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    Clinical Trial Results:
    A multicenter, randomized, blinded study to assess safety and efficacy of Pasireotide LAR vs octreotide LAR in patients with active acromegaly Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

    Summary
    EudraCT number
    		 2007-001972-36
    Trial protocol
    		 CZ   FR   BE   GB   GR   IT   ES   NL   DK   SE   HU   PL   PT   DE  
    Global end of trial date
    11 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jul 2018
    First version publication date
    19 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SOM230C2305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00600886
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare proportion of patients with reduction of GH to <2.5 μg/L and normalization of IGF-1 (age and sex related) between the two treatment groups at 12 months.
    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
    11 Feb 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    China: 35
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Brazil: 40
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    358
    EEA total number of subjects
    101
    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)
    335
    From 65 to 84 years
    22
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 151 patients (pts) planned per treatment group; study enrolled 358 pts. 176 & 182 were randomized to receive pasireotide & octreotide, respectively. From pasireotide group, 74 pts continued same treatment in extension & 38 crossed over to octreotide; from octreotide group 46 pts continued same treatment in extension & 81 crossed over to pasireotide

    Period 1
    Period 1 title
    Core Phase - Full Analysis Set (FAS)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide LAR
    Arm description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide LAR - intramuscular (i.m.) depot injection given once every 28 days.

    Arm title
    		 Octreotide LAR
    Arm description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Octreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Octreotide LAR - i.m. depot injection given once every 28 days.

    Number of subjects in period 1
    		Pasireotide LAR Octreotide LAR
    Started
    176
    182
    Completed
    141
    156
    Not completed
    35
    26
         Abnormal laboratory value(s)
    1
    -
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    5
    3
         Adverse event, non-fatal
    14
    6
         Administrative Problems
    2
    -
         Lost to follow-up
    1
    -
         Lack of efficacy
    5
    8
         Protocol deviation
    7
    8
    Period 2
    Period 2 title
    Extension - Same Treatment (FAS)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide LAR
    Arm description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide LAR - intramuscular (i.m.) depot injection given once every 28 days.

    Arm title
    		 Octreotide LAR
    Arm description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Octreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Octreotide LAR - i.m. depot injection given once every 28 days.

    Number of subjects in period 2 [1]
    		Pasireotide LAR Octreotide LAR
    Started
    74
    46
    Completed
    28
    35
    Not completed
    46
    11
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    16
    2
         Adverse event, non-fatal
    4
    1
         Abnormal Lab Value (s)
    4
    -
         Condition no longer requires study drug
    6
    -
         Administrative Problems
    9
    3
         Lost to follow-up
    3
    1
         Lack of efficacy
    3
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Completed = anyone who did not discontinue prior to month 12.. I t di not mean completed the study.
    Period 3
    Period 3 title
    Extension - after crossover (CAS)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Pasireotide LAR
    Arm description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide LAR - intramuscular (i.m.) depot injection given once every 28 days.

    Arm title
    		 Octreotide LAR
    Arm description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Octreotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Octreotide LAR - i.m. depot injection given once every 28 days.

    Number of subjects in period 3
    		Pasireotide LAR Octreotide LAR
    Started
    81
    38
    Completed
    19
    25
    Not completed
    62
    13
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    19
    4
         Adverse event, non-fatal
    19
    1
         Subject no longer requires study drug
    3
    -
         Abnormal Lab Value (s)
    3
    -
         Administrative Problems
    4
    4
         Lack of efficacy
    13
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.

    Reporting group title
    Octreotide LAR
    Reporting group description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.

    Reporting group values
    		 Pasireotide LAR Octreotide LAR Total
    Number of subjects
    		 176 182 358
    Age Categorical
    Units: Subjects
        <65 Years
    		 168 167 335
        >=65 years
    		 8 15 23
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 45.1 ( 12.37 ) 45.6 ( 12.97 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 91 95 186
        Male
    		 85 87 172

    End points

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    End points reporting groups
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.

    Reporting group title
    Octreotide LAR
    Reporting group description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.

