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    Clinical Trial Results:
    A phase III, multicenter, randomized, parallel-group study to assess the efficacy and safety of double-blind pasireotide LAR 40 mg and pasireotide LAR 60 mg versus open-label octreotide LAR or lanreotide ATG in patients with inadequately controlled acromegaly

    Summary
    EudraCT number
    		 2009-016722-13
    Trial protocol
    		 FR   ES   IT   NO   BE   DE   PL   GB  
    Global end of trial date
    28 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2018
    First version publication date
    16 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSOM230C2402
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01137682
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novaratis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    28 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the proportion of patients achieving biochemical control defined as mean GH levels < 2.5 μg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continuing the same treatment with octreotide LAR 30 mg or lanreotide ATG 120 mg
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 62
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Saudi Arabia: 4
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    198
    EEA total number of subjects
    93
    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)
    182
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 One hundred ninety-eight patients were randomized and 5 patients in CORE and 1 patient in extension did not receive any study treatment

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide LAR 40 mg
    Arm description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    pasireotide LAR
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    20 mg and/or 40 mg powder in vials and 2 mL vehicle ampoules for reconstitution. Administered every 28 ± 2 days

    Arm title
    		 Pasireotide LAR 60 mg
    Arm description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    pasireotide LAR
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    20 mg and/or 40 mg powder in vials and 2 mL vehicle ampoules for reconstitution.

    Arm title
    		 Control arm (octreotide or lanreotide)
    Arm description
    		 Open label octreotide LAR 30 mg or lanreotide ATG 120 mg supplied either locally or from designated depot. Administered intramuscular every 28 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    lanreotide ATG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    lanreotide ATG 120 mg every 28 ± 2 days

    Investigational medicinal product name
    octreotide LAR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    30 mg every 28 ± 2 days

    Number of subjects in period 1
    		Pasireotide LAR 40 mg Pasireotide LAR 60 mg Control arm (octreotide or lanreotide)
    Started
    65
    65
    68
    Not Treated
    2 [1]
    2 [2]
    1 [3]
    Treated
    63
    63
    67
    Completed 24-Week Core Phase
    59
    57
    65
    Not Continuing into Extension
    2 [4]
    3 [5]
    2 [6]
    Continuing into Extension
    57
    54
    63
    Safety Set - CORE
    63
    62
    66
    Safety Set - Extension
    57
    54
    62
    Completed
    28
    25
    34
    Not completed
    37
    40
    34
         Adverse Event-CORE
    2
    4
    -
         Did not enter extension
    2
    3
    2
         Protocol Violation-CORE
    -
    1
    1
         Lack of Efficacy-Extension
    15
    9
    13
         Withdrawal by Subject-Extension
    6
    8
    8
         Death-Extension
    2
    -
    -
         Administrative problems-Extension
    -
    2
    -
         Administrative problems-CORE
    2
    1
    -
         Did not receive treatment in extension
    -
    -
    1
         Adverse Event-Extension
    4
    8
    7
         Lost to Follow Up-Extension
    -
    1
    -
         Withdrawal by Subject-CORE
    2
    2
    2
         Protocol Violation-Extension
    2
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The core and extension phase were combined into Overall Study. The milestone categories were used to present more detail on the status of patients throughout the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pasireotide LAR 40 mg
    Reporting group description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days

    Reporting group title
    Pasireotide LAR 60 mg
    Reporting group description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days

    Reporting group title
    Control arm (octreotide or lanreotide)
    Reporting group description
    		 Open label octreotide LAR 30 mg or lanreotide ATG 120 mg supplied either locally or from designated depot. Administered intramuscular every 28 days

    Reporting group values
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg Control arm (octreotide or lanreotide) Total
    Number of subjects
    		 65 65 68 198
    Age, Customized
    CORE Period
    Units: Subjects
        <65 Years|
    		 62 57 63 182
        ≥ 65 Years|
    		 3 8 5 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ( 14.05 ) 45.8 ( 14.07 ) 46.2 ( 13.11 ) -
    Sex: Female, Male
    CORE Period
    Units: Subjects
        Female
    		 38 35 38 111
        Male
    		 27 30 30 87
    Race/Ethnicity, Customized
    CORE Period
    Units: Subjects
        Caucasian|
    		 53 52 56 161
        Black|
    		 3 8 4 15
        Other|
    		 4 3 7 14
        Native American|
    		 2 1 1 4
        Asian|
    		 3 1 0 4
    Subject analysis sets

    Subject analysis set title
    Pasireotide LAR 40 mg Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    If controlled on 40 mg in CORE, remain on blinded 40 mg in extension. If patient became uncontrolled, switch to open label 60 mg

    Subject analysis set title
    Pasireotide LAR 60 mg Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    If controlled on 60 mg in CORE, remain on blinded 60 mg in extension. If patient became uncontrolled, switch to open label 60 mg

    Subject analysis set title
    Cross over to pasireotide Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Open - label 60 mg pasireotide. Control group from CORE discontinued study if controlled in CORE. If uncontrolled in CORE, switched to open label 60 mg pasireotide. Extension blinded 40 and 60 mg switched to open label if became uncontrolled.

    Subject analysis set title
    PK trough
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK trough concentrations for patients on 40 and 60 mg pasireotide LAR in extension phase

    Subject analysis sets values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension PK trough
    Number of subjects
    57
    54
    62
    98
    Age, Customized
    CORE Period
    Units: Subjects
        <65 Years|
        ≥ 65 Years|
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.5 ( 13.11 )
    45.1 ( 14.22 )
    46.8 ( 13.31 )
    ( )
    Sex: Female, Male
    CORE Period
    Units: Subjects
        Female
        Male
    Race/Ethnicity, Customized
    CORE Period
    Units: Subjects
        Caucasian|
        Black|
        Other|
        Native American|
        Asian|

    End points

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    End points reporting groups
    Reporting group title
    Pasireotide LAR 40 mg
    Reporting group description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days

    Reporting group title
    Pasireotide LAR 60 mg
    Reporting group description
    		 Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) for intramuscular administration every 28 days

    Reporting group title
    Control arm (octreotide or lanreotide)
    Reporting group description
    		 Open label octreotide LAR 30 mg or lanreotide ATG 120 mg supplied either locally or from designated depot. Administered intramuscular every 28 days

    Subject analysis set title
    Pasireotide LAR 40 mg Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    If controlled on 40 mg in CORE, remain on blinded 40 mg in extension. If patient became uncontrolled, switch to open label 60 mg

    Subject analysis set title
    Pasireotide LAR 60 mg Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    If controlled on 60 mg in CORE, remain on blinded 60 mg in extension. If patient became uncontrolled, switch to open label 60 mg

    Subject analysis set title
    Cross over to pasireotide Extension
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Open - label 60 mg pasireotide. Control group from CORE discontinued study if controlled in CORE. If uncontrolled in CORE, switched to open label 60 mg pasireotide. Extension blinded 40 and 60 mg switched to open label if became uncontrolled.

