set includes patients who were randomised to either lanreotide or placebo in the double-blind phase and entered into the inital open-label phase. As such the analysis set includes 101 patients, consisting of 56 patients who were randomised to lanreotide and 45 patients randomised to placebo in the double-blind phase.

    Reporting group title
    Lanreotide (Long-term Open-label extension)
    Reporting group description
    		 In the long-term open-label extension, patients continued to receive lanreotide Autogel 120 mg deep s.c. injections every 4 weeks having completed the initial open-label phase. The analysis set includes patients who were initially randomised to either lanreotide or placebo in the double-blind phase. As such the analysis set includes 57 patients, consisting of 32 patients who were randomised to lanreotide and 25 patients randomised to placebo in the double-blind phase.

    Serious adverse events
    		 Placebo (Double-blind phase) Lanreotide (Double-blind phase) Lanreotide (Initial Open-label phase) Lanreotide (Long-term Open-label extension)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 57 (8.77%)
    2 / 58 (3.45%)
    8 / 101 (7.92%)
    15 / 57 (26.32%)
         number of deaths (all causes)
    2
    0
    2
    6
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 101 (0.00%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (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
    Metastases to liver
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Metastases to pleura
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Metastases to spine
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Tumour necrosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    2 / 57 (3.51%)
         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 / 2
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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 / 1
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Death
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Pyrexia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Pneumothorax
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Patella fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Pericardial effusion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (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
    Dizziness
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Sciatica
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Syncope
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Ear and labyrinth disorders
    Deafness permanent
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 101 (0.00%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    3 / 101 (2.97%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Diarrhoea
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Renal and urinary disorders
    Ureteric stenosis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    1 / 57 (1.75%)
         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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    0 / 57 (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
    Pain in extremity
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    1 / 57 (1.75%)
         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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    0 / 57 (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
    Urosepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    1 / 57 (1.75%)
         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
    Sepsis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    2 / 57 (3.51%)
         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 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Infection
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Hyperglycaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         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
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         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 (Double-blind phase) Lanreotide (Double-blind phase) Lanreotide (Initial Open-label phase) Lanreotide (Long-term Open-label extension)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 57 (54.39%)
    20 / 58 (34.48%)
    59 / 101 (58.42%)
    43 / 57 (75.44%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    9 / 101 (8.91%)
    0 / 57 (0.00%)
         occurrences all number
    0
    1
    9
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    2 / 101 (1.98%)
    4 / 57 (7.02%)
         occurrences all number
    0
    0
    2
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    2 / 101 (1.98%)
    5 / 57 (8.77%)
         occurrences all number
    0
    0
    2
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    3 / 57 (5.26%)
         occurrences all number
    0
    0
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    2 / 101 (1.98%)
    3 / 57 (5.26%)
         occurrences all number
    1
    0
    2
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    9 / 101 (8.91%)
    5 / 57 (8.77%)
         occurrences all number
    1
    0
    10
    5
    Flushing
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    3 / 57 (5.26%)
         occurrences all number
    0
    0
    1
    3
    Hot flush
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    3 / 57 (5.26%)
         occurrences all number
    0
    0
    1
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 57 (5.26%)
    7 / 58 (12.07%)
    10 / 101 (9.90%)
    5 / 57 (8.77%)
         occurrences all number
    3
    7
    15
    7
    Dizziness
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 58 (6.90%)
    5 / 101 (4.95%)
    2 / 57 (3.51%)
         occurrences all number
    0
    4
    5
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 57 (7.02%)
    2 / 58 (3.45%)
    10 / 101 (9.90%)
    9 / 57 (15.79%)
         occurrences all number
    4
    2
    10
    14
    Oedema peripheral
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 58 (0.00%)
    3 / 101 (2.97%)
    3 / 57 (5.26%)
         occurrences all number
    3
    0
    3
    3
    Asthenia
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 58 (3.45%)
    2 / 101 (1.98%)
    6 / 57 (10.53%)
         occurrences all number
    1
    2
    2
    9
    Influenza like illness
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    0
    0
    4
    Disease progression
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    5 / 57 (8.77%)
         occurrences all number
    0