    Reporting group title
    Octreotide LAR
    Reporting group description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.
    Reporting group title
    Pasireotide LAR
    Reporting group description
    		 Patients in this arm received Pasireotide LAR 40 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 20 or 60 mg, respectively. Patients who responded to Pasireotide LAR (i.e. the randomized treatment) at the end of the core (Month 12), continued Pasireotide LAR treatment in the extension. Patients who did not respond to Pasireotide LAR at the end of the core (Month 12) were allowed to switch to receive Octreotide LAR in the extension.

    Reporting group title
    Octreotide LAR
    Reporting group description
    		 Patients in this arm received Octreotide LAR 20 mg im depot injection, blinded, once every 28 days (± 2 days) for 12 months. Dose could be down- or up-titrated to 10 or 30 mg, respectively. Patients who responded to Octreotide LAR (i.e. the randomized treatment) at the end of the core (Month 12) continued Octreotide LAR treatment in the extension (up to 2 years of treatment). Patients who did not respond to Octreotide LAR at the end of the core (Month 12) were allowed to switch to receive Pasireotide LAR in the extension.

    Subject analysis set title
    Pasireotide LAR (Core)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes data from the 12-month blinded core phase for patients randomized to receive Pasireotide LAR.

    Subject analysis set title
    Octreotide LAR (Core)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes data from the 12-month blinded core phase for patients randomized to receive Octreotide LAR.

    Subject analysis set title
    Pasireotide LAR (Core & Extension)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes data from both blinded core and extension phase (up to Month 26) for patients who continued the same treatment (Pasireotide LAR) as in the core. For patients who switched from blinded Pasireotide LAR to Octreotide LAR treatment in the extension, only data collected before crossover is included.

    Subject analysis set title
    Octreotide LAR (Core & Extension)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Includes data from both blinded core and extension phase (up to Month 26) for patients who continued the same treatment (Octreotide LAR) as in the core. For patients who switched from blinded Octreotide LAR to Pasireotide LAR treatment in the extension, only data collected before crossover is included.

    Subject analysis set title
    Pasireotide LAR 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Pasireotide LAR 20 mg injection prior to PK sample collection.

    Subject analysis set title
    Pasireotide LAR 40 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Pasireotide LAR 40 mg injection prior to PK sample collection.

    Subject analysis set title
    Pasireotide LAR 60mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Pasireotide LAR 60 mg injection prior to PK sample collection.

    Subject analysis set title
    Octreotide LAR 10mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Octreotide LAR 10 mg injection prior to PK sample collection.

    Subject analysis set title
    Octreotide LAR 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Octreotide LAR 20 mg injection prior to PK sample collection.

    Subject analysis set title
    Octreotide LAR 30 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients in this arm received Octreotide LAR 30 mg injection prior to PK sample collection.

    Subject analysis set title
    Crossed over to Pasireotide LAR (Extension)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes data from the blinded extension phase (up to Month 26) collected after the crossover time point for patients who crossed over from Octreotide LAR treatment in the core to Pasireotide LAR treatment in the extension phase.

    Subject analysis set title
    Crossed over to Octreotide LAR (Extension)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Includes data from the blinded extension phase (up to Month 26) collected after the crossover time point for patients who crossed over from Pasireotide LAR treatment in the core to Octreotide LAR treatment in the extension phase.

    Primary: Percentage of participants with a reduction of Mean GH Level to <2.5 μg/L and the Normalization of IGF-1

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    End point title
    		 Percentage of participants with a reduction of Mean GH Level to <2.5 μg/L and the Normalization of IGF-1
    End point description
    Percentage of participants with a reduction of mean GH levels to <2.5μg/L (based on a 5-point 2-hour profile). Missing mean GH levels at M12 were imputed using data obtained at or after M6 by the last observation carried forward method; otherwise, patients were considered as non-responders. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Pasireotide LAR (Core) Octreotide LAR (Core)
    Number of subjects analysed
    176
    182
    Units: Percentage of Participants
    number (confidence interval 95%)
        Overall (N=176, 182)
    31.3 (24.5 to 38.7)
    19.2 (13.8 to 25.7)
        Post Surgery (N=71, 78)
    39.4 (28 to 51.7)
    21.8 (13.2 to 32.6)
        De novo (N=105, 104)
    25.7 (17.7 to 35.2)
    17.3 (10.6 to 26)
    Statistical analysis title
    		 Stats Analysis between treatment groups -Overall
    Comparison groups
    Pasireotide LAR (Core) v Octreotide LAR (Core)
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.942
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 3.168
    Statistical analysis title
    		 Analysis between treatment groups: Post Surgery
    Comparison groups
    Pasireotide LAR (Core) v Octreotide LAR (Core)
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 4.79
    Statistical analysis title
    		 Analysis between treatment groups: De Novo
    Comparison groups
    Pasireotide LAR (Core) v Octreotide LAR (Core)
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.654
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.846
         upper limit
    		 3.234