    Subject analysis set title
    PK trough
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK trough concentrations for patients on 40 and 60 mg pasireotide LAR in extension phase

    Primary: Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1.

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    End point title
    		 Percentage of participants with a reduction of mean GH levels to < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1.
    End point description
    The primary objective of this study was to compare the percentage of patients achieving biochemical control (defined as mean GH levels <2.5 µg/L and normalization of sex- and age- adjusted IGF-1) at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continuing the same treatment with octreotide LAR 30 mg or lanreotide ATG 120 mg.
    End point type
    Primary
    End point timeframe
    At 24 weeks
    End point values
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg Control arm (octreotide or lanreotide)
    Number of subjects analysed
    65
    65
    68
    Units: percentage of participants
        number (confidence interval 95%)
    15.4 (7.63 to 26.48)
    20.0 (11.10 to 31.77)
    0 (0 to 5.28)
    Statistical analysis title
    		 40 LAR vs. Control
    Comparison groups
    Pasireotide LAR 40 mg v Control arm (octreotide or lanreotide)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0006
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
    Variability estimate
    Standard error of the mean
    Dispersion value
    16.63
    Statistical analysis title
    		 60 LAR vs. Control
    Comparison groups
    Pasireotide LAR 60 mg v Control arm (octreotide or lanreotide)
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Confidence interval
    Variability estimate
    Standard error of the mean
    Dispersion value
    23.03

    Secondary: Percentage of patients with mean GH < 2.5 μg/L and normalization of IGF-1, treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)

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    End point title
    		 Percentage of patients with mean GH < 2.5 μg/L and normalization of IGF-1, treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)
    End point description
    The percentage of patients achieving mean growth hormone (GH) levels < 2.5 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (extension full analysis set)
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately week 268
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: percentage of participants
    number (confidence interval 95%)
        Week 16|
    19.3 (10.05 to 31.91)
    25.9 (14.96 to 39.65)
    19.4 (10.42 to 31.37)
        Week 28|
    17.5 (8.75 to 29.91)
    25.9 (14.96 to 39.65)
    19.4 (10.42 to 31.37)
        Week 40|
    21.1 (11.38 to 33.89)
    27.8 (16.46 to 41.64)
    17.7 (9.20 to 29.53)
        Week 52|
    21.1 (11.38 to 33.89)
    29.6 (17.98 to 43.61)
    21.0 (11.66 to 33.18)
        Week 64|
    22.8 (12.74 to 35.84)
    20.4 (10.63 to 33.53)
    25.8 (15.53 to 38.50)
        Week 76|
    21.1 (11.38 to 33.89)
    29.6 (17.98 to 43.61)
    27.4 (16.85 to 40.23)
        Week 88|
    24.6 (14.13 to 37.76)
    31.5 (19.52 to 45.55)
    25.8 (15.53 to 38.50)
        Week 100|
    24.6 (14.13 to 37.76)
    24.1 (13.49 to 37.64)
    32.3 (20.94 to 45.34)
        Week 112|
    24.6 (14.13 to 37.76)
    25.9 (14.96 to 39.65)
    25.8 (15.53 to 38.50)
        Week 124|
    21.1 (11.38 to 33.89)
    24.1 (13.49 to 37.64)
    25.8 (15.53 to 38.50)
        Week 136|
    15.8 (7.48 to 27.87)
    24.1 (13.49 to 37.64)
    29.0 (18.20 to 41.95)
        Week 148|
    21.1 (11.38 to 33.89)
    20.4 (10.63 to 33.53)
    29.0 (18.20 to 41.95)
        Week 160|
    19.3 (10.05 to 31.91)
    20.4 (10.63 to 33.53)
    30.6 (19.56 to 43.65)
        Week 172|
    22.8 (12.74 to 35.84)
    20.4 (10.63 to 33.53)
    21.0 (11.66 to 33.18)
        Week 184|
    17.5 (8.75 to 29.91)
    20.4 (10.63 to 33.53)
    17.7 (9.20 to 29.53)
        Week 196|
    15.8 (7.48 to 27.87)
    20.4 (10.63 to 33.53)
    24.2 (14.22 to 36.74)
        Week 208|
    17.5 (8.75 to 29.91)
    18.5 (9.25 to 31.43)
    19.4 (10.42 to 31.37)
        Week 220|
    21.1 (11.38 to 33.89)
    11.1 (4.19 to 22.63)
    14.5 (6.86 to 25.78)
        Week 232|
    14.0 (6.26 to 25.79)
    14.8 (6.62 to 27.12)
    14.5 (6.86 to 25.78)
        Week 244|
    14.0 (6.26 to 25.79)
    7.4 (2.06 to 17.89)
    11.3 (4.66 to 21.89)
        Week 256|
    10.5 (3.96 to 21.52)
    7.4 (2.06 to 17.89)
    3.2 (0.39 to 11.17)
        Week 268|
    5.3 (1.10 to 14.62)
    5.6 (1.16 to 15.39)
    1.6 (0.04 to 8.66)
    No statistical analyses for this end point

    Secondary: Percentage of participants with normalization of sex- and age-adjusted IGF-1treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set).

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    End point title
    		 Percentage of participants with normalization of sex- and age-adjusted IGF-1treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set).
    End point description
    The percentage of patients achieving normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately week 268
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: percentage of participants
    number (confidence interval 95%)
        Week 16|
    33.3 (21.40 to 47.06)
    29.0 (17.98 to 43.61)
    25.8 (15.53 to 38.50)
        Week 28|
    29.8 (18.43 to 43.40)
    33.3 (21.09 to 47.47)
    22.6 (12.93 to 34.97)
        Week 40|
    36.8 (24.45 to 50.66)
    37.0 (24.29 to 51.26)
    24.2 (14.22 to 36.74)
        Week 52|
    28.1 (16.97 to 41.54)
    33.3 (21.09 to 47.47)
    25.8 (15.53 to 38.50)
        Week 64|
    33.3 (21.40 to 47.06)
    27.8 (16.46 to 41.64)
    29.0 (18.20 to 41.95)
        Week 76|
    26.3 (15.54 to 39.66)
    35.2 (22.68 to 49.38)
    29.0 (18.20 to 41.95)
        Week 88|
    28.1 (16.97 to 41.54)
    35.2 (22.68 to 49.38)
    25.8 (15.53 to 38.50)
        Week 100|
    31.6 (19.91 to 45.24)
    29.6 (17.98 to 43.61)
    32.3 (20.94 to 45.34)
        Week 112|
    31.6 (19.91 to 45.24)
    27.8 (16.46 to 41.64)
    30.6 (19.56 to 43.65)
        Week 124|
    24.6 (14.13 to 37.76)
    31.5 (19.52 to 45.55)
    29.0 (18.20 to 41.95)
        Week 136|
    21.1 (11.38 to 33.89)
    25.9 (14.96 to 39.65)
    37.1 (25.16 to 50.31)
        Week 148|
    26.3 (15.54 to 39.66)
    22.2 (12.04 to 35.60)
    33.9 (22.33 to 47.01)
        Week 160|
    24.6 (14.13 to 37.76)
    25.9 (14.96 to 39.65)
    33.9 (22.33 to 47.01)
        Week 172|
    26.3 (15.54 to 39.66)
    22.2 (12.04 to 35.60)
    22.6 (12.93 to 34.97)
        Week 184|
    19.3 (10.05 to 31.91)
    22.2 (12.04 to 35.60)
    22.6 (12.93 to 34.97)
        Week 196|
    24.6 (14.13 to 37.76)
    22.2 (12.04 to 35.60)
    27.4 (16.85 to 40.23)
        Week 208|
    22.8 (12.74 to 35.84)
    22.2 (12.04 to 35.60)
    21.0 (11.66 to 33.18)
        Week 220|
    22.8 (12.74 to 35.84)
    11.1 (4.19 to 22.63)
    19.4 (10.42 to 31.37)
        Week 232|
    14.0 (6.26 to 25.79)
    14.8 (6.62 to 27.12)
    17.7 (9.20 to 29.53)
        Week 244|
    14.0 (6.26 to 25.79)
    9.3 (3.08 to 20.30)
    14.5 (6.86 to 25.78)
        Week 256|
    12.3 (5.08 to 23.68)
    7.4 (2.06 to 17.89)
    6.5 (1.79 to 15.70)
        Week 268|
    5.3 (1.10 to 14.62)
    5.6 (1.16 to 15.39)
    1.6 (0.04 to 8.66)
    No statistical analyses for this end point