    0
    0
    5
    Pyrexia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    1 / 101 (0.99%)
    5 / 57 (8.77%)
         occurrences all number
    1
    1
    1
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    4 / 101 (3.96%)
    6 / 57 (10.53%)
         occurrences all number
    0
    0
    4
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 57 (12.28%)
    5 / 58 (8.62%)
    11 / 101 (10.89%)
    13 / 57 (22.81%)
         occurrences all number
    7
    5
    14
    25
    Nausea
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 58 (8.62%)
    8 / 101 (7.92%)
    4 / 57 (7.02%)
         occurrences all number
    5
    5
    9
    5
    Vomiting
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 58 (6.90%)
    6 / 101 (5.94%)
    5 / 57 (8.77%)
         occurrences all number
    2
    6
    6
    8
    Flatulence
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 58 (5.17%)
    3 / 101 (2.97%)
    0 / 57 (0.00%)
         occurrences all number
    2
    3
    3
    0
    Diarrhoea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    8 / 57 (14.04%)
         occurrences all number
    0
    0
    0
    10
    Constipation
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 58 (3.45%)
    4 / 101 (3.96%)
    5 / 57 (8.77%)
         occurrences all number
    2
    2
    5
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    4 / 101 (3.96%)
    7 / 57 (12.28%)
         occurrences all number
    1
    1
    4
    9
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 58 (0.00%)
    6 / 101 (5.94%)
    2 / 57 (3.51%)
         occurrences all number
    4
    0
    6
    2
    Cough
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 58 (3.45%)
    3 / 101 (2.97%)
    3 / 57 (5.26%)
         occurrences all number
    1
    2
    3
    3
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    5 / 101 (4.95%)
    4 / 57 (7.02%)
         occurrences all number
    1
    0
    5
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    3 / 101 (2.97%)
    3 / 57 (5.26%)
         occurrences all number
    1
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 58 (5.17%)
    6 / 101 (5.94%)
    1 / 57 (1.75%)
         occurrences all number
    0
    3
    6
    1
    Back pain
         subjects affected / exposed
    4 / 57 (7.02%)
    1 / 58 (1.72%)
    5 / 101 (4.95%)
    8 / 57 (14.04%)
         occurrences all number
    4
    1
    5
    10
    Arthralgia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    7 / 101 (6.93%)
    6 / 57 (10.53%)
         occurrences all number
    1
    0
    8
    9
    Musculoskeletal pain
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    4 / 57 (7.02%)
         occurrences all number
    1
    0
    1
    4
    Pain in extremity
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    3 / 101 (2.97%)
    4 / 57 (7.02%)
         occurrences all number
    1
    0
    3
    4
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 58 (0.00%)
    1 / 101 (0.99%)
    3 / 57 (5.26%)
         occurrences all number
    0
    0
    1
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 58 (3.45%)
    1 / 101 (0.99%)
    7 / 57 (12.28%)
         occurrences all number
    2
    2
    1
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 58 (0.00%)
    3 / 101 (2.97%)
    3 / 57 (5.26%)
         occurrences all number
    2
    0
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    7 / 101 (6.93%)
    5 / 57 (8.77%)
         occurrences all number
    1
    1
    8
    5
    Hyperglycaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    4 / 101 (3.96%)
    7 / 57 (12.28%)
         occurrences all number
    1
    0
    9
    12
    Hypoglycaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 58 (3.45%)
    0 / 101 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    1
    2
    0
    7
    Gout
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 101 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    1
    0
    0
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    2 / 101 (1.98%)
    3 / 57 (5.26%)
         occurrences all number
    1
    1
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2008
    -Clarification of the timing of somatostatin receptor scintigraphy. -Modification of inclusion criterion relating to prior somatostatin analogue treatment to include a more clinically relevant patient population. -Clarification of the monitoring of patient compliance for the IVRS diary.
    01 Mar 2010
    -Tercica became part of the Ipsen Group resulting in several administrative changes to the protocol. -Further clarifications of some of the protocol requirements and inclusion and exclusion criteria were made.
    08 Jul 2010
    -Technical change to extend the screening period to 4 months for any country where a computerised tomography scan was not performed as part of the routine examination for patients with neuroendocrine tumours.
    18 Mar 2011
    -Addition of the long-term open-label extension phase in order to allow patients in countries where lanreotide Autogel had not yet been approved for the treatment of carcinoid syndrome, who were well controlled at the end of the 32-week inital open-label phase and who chose to continue receiving lanreotide Autogel to continue receiving the treatment.
    21 Jul 2011
    -Additional clarification to the exclusion criterion related to liver impairment, so that patients with a bilirubin level more than 1.5 mg/dL but no other evidence of liver impairment to be included in the study. -Additional text relating to Sponsor responsibilities regarding AE follow up added. -The composition of the Data and Safety Monitoring Committee was amended to reflect its charter.
    29 Oct 2012
    -To include additional statistical information relating to the addition of 2 baseline covariates in the ANCOVA model used for the primary efficacy analysis, and clarification of the planned imputation for the primary efficacy endpoint calculation. -Clarification of the analysis planned for the secondary efficacy endpoints. -Addition of information regarding the definition of the per protocol population to ensure consistency with the reporting and analysis plan.
    16 Jul 2014
    -To cancel the second clinical study report which was to have been written with the results of a second analysis performed when the last patient in the double-blind treatment phase completed the 32-week initial open-label phase.

    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
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