    Secondary: Percentage of participants with a reduction of mean GH Level to < 2.5μg/L

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    End point title
    		 Percentage of participants with a reduction of mean GH Level to < 2.5μg/L
    End point description
    Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Missing mean GH levels at M12 were imputed using data obtained at or after M6 by the last observation carried forward method; otherwise, patients were considered as non-responders. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated.
    End point type
    Secondary
    End point timeframe
    12 Months
    End point values
    		 Pasireotide LAR (Core) Octreotide LAR (Core)
    Number of subjects analysed
    176
    182
    Units: Percentage of participants
    number (confidence interval 95%)
        Overall (n = 176, n = 182)
    48.3 (40.7 to 55.9)
    51.6 (44.1 to 59.1)
        Post surgery (n = 71, n = 78)
    52.1 (39.9 to 64.1)
    51.3 (39.7 to 62.8)
        De novo (n = 105, n = 104)
    45.7 (36 to 55.7)
    51.9 (41.9 to 61.8)
    No statistical analyses for this end point

    Secondary: Change from baseline in tumor volume at 12 months

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    End point title
    		 Change from baseline in tumor volume at 12 months
    End point description
    Absolute and percentage change from baseline in tumor volume (assessed by pituitary MRI) Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 Months
    End point values
    		 Pasireotide LAR (Core) Octreotide LAR (Core)
    Number of subjects analysed
    176
    182
    Units: mm^3
    arithmetic mean (standard deviation)
        Overall (n = 166, 169) at baseline
    2420.7 ( 4159.21 )
    2259.2 ( 3390.2 )
        Overall (n = 120, 124) % change at month 12
    -39.7 ( 21.83 )
    -38 ( 24.47 )
        Post surgery (n = 70, 74) at baseline
    2185.2 ( 2861.09 )
    2196.5 ( 3922.08 )
        Post surgery (n = 44, 52) % change at month 12
    -39.5 ( 20.6 )
    -39 ( 23.81 )
        De novo (n = 96, 95) at baseline
    2592.4 ( 4901.99 )
    2308.1 ( 2930.84 )
        De novo (n = 76, 72) % change at month 12
    -39.9 ( 22.65 )
    -37.2 ( 25.07 )
        Overall (n = 121, 128) absolute change at month 12
    -987.1 ( 2448.14 )
    -801.2 ( 1676.62 )
        Post surgery (n = 44, 55) abs. change at month 12
    -873.7 ( 1282.06 )
    -713.8 ( 1708.2 )
        De novo (n = 77, 73) absolute change at month 12
    -1051.9 ( 2919.18 )
    -867.1 ( 1661.24 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with normalization of IGF-1

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    End point title
    		 Percentage of participants with normalization of IGF-1
    End point description
    Percentage of participants with normalization of sex- and age-adjusted IGF-1. Missing IGF-1 levels at M12 were imputed using data obtained at or after M6 by the last observation carried forward method; otherwise, patients were considered as non-responders. Post surgery = patients with prior. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated.
    End point type
    Secondary
    End point timeframe
    12 Months
    End point values
    		 Pasireotide LAR (Core) Octreotide LAR (Core)
    Number of subjects analysed
    176
    182
    Units: Percentage of participants
    number (confidence interval 95%)
        Overall (n = 176, 182)
    38.6 (31.4 to 46.3)
    23.6 (17.7 to 30.5)
        Post surgery (n = 71, 78)
    50.7 (38.6 to 62.8)
    26.9 (17.5 to 38.2)
        De novo (n = 105, 104)
    30.5 (21.9 to 40.2)
    21.2 (13.8 to 30.3)
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction of mean GH Level to < 2.5μg/L and normalization of IGF-1