    Secondary: Percentage of patients with mean GH < 2.5 μg/L treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (extension full analysis set)

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    End point title
    		 Percentage of patients with mean GH < 2.5 μg/L treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (extension full analysis set)
    End point description
    The percentage of patients achieving mean growth hormone (GH) levels < 2.5 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately week 268
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension
    Number of subjects analysed
    57
    54
    Units: percentage of participants
    number (confidence interval 95%)
        Week 16|
    38.6 (26.00 to 52.43)
    55.6 (41.40 to 69.08)
        Week 28|
    40.4 (27.56 to 54.18)
    44.4 (30.92 to 58.60)
        Week 40|
    38.6 (26.00 to 52.43)
    42.6 (29.23 to 56.79)
        Week 52|
    38.6 (26.00 to 52.43)
    46.3 (32.62 to 60.39)
        Week 64|
    40.4 (27.56 to 54.18)
    37.0 (24.29 to 51.26)
        Week 76|
    33.3 (21.40 to 47.06)
    44.4 (30.92 to 58.60)
        Week 88|
    40.4 (27.56 to 54.18)
    42.6 (29.23 to 56.79)
        Week 100|
    40.4 (27.56 to 54.18)
    40.7 (27.57 to 54.97)
        Week 112|
    36.8 (24.45 to 50.66)
    44.4 (30.92 to 58.60)
        Week 124|
    40.4 (27.56 to 54.18)
    31.5 (19.52 to 45.55)
        Week 136|
    36.8 (24.45 to 50.66)
    35.2 (22.68 to 49.38)
        Week 148|
    40.4 (27.56 to 54.18)
    33.3 (21.09 to 47.47)
        Week 160|
    38.6 (26.00 to 52.43)
    33.3 (21.09 to 47.47)
        Week 172|
    40.4 (27.56 to 54.18)
    37.0 (24.29 to 51.26)
        Week 184|
    33.3 (21.40 to 47.06)
    31.5 (19.52 to 45.55)
        Week 196|
    29.8 (18.43 to 43.40)
    29.6 (17.98 to 43.61)
        Week 208|
    31.6 (19.91 to 45.24)
    24.1 (13.49 to 37.64)
        Week 220|
    29.8 (18.43 to 43.40)
    18.5 (9.25 to 31.43)
        Week 232|
    24.6 (14.3 to 37.76)
    18.5 (9.25 to 31.43)
        Week 244|
    19.3 (10.05 to 31.91)
    11.1 (4.19 to 22.63)
        Week 256|
    15.8 (7.48 to 27.87)
    9.3 (3.08 to 20.30)
        Week 268|
    7.0 (1.95 to 17.00)
    5.6 (1.16 to 15.39)
    No statistical analyses for this end point

    Secondary: Percentage of patients with mean GH < 1.0 μg/L and normalization of IGF-1, treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)

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    End point title
    		 Percentage of patients with mean GH < 1.0 μg/L and normalization of IGF-1, treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)
    End point description
    The percentage of patients achieving mean growth hormone (GH) levels < 1.0 μg/L and normalization of sex and age-adjusted IGF-1 was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Total insulin-like growth factor (IGF-1) levels were assessed with one pre-dose sample at the same visits as GH. Concomitant medication known to affect GH or IGF-1 levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately week 268
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: Participants
    number (confidence interval 95%)
        Week 16|
    10.5 (3.96 to 21.52)
    16.7 (7.92 to 29.29)
    6.5 (1.79 to 15.70)
        Week 28|
    8.8 (2.91 to 19.30)
    14.8 (6.62 to 27.12)
    8.1 (2.67 to 17.83)
        Week 40|
    10.5 (3.96 to 21.52)
    9.3 (3.08 to 20.30)
    4.8 (1.01 to 13.50)
        Week 52|
    8.8 (2.91 to 19.30)
    13.0 (5.37 to 24.90)
    4.8 (1.01 to 13.50)
        Week 64|
    8.8 (2.91 to 19.30)
    13.0 (5.37 to 24.90)
    9.7 (3.63 to 19.88)
        Week 76|
    10.5 (3.96 to 21.52)
    13.0 (5.37 to 24.90)
    6.5 (1.79 to 15.70)
        Week 88|
    7.0 (1.95 to 17.00)
    20.4 (10.63 to 33.53)
    4.8 (1.01 to 13.50)
        Week 100|
    12.3 (5.08 to 23.68)
    14.8 (6.62 to 27.12)
    8.1 (2.67 to 17.83)
        Week 112|
    14.0 (6.26 to 25.79)
    20.4 (10.63 to 33.53)
    9.7 (3.63 to 19.88)
        Week 124|
    7.0 (1.95 to 17.00)
    14.8 (6.62 to 27.12)
    8.1 (2.67 to 17.83)
        Week 136|
    3.5 (0.43 to 12.11)
    18.5 (9.25 to 31.43)
    11.3 (4.66 to 21.89)
        Week 148|
    10.5 (3.96 to 21.52)
    14.8 (6.62 to 27.12)
    8.1 (2.67 to 17.83)
        Week 160|
    8.8 (2.91 to 19.30)
    14.8 (6.62 to 27.12)
    9.7 (3.63 to 19.88)
        Week 172|
    14.0 (6.26 to 25.79)
    13.0 (5.37 to 24.90)
    8.1 (2.67 to 17.83)
        Week 184|
    7.0 (1.95 to 17.00)
    13.0 (5.37 to 24.90)
    3.2 (0.39 to 11.17)
        Week 196|
    8.8 (2.91 to 19.30)
    13.0 (5.37 to 24.90)
    8.1 (2.67 to 17.83)
        Week 208|
    8.8 (2.91 to 19.30)
    9.3 (3.08 to 20.30)
    6.5 (1.79 to 15.70)
        Week 220|
    10.5 (3.96 to 21.52)
    7.4 (2.06 to 17.89)
    6.5 (1.79 to 15.70)
        Week 232|
    10.5 (3.96 to 21.52)
    3.7 (0.45 to 12.75)
    4.8 (1.01 to 13.50)
        Week 244|
    8.8 (2.91 to 19.30)
    3.7 (0.45 to 12.75)
    6.5 (1.79 to 15.70)
        Week 256|
    8.8 (2.91 to 19.30)
    3.7 (0.45 to 12.75)
    3.2 (0.39 to 11.17)
        Week 268|
    1.8 (0.04 to 9.39)
    3.7 (0.45 to 12.75)
    1.6 (0.04 to 8.66)
    No statistical analyses for this end point

    Secondary: Percentage of patients with mean GH <1.0 μg/L treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)

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    End point title
    		 Percentage of patients with mean GH <1.0 μg/L treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly (Extension Full analysis set)
    End point description
    The percentage of patients achieving mean growth hormone (GH) levels < 1.0 μg/L was calculated with two sided 95% confidence interval. All GH assessments were based on a 5-point mean growth hormone (GH) assessed from a 2-hour profile. Scheduled time points for blood sampling were pre-dose at 0, 30, 60, 90 and 120 minutes. Concomitant medication known to affect GH levels were allowed in patients who were not biochemically controlled after at least one year treatment with pasireotide LAR monotherapy: dopamine agonists and growth hormone receptor antagonists (Extension full analysis set)
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately week 268
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: percentage of participants
    number (confidence interval 95%)
        Week 16|
    14.0 (6.26 to 25.79)
    27.8 (16.46 to 41.64)
    8.1 (2.67 to 17.83)
        Week 28|
    14.0 (6.26 to 25.79)
    22.2 (12.04 to 35.60)
    9.7 (3.63 to 19.88)
        Week 40|
    14.0 (6.26 to 25.79)
    13.0 (5.37 to 24.90)
    4.8 (1.01 to 13.50)
        Week 52|
    12.3 (5.08 to 23.68)
    22.2 (12.04 to 35.60)
    9.7 (3.63 to 19.88)
        Week 64|
    15.8 (7.48 to 27.87)
    18.5 (9.25 to 31.43)
    11.3 (4.66 to 21.89)
        Week 76|
    12.3 (5.08 to 23.68)
    22.2 (12.04 to 35.60)
    11.3 (4.66 to 21.89)
        Week 88|
    15.8 (7.48 to 27.87)
    22.2 (12.04 to 35.60)
    11.3 (4.66 to 21.89)
        Week 100|
    17.5 (8.75 to 29.91)
    20.4 (10.63 to 33.53)
    17.7 (9.20 to 29.53)
        Week 112|
    17.5 (8.75 to 29.91)
    25.9 (14.96 to 39.65)
    16.1 (8.02 to 27.67)
        Week 124|
    12.3 (5.08 to 23.68)
    16.7 (7.92 to 29.29)
    14.5 (6.86 to 25.78)
        Week 136|
    8.8 (2.91 to 19.30)
    25.9 (14.96 to 39.65)
    14.5 (6.86 to 25.78)
        Week 148|
    14.0 (6.26 to 25.79)
    16.7 (7.92 to 29.29)
    14.5 (6.86 to 25.78)
        Week 160|
    17.5 (8.75 to 29.91)
    18.5 (9.25 to 31.43)
    14.5 (6.86 to 25.78)
        Week 172|
    17.5 (8.75 to 29.91)
    14.8 (6.62 to 27.12)
    14.5 (6.86 to 25.78)
        Week 184|
    17.5 (8.75 to 29.91)
    18.5 (9.25 to 31.43)
    6.5 (1.79 to 15.70)
        Week 196|
    15.8 (7.48 to 27.87)
    13.0 (5.37 to 24.90)
    12.9 (5.74 to 23.85)
        Week 208|
    17.5 (8.75 to 29.91)
    13.0 (5.37 to 24.90)
    9.7 (3.63 to 19.88)
        Week 220|
    15.8 (7.48 to 27.87)
    11.1 (4.19 to 22.63)
    9.7 (3.63 to 19.88)
        Week 232|
    15.8 (7.48 to 27.87)
    3.7 (0.45 to 12.75)
    8.1 (2.67 to 17.83)
        Week 244|
    12.3 (5.08 to 23.68)
    5.6 (1.16 to 15.39)
    8.1 (2.67 to 17.83)
        Week 256|
    12.3 (5.08 to 23.68)
    3.7 (0.45 to 12.75)
    4.8 (1.01 to 13.50)
        Week 268|
    3.5 (0.43 to 12.11)
    3.7 (0.45 to 12.75)
    1.6 (0.04 to 8.66)
    No statistical analyses for this end point

    Secondary: Change from baseline in mean GH values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits (extension full analysis set)

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    End point title
    		 Change from baseline in mean GH values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits (extension full analysis set) [1]
    End point description
    End point type
    Secondary
    End point timeframe
    CORE baseline up to approximately 24 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint means presented was for the two active arms (40 and 60 mg) compared to the control arm.
    End point values
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg
    Number of subjects analysed
    57
    54
    Units: mcg/L
    arithmetic mean (standard deviation)
        Week 12 - CORE (n=57,52)|
    -0.8 ( 29.77 )
    -6.4 ( 14.35 )
        Week 24 - CORE (n=54,48)|
    -0.6 ( 32.38 )
    -7.2 ( 15.19 )
    No statistical analyses for this end point

    Secondary: Change from baseline in mean GH values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)

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    End point title
    		 Change from baseline in mean GH values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)
    End point description
    Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm.
    End point type
    Secondary
    End point timeframe
    CORE and extension baseline up to approximately 268 weeks
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: mcg/L
    arithmetic mean (standard deviation)
        Week 16 - extension (n=44,46,57)|
    -7.9 ( 24.90 )
    -6.9 ( 14.88 )
    -8.4 ( 49.64 )
        Week 28 - extension (n=44,39,56)|
    -9.0 ( 24.21 )
    -4.5 ( 4.12 )
    -3.0 ( 3.86 )
        Week 40 - extension (n=38,36,50)|
    -9.7 ( 25.40 )
    -5.8 ( 13.93 )
    -11.2 ( 58.28 )
        Week 52 - extension (n=36,35,46)|
    -10.7 ( 26.60 )
    -7.1 ( 17.08 )
    -2.5 ( 3.02 )
        Week 64 - extension (n=37,33,39)|
    -11.3 ( 28.37 )
    -7.9 ( 17.30 )
    -15.7 ( 76.06 )
        Week 76 - extension (n=32,36,42)|
    -5.5 ( 5.96 )
    -7.2 ( 16.16 )
    -3.5 ( 4.27 )
        Week 88 - extension (n=32,32,40)|
    -5.7 ( 6.21 )
    -6.2 ( 8.55 )
    -3.6 ( 3.22 )
        Week 100 - extension (n=34,31,39)|
    -5.6 ( 5.71 )
    -5.3 ( 5.06 )
    -3.8 ( 4.28 )
        Week 112 - extension (n=30,32,35)|
    -5.8 ( 6.03 )
    -4.4 ( 6.57 )
    -3.9 ( 5.13 )
        Week 124 - extension (n=30,26,35)|
    -5.5 ( 5.85 )
    -6.0 ( 6.26 )
    -4.0 ( 4.36 )
        Week 136 - extension (n=28,26,36)|
    -6.0 ( 6.59 )
    -5.3 ( 4.99 )
    -4.0 ( 4.44 )
        Week 148 - extension (n=29,25,35)|
    -6.3 ( 6.21 )
    6.1 ( 6.28 )
    -3.8 ( 3.11 )
        Week 160 - extension (n=29,26,33)|
    -5.5 ( 4.70 )
    -4.9 ( 5.33 )
    -3.2 ( 2.25 )
        Week 172 - extension (n=27,26,31)|
    -6.3 ( 6.34 )
    -5.9 ( 5.97 )
    -3.0 ( 2.47 )
        Week 184 - extension (n=23,25,29)|
    -6.3 ( 5.44 )
    -5.8 ( 5.79 )
    -3.3 ( 2.31 )
        Week 196 - extension (n=22,21,29)|
    -7.1 ( 6.81 )
    -6.5 ( 7.17 )
    -3.4 ( 2.71 )
        Week 208 - extension (n=22,20,23)|
    -7.0 ( 6.82 )
    -6.2 ( 6.22 )
    -3.5 ( 2.50 )
        Week 220 - extension (n=20,14,20)|
    -7.1 ( 6.91 )
    -7.1 ( 8.12 )
    -3.8 ( 2.48 )
        Week 232 - extension (n=16,15,14)|
    -5.7 ( 5.46 )
    -6.8 ( 8.10 )
    -4.2 ( 2.46 )
        Week 244 - extension (n=12,7,11)|
    -6.0 ( 6.03 )
    -2.4 ( 0.90 )
    -4.2 ( 2.58 )
        Week 256 - extension (n=10,6,6)|
    -6.4 ( 5.91 )
    -4.9 ( 3.49 )
    -5.0 ( 3.26 )
        Week 268 - extension (n=4,3,3)|
    -3.6 ( 1.58 )
    -2.5 ( 0.57 )
    -3.7 ( 2.23 )
    No statistical analyses for this end point

    Secondary: Change from baseline in standardized IGF-1 values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits (extension full analysis set)

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    End point title
    		 Change from baseline in standardized IGF-1 values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits (extension full analysis set) [2]
    End point description
    Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range
    End point type
    Secondary
    End point timeframe
    CORE baseline up to approximately 24 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint means presented was for the two active arms (40 and 60 mg) compared to the control arm.
    End point values
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg
    Number of subjects analysed
    57
    54
    Units: mcg/L
    arithmetic mean (standard deviation)
        CORE Week 12 (n=57,53)|
    0.7 ( 0.97 )
    -1.1 ( 1.03 )
        CORE Week 24 (n=56,49)|
    -0.7 ( 0.97 )
    -1.1 ( 1.12 )
    No statistical analyses for this end point

    Secondary: Change from baseline in standardized IGF-1 values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)

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    End point title
    		 Change from baseline in standardized IGF-1 values for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)
    End point description
    Change from CORE baseline at each scheduled assessment was performed for patients randomized to pasireotide arms. Change from extension baseline at each scheduled assessment was performed for patients randomized to active control arm. Standardized IGF-1 = IGF-1 value / ULN, where ULN is the upper limit of the normal range
    End point type
    Secondary
    End point timeframe
    CORE and extension baseline up to approximately 268 weeks
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: mcg/L
    arithmetic mean (standard deviation)
        Week 16 extension (n=49,47,61)|
    -0.8 ( 0.99 )
    -1.4 ( 0.97 )
    -0.9 ( 0.81 )
        Week 28 extension (n=45,39,58)|
    -0.9 ( 1.00 )
    -1.3 ( 1.13 )
    -0.9 ( 0.88 )
        Week 40 extension (n=42,37,51)|
    -1.1 ( 0.95 )
    -1.4 ( 0.94 )
    -1.1 ( 0.91 )
        Week 52 extension (n=39,37,46)|
    -1.1 ( 0.90 )
    -1.3 ( 0.95 )
    -1.1 ( 0.95 )
        Week 64 extension (n=37,35,42)|
    -1.3 ( 0.99 )
    -1.4 ( 0.98 )
    -1.3 ( 0.81 )
        Week 76 extension (n=33,36,43)|
    -1.3 ( 0.87 )
    -1.5 ( 0.94 )
    -1.3 ( 0.84 )
        Week 88 extension (n=33,32,41)|
    -1.3 ( 0.80 )
    -1.6 ( 1.01 )
    -1.3 ( 0.90 )
        Week 100 extension (n=32,32,40)|
    -1.4 ( 0.93 )
    -1.5 ( 0.95 )
    -1.3 ( 0.92 )
        Week 112 extension (n=31,32,38)|
    -1.5 ( 0.87 )
    -1.5 ( 1.00 )
    -1.4 ( 0.89 )
        Week 124 extension (n=31,28,38)|
    -1.4 ( 0.86 )
    -1.5 ( 0.95 )
    -1.3 ( 0.97 )
        Week 136 extension (n=29,27,38)|
    -1.4 ( 0.91 )
    -1.7 ( 0.92 )
    -1.4 ( 0.86 )
        Week 148 extension (n=28,26,36)|
    -1.4 ( 0.86 )
    -1.5 ( 0.99 )
    -1.3 ( 0.84 )
        Week 160 extension (n=29,28,34)|
    -1.4 ( 0.90 )
    -1.6 ( 0.87 )
    -1.4 ( 0.94 )
        Week 172 extension (n=26,27,31)|
    -1.5 ( 0.81 )
    -1.6 ( 0.97 )
    -1.3 ( 0.98 )
        Week 184 extension (n=23,25,31)|
    -1.3 ( 0.70 )
    -1.5 ( 1.03 )
    -1.4 ( 0.93 )
        Week 196 extension (n=23,22,29)|
    -1.4 ( 0.81 )
    -1.5 ( 1.11 )
    -1.3 ( 1.11 )
        Week 208 extension (n=23,22,22)|
    -1.4 ( 0.79 )
    -1.6 ( 1.00 )
    -1.2 ( 0.98 )
        Week 220 extension (n=20,14,20)|
    -1.4 ( 0.94 )
    -1.6 ( 1.06 )
    -1.4 ( 0.91 )
        Week 232 extension (n=15,15,15)|
    -1.4 ( 0.92 )
    -1.5 ( 1.13 )
    -1.7 ( 0.82 )
        Week 244 extension (n=12,8,11)|
    -1.3 ( 0.75 )
    -1.9 ( 1.12 )
    -1.5 ( 0.79 )
        Week 256 extension (n=10,6,6)|
    -1.3 ( 0.58 )
    -1.4 ( 1.39 )
    -1.8 ( 0.90 )
        Week 268 extension (n=4,3,3)|
    -1.4 ( 0.43 )
    -1.7 ( 0.39 )
    -1.7 ( 0.81 )
    No statistical analyses for this end point

    Secondary: Duration of the first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1 and treated with Pasireotide LAR alone or with concomitant medications used to treat acromegaly (extension full analysis set)

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    End point title
    		 Duration of the first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1 and treated with Pasireotide LAR alone or with concomitant medications used to treat acromegaly (extension full analysis set)
    End point description
    n is the number of patients achieving response criteria. The weeks correspond to duration of first response (in weeks) for patients achieving biomedical control. Median and 95% CI are derived from Kaplan-Meier curves. Kaplan-Meier estimates [95% CI] at each time point are estimates of probability of response.
    End point type
    Secondary
    End point timeframe
    CORE baseline up to approximately 268 weeks
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: weeks
        median (confidence interval 95%)
    29.1 (15.6 to 48.1)
    26.9 (12.7 to 48.0)
    24.9 (12.4 to 47.4)
    No statistical analyses for this end point

    Secondary: Time to first response (weeks) by treatment for patients achieving a reduction of mean GH level to < 2.5 µg/L and normalization of IGF-1 and treated with Pasireotide LAR alone or with concomitant medications used to treat acromegaly

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    End point title
    		 Time to first response (weeks) by treatment for patients achieving a reduction of mean GH level to < 2.5 µg/L and normalization of IGF-1 and treated with Pasireotide LAR alone or with concomitant medications used to treat acromegaly
    End point description
    Time to first response is defined as the time from the date of first dose to the date of first occurrence of a reduction of mean GH < 2.5 µg/L and the normalization of IGF-1. The weeks correspond to time taken to achieve first mean GH < 2.5 µg/L and the normalization of IGF-1.
    End point type
    Secondary
    End point timeframe
    CORE baseline up to approximately 268 weeks
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: weeks
        median (confidence interval 95%)
    112.3 (76.1 to 254.1)
    65.3 (40.4 to 94.9)
    95.1 (65.3 to 156.0)
    No statistical analyses for this end point

    Secondary: Change from baseline in AcroQoL total scores for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits(extension full analysis set)

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    End point title
    		 Change from baseline in AcroQoL total scores for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for CORE visits(extension full analysis set) [3]
    End point description
    Acromegaly Quality of Life questionnaire (AcroQoL). AcroQoL is a validated disease specific questionnaire to measure quality of life in patients with acromegaly. The questionnaire is uni-dimensional and contains 22 items divided in two scales: one that evaluates physical aspects (8 items) and another one that evaluates psychological aspects (14 items). The latter is also divided in two sub-scales: physical appearance and personal relationships of the patient (seven items each). The total score and sub-scores will be calculated using the following formula established by the tool developer (Badia, et al 2004): ((X - Y) / 4Y) x 100, X=sum of the scores for individual items (between 1 and 5 for each item),Y=number of individual items included in above sum (i.e. 22 for the total score, 8 for the physical sub-score, 14 for the psychological sub-score, 7 for the sub-score ‘appearance’ and ‘personal relations’). If more than 25% of items are not completed, results will be considered invalid.
    End point type
    Secondary
    End point timeframe
    CORE baseline up to approximately 24 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint means presented was for the two active arms (40 and 60 mg) compared to the control arm.
    End point values
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg
    Number of subjects analysed
    57
    54
    Units: scores
    arithmetic mean (standard deviation)
        Week 4 CORE (n=55,52)|
    3.5 ( 11.28 )
    2.3 ( 11.08 )
        Week 8 CORE (n=54,52)|
    2.4 ( 12.97 )
    2.5 ( 12.11 )
        Week 12 CORE (n=53,50)|
    3.0 ( 12.41 )
    1.9 ( 11.50 )
        Week 16 CORE (n=55,52)|
    3.3 ( 12.99 )
    6.6 ( 15.33 )
        Week 20 CORE (n=56,50)|
    3.5 ( 12.89 )
    4.0 ( 16.02 )
        Week24 CORE (n=55,53)|
    3.0 ( 16.61 )
    5.4 ( 17.77 )
    No statistical analyses for this end point

    Secondary: Change from baseline in AcroQoL total scores for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)

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    End point title
    		 Change from baseline in AcroQoL total scores for patients treated with pasireotide LAR alone or with concomitant medications used to treat acromegaly for extension visits (extension full analysis set)
    End point description
    Acromegaly Quality of Life questionnaire (AcroQoL). AcroQoL is a validated disease specific questionnaire to measure quality of life in patients with acromegaly. The questionnaire is uni-dimensional and contains 22 items divided in two scales: one that evaluates physical aspects (8 items) and another one that evaluates psychological aspects (14 items). The latter is also divided in two sub-scales: physical appearance and personal relationships of the patient (seven items each). The total score and sub-scores will be calculated using the following formula established by the tool developer (Badia, et al 2004): ((X - Y) / 4Y) x 100, X=sum of the scores for individual items (between 1 and 5 for each item),Y=number of individual items included in above sum (i.e. 22 for the total score, 8 for the physical sub-score, 14 for the psychological sub-score, 7 for the sub-score ‘appearance’ and ‘personal relations’). If more than 25% of items are not completed, results will be considered invalid.
    End point type
    Secondary
    End point timeframe
    CORE Baseline and extension baseline up to approximately 268 weeks
    End point values
    		 Pasireotide LAR 40 mg Extension Pasireotide LAR 60 mg Extension Cross over to pasireotide Extension
    Number of subjects analysed
    57
    54
    62
    Units: scores
    arithmetic mean (standard deviation)
        Week 16 extension (n=50,46,61)|
    4.2 ( 16.34 )
    2.9 ( 19.09 )
    0.8 ( 10.22 )
        Week 28 extension (n=46,40,54)|
    5.6 ( 13.21 )
    4.8 ( 16.83 )
    3.3 ( 10.70 )
        Week 40 extension (n=44,41,51)|
    3.2 ( 15.78 )
    2.5 ( 18.21 )
    3.2 ( 10.31 )
        Week 52 extension (n=41,36,46)|
    6.1 ( 14.28 )
    5.7 ( 18.69 )
    4.2 ( 11.01 )
        Week 64 extension (n=37,35,43)|
    5.8 ( 13.65 )
    4.2 ( 18.89 )
    5.4 ( 12.12 )
        Week 76 extension (n=31,36,42)|
    7.7 ( 14.93 )
    2.5 ( 19.30 )
    7.7 ( 15.17 )
        Week 88 extension (n=35,32,42)|
    4.6 ( 15.11 )
    5.6 ( 18.08 )
    6.4 ( 10.29 )
        Week 100 extension (n=34,32,40)|
    4.3 ( 14.80 )
    3.9 ( 16.91 )
    5.9 ( 11.13 )
        Week 112 extension (n=32,31,39)|
    4.6 ( 15.83 )
    6.5 ( 18.36 )
    4.1 ( 10.35 )
        Week 124 extension (n=28,30,37)|
    5.8 ( 16.46 )
    2.0 ( 17.95 )
    2.0 ( 10.97 )
        Week 136 extension (n=28,28,39)|
    7.5 ( 18.72 )
    5.4 ( 16.73 )
    6.5 ( 11.82 )
        Week 148 extension (n=29,26,37)|
    7.6 ( 18.56 )
    6.8 ( 16.65 )
    5.5 ( 12.95 )
        Week 160 extension (n=30,26,31)|
    7.0 ( 19.10 )
    5.1 ( 15.70 )
    1.5 ( 13.36 )
        Week 172 extension (n=28,26,31)|
    4.8 ( 17.97 )
    5.7 ( 17.52 )
    2.1 ( 12.13 )
        Week 184 extension (n=23,25,29)|
    5.8 ( 15.31 )
    5.8 ( 16.83 )
    1.6 ( 12.45 )
        Week 196 extension (n=21,22,27)|
    6.1 ( 16.94 )
    6.0 ( 18.58 )
    3.8 ( 13.11 )
        Week 208 extension (n=22,23,21)|
    1.2 ( 13.27 )
    6.2 ( 17.31 )
    4.5 ( 12.62 )
        Week 220 extension (n=19,16,21)|
    4.8 ( 21.99 )
    5.8 ( 17.12 )
    7.3 ( 16.28 )
        Week 232 extension (n=19,12,16)|
    2.1 ( 17.51 )
    -0.2 ( 16.73 )
    7.0 ( 15.15 )
        Week 244 extension (n=13,7,10)|
    4.5 ( 20.06 )
    6.3 ( 11.05 )
    3.0 ( 18.65 )
        Week 256 extension (n=10,6,7)|
    6.1 ( 25.91 )
    -3.0 ( 7.07 )
    0.3 ( 14.08 )
        Week 268 extension (n=4,3,3)|
    0.6 ( 16.74 )
    -4.9 ( 4.30 )
    -10.6 ( 7.57 )
    No statistical analyses for this end point

    Secondary: Summary of pasireotide trough concentrations in acromegaly patients following monthly i.m. injections of pasireotide LAR by incident dose from start of extension phase up to Week 196 of the extension phase (PK set)

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    End point title
    		 Summary of pasireotide trough concentrations in acromegaly patients following monthly i.m. injections of pasireotide LAR by incident dose from start of extension phase up to Week 196 of the extension phase (PK set)
    End point description
    PK samples were collected for those patients treated with pasireotide LAR in the core study and who continued on pasireotide LAR in the extension phase. PK samples were collected before the injection of pasireotide LAR only at weeks 112 and 196. PK samples were also collected at weeks 48 and 132 only for all patients treated with octreotide LAR 30 mg or lanreotide ATG 120 mg in the core study who started treatment with pasireotide LAR in the extension study. Blood samples (2.5 mL each sample) were collected to yield 1-mL plasma for analysis of pasireotide LAR oncentration.
    End point type
    Secondary
    End point timeframe
    Extension baseline up to approximately 196 weeks
    End point values
    		 PK trough
    Number of subjects analysed
    98
    Units: mL
    arithmetic mean (standard deviation)
        40 mg Week 48 (n=51)
    5.70 ( 3.159 )
        40 mg Week 112 (n=25)
    8.66 ( 4.154 )
        40 mg Week 132 (n=35)
    9.28 ( 5.067 )
        40 mg Week 196 (n=21)
    10.32 ( 5.473 )
        60 mg Week 112 (n=72)
    14.06 ( 9.807 )
        60 mg Week 196 (n=65)
    14.96 ( 10.210 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Pasireotide LAR 40 mg
    Reporting group description
    		 Pasireotide LAR 40 mg

    Reporting group title
    Pasireotide LAR 60 mg
    Reporting group description
    		 Pasireotide LAR 60 mg

    Reporting group title
    Cross-over to pasireotide
    Reporting group description
    		 Cross-over to pasireotide

    Serious adverse events
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg Cross-over to pasireotide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 63 (28.57%)
    14 / 62 (22.58%)
    20 / 62 (32.26%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Joint arthroplasty
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Maxillofacial operation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral surgery
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Drug ineffective
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Drug administration error
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocephalus
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cowden's disease
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flavivirus infection
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia unawareness
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pasireotide LAR 40 mg Pasireotide LAR 60 mg Cross-over to pasireotide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 63 (93.65%)
    58 / 62 (93.55%)
    61 / 62 (98.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 63 (11.11%)
    4 / 62 (6.45%)
    5 / 62 (8.06%)
         occurrences all number
    7
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 63 (1.59%)
    5 / 62 (8.06%)
    5 / 62 (8.06%)
         occurrences all number
    1
    5
    5
    Fatigue
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 62 (6.45%)
    2 / 62 (3.23%)
         occurrences all number
    4
    4
    2
    Pyrexia
         subjects affected / exposed
    7 / 63 (11.11%)
    1 / 62 (1.61%)
    2 / 62 (3.23%)
         occurrences all number
    9
    3
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 63 (7.94%)
    3 / 62 (4.84%)
    2 / 62 (3.23%)
         occurrences all number
    5
    3
    2
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 62 (1.61%)
    6 / 62 (9.68%)
         occurrences all number
    2
    0
    8
    Blood glucose increased
         subjects affected / exposed
    3 / 63 (4.76%)
    6 / 62 (9.68%)
    0 / 62 (0.00%)
         occurrences all number
    3
    6
    0
    Insulin-like growth factor decreased
         subjects affected / exposed
    2 / 63 (3.17%)
    4 / 62 (6.45%)
    2 / 62 (3.23%)
         occurrences all number
    2
    6
    2
    Lipase increased
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 62 (1.61%)
    4 / 62 (6.45%)
         occurrences all number
    6
    1
    6
    Weight increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    1
    0
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 63 (0.00%)
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    0
    6
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    6 / 63 (9.52%)
    2 / 62 (3.23%)
    2 / 62 (3.23%)
         occurrences all number
    15
    2
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 63 (12.70%)
    3 / 62 (4.84%)
    3 / 62 (4.84%)
         occurrences all number
    12
    7
    4
    Headache
         subjects affected / exposed
    18 / 63 (28.57%)
    6 / 62 (9.68%)
    8 / 62 (12.90%)
         occurrences all number
    36
    17
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 63 (14.29%)
    10 / 62 (16.13%)
    16 / 62 (25.81%)
         occurrences all number
    17
    13
    17
    Leukopenia
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 62 (3.23%)
    4 / 62 (6.45%)
         occurrences all number
    0
    3
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 63 (15.87%)
    10 / 62 (16.13%)
    6 / 62 (9.68%)
         occurrences all number
    19
    13
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 63 (9.52%)
    3 / 62 (4.84%)
    1 / 62 (1.61%)
         occurrences all number
    6
    8
    1
    Constipation
         subjects affected / exposed
    5 / 63 (7.94%)
    3 / 62 (4.84%)
    3 / 62 (4.84%)
         occurrences all number
    5
    4
    3
    Diarrhoea
         subjects affected / exposed
    14 / 63 (22.22%)
    17 / 62 (27.42%)
    11 / 62 (17.74%)
         occurrences all number
    26
    47
    19
    Large intestine polyp
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 62 (1.61%)
    4 / 62 (6.45%)
         occurrences all number
    2
    1
    4
    Nausea
         subjects affected / exposed
    7 / 63 (11.11%)
    7 / 62 (11.29%)
    3 / 62 (4.84%)
         occurrences all number
    13
    12
    5
    Vomiting
         subjects affected / exposed
    8 / 63 (12.70%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences all number
    11
    1
    0
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    3 / 63 (4.76%)
    3 / 62 (4.84%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    4
    Cholelithiasis
         subjects affected / exposed
    21 / 63 (33.33%)
    20 / 62 (32.26%)
    17 / 62 (27.42%)
         occurrences all number
    25
    24
    16
    Gallbladder polyp
         subjects affected / exposed
    4 / 63 (6.35%)
    3 / 62 (4.84%)
    1 / 62 (1.61%)
         occurrences all number
    4
    3
    1
    Hepatic steatosis
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 62 (6.45%)
    2 / 62 (3.23%)
         occurrences all number
    3
    4
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 63 (4.76%)
    8 / 62 (12.90%)
    2 / 62 (3.23%)
         occurrences all number
    3
    8
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    7 / 63 (11.11%)
    2 / 62 (3.23%)
    0 / 62 (0.00%)
         occurrences all number
    7
    3
    0
    Renal cyst
         subjects affected / exposed
    3 / 63 (4.76%)
    5 / 62 (8.06%)
    2 / 62 (3.23%)
         occurrences all number
    3
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 63 (11.11%)
    9 / 62 (14.52%)
    3 / 62 (4.84%)
         occurrences all number
    7
    11
    3
    Back pain
         subjects affected / exposed
    13 / 63 (20.63%)
    7 / 62 (11.29%)
    3 / 62 (4.84%)
         occurrences all number
    16
    9
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    0
    5
    0
    Pain in extremity
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 62 (3.23%)
    4 / 62 (6.45%)
         occurrences all number
    5
    3
    4
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 63 (3.17%)
    6 / 62 (9.68%)
    0 / 62 (0.00%)
         occurrences all number
    3
    7
    0
    Influenza
         subjects affected / exposed
    9 / 63 (14.29%)
    9 / 62 (14.52%)
    5 / 62 (8.06%)
         occurrences all number
    11
    11
    5
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 63 (6.35%)
    3 / 62 (4.84%)
    1 / 62 (1.61%)
         occurrences all number
    5
    5
    1
    Urinary tract infection
         subjects affected / exposed
    6 / 63 (9.52%)
    5 / 62 (8.06%)
    9 / 62 (14.52%)
         occurrences all number
    9
    7
    12
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 63 (11.11%)
    9 / 62 (14.52%)
    5 / 62 (8.06%)
         occurrences all number
    16
    15
    7
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    20 / 63 (31.75%)
    25 / 62 (40.32%)
    16 / 62 (25.81%)
         occurrences all number
    20
    27
    20
    Dyslipidaemia
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences all number
    4
    1
    3
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 63 (7.94%)
    6 / 62 (9.68%)
    8 / 62 (12.90%)
         occurrences all number
    7
    9
    11
    Hyperglycaemia
         subjects affected / exposed
    25 / 63 (39.68%)
    24 / 62 (38.71%)
    15 / 62 (24.19%)
         occurrences all number
    45
    31
    19
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    1
    7
    1
    Hypoglycaemia
         subjects affected / exposed
    7 / 63 (11.11%)
    7 / 62 (11.29%)
    4 / 62 (6.45%)
         occurrences all number
    11
    11
    5
    Hypomagnesaemia
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 62 (3.23%)
    0 / 62 (0.00%)
         occurrences all number
    5
    2
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 62 (4.84%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2011
    To clarify that patients treated with octreotide LAR 30 mg or lanreotide ATG 120 mg and concomitant GHR-antagonist or dopamine agonists could only be included in the study if the GHR-antagonist or dopamine agonists were discontinued 8 weeks before Visit 1 (Screening) as stated in the current version of the protocol and if they fulfilled the following, additional requirement: such patients must have been treated with octreotide LAR 30 mg or lanreotide ATG 120 mg as monotherapy for at least 6 months prior to the start of concomitant GHR-antagonist or dopamine agonists. During the 6-month monotherapy patients should not have been biochemically controlled.  To ensure consistency of the secondary objectives and variables concerning tumor volume with the visit evaluation schedule. According to the visit evaluation schedule in the current protocol, MRI was to be performed at Visit 1 (Screening) and not at Visit 2. corresponding analysis concerning time to response. GH and IGF-1 was only scheduled to be assessed at 12 weeks (Visit 6) and study completion which did not give suitable time intervals to calculate meaningful Kaplan-Meier estimates. To include an extension phase to the core study 
    01 May 2011
    To specify an end-date of the extension phase (Appendix 16.1.1- Appendix 3) for Norway and the UK as Health Authorities in both countries do not accept commercial availability of the study drug (pasireotide LAR) as a valid scientific treatment endpoint
    01 Dec 2011
    To define a key secondary objective and related endpoint. IGF-1 was currently considered the most reliable measure of disease activity in patients with acromegaly and frequently used as the main driver for treatment decision (Giustina et al 2010). Therefore, the effect of pasireotide LAR 40 mg or 60 mg versus continuing the same treatment on the proportion of patients achieving normal sex- and age-adjusted IGF-1 levels at 24 weeks would become the key secondary objective
    16 Dec 2011
    To extend the end-date of the extension phase (Appendix 3) as required by the Health Authorities in Norway and the UK to 31-Dec-2015.
    22 Mar 2013
    To extend the end-date of the extension phase (Appendix 3) as required by the Health Authorities in Norway and the UK to 31-Dec-2015
    22 Mar 2013
    To allow for use of concomitant medications used to treat acromegaly with pasireotide LAR 40 mg and 60 mg in the extension phase of this study in patients who have not achieved biochemical control of acromegaly on pasireotide LAR monotherapy after a minimum of one year. To allow for use of medications with conditional risk for Torsade des Pointes and congenital long QT interval in the extension phase of this study
    13 Feb 2015
    To include a detailed description of the transition phase; Patients must be transitioned to commercial pasireotide LAR within 3 months after approval

    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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