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    End point title
    		 Percentage of participants with a reduction of mean GH Level to < 2.5μg/L and normalization of IGF-1
    End point description
    Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Denominator for time points up to Month 12 is the Full Analysis Set (FAS). Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover. Analysis was based on data up to crossover (i.e., included data from both blinded core & ext. phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included.)
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12, 16, 19, 22, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 3 (n = 176, 182)
    30.1 (23.4 to 37.5)
    21.4 (15.7 to 28.1)
        Month 6 (n = 176, 182)
    30.1 (23.4 to 37.5)
    19.8 (14.3 to 26.3)
        Month 9 (n = 176, 182)
    27.8 (21.4 to 35.1)
    23.1 (17.2 to 29.9)
        Month 12 (n = 176, 182)
    29 (22.4 to 36.3)
    17.6 (12.3 to 23.9)
        Month 16 (n = 147, 153)
    25.2 (18.4 to 33)
    12.4 (7.6 to 18.7)
        Month 19 (n = 147, 153)
    23.1 (16.6 to 30.8)
    13.7 (8.7 to 20.2)
        Month 22 (n = 147, 153)
    25.2 (18.4 to 33)
    16.3 (10.9 to 23.2)
        Month 25 (n = 147, 153)
    24.5 (17.8 to 32.3)
    13.7 (8.7 to 20.2)
    No statistical analyses for this end point

    Secondary: Summary of mean GH values

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    End point title
    		 Summary of mean GH values
    End point description
    Mean GH levels (based on a 5-point profile over 2 hours). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, Months 3, 6, 9, 12, 16, 19, 22, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: μg/L
    arithmetic mean (standard deviation)
        Baseline (n = 167, 178)
    21.9 ( 32.14 )
    18.8 ( 25.95 )
        Month 3 (n = 164, 173)
    6.3 ( 12.54 )
    5.8 ( 12.87 )
        Month 6 (n = 151, 165)
    5.6 ( 11.47 )
    5.2 ( 10.99 )
        Month 9 (n = 136, 157)
    4.9 ( 9.62 )
    4.3 ( 9.7 )
        Month 12 (n = 136, 151)
    4.6 ( 9.51 )
    4.5 ( 11.34 )
        Month 16 (n = 64, 38)
    2.3 ( 5.64 )
    1.4 ( 1.49 )
        Month 19 (n = 62, 38)
    2.1 ( 5.68 )
    1.5 ( 1.68 )
        Month 22 (n = 60, 39)
    2.1 ( 6.15 )
    1.4 ( 1.43 )
        Month 25 (n = 62, 40)
    2 ( 5.02 )
    1.2 ( 1.11 )
    No statistical analyses for this end point

    Secondary: Time to first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1 (No. of Responders: Pasireotite LAR = 81, Octreotide LAR = 63) )

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    End point title
    		 Time to first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1 (No. of Responders: Pasireotite LAR = 81, Octreotide LAR = 63) )
    End point description
    Time to first response for patients achieving a reduction of mean GH level to < 2.5 μg/L and normalization of IGF-1. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Up to 26 months
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Weeks
        median (confidence interval 95%)
    12.6 (12.3 to 13)
    12.4 (12.3 to 13.7)
    No statistical analyses for this end point

    Secondary: Severity scores of acromegaly symptoms

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    End point title
    		 Severity scores of acromegaly symptoms
    End point description
    Severity scores of acromegaly symptoms (Headache, Fatigue, Perspiration, Paresthesias, Osteoarthralgia). Symptoms were scored from 0 (no symptom) to 4 (very severe). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Headache - Baseline (n = 175, 181)
    0.9 ( 1.05 )
    1 ( 1.14 )
        Fatigue - Baseline (n = 175, 181)
    1.2 ( 1.13 )
    1.4 ( 1.23 )
        Perspiration - Baseline (n = 175, 181)
    1.1 ( 1.21 )
    1.3 ( 1.31 )
        Paresthesia - Baseline (n = 175, 180)
    0.7 ( 1 )
    0.8 ( 1.15 )
        Osteoarthraliga - Baseline (n = 174, 178)
    1 ( 1.05 )
    1.3 ( 1.26 )
        Headache - M12 (n = 138, 149)
    0.5 ( 0.77 )
    0.6 ( 0.79 )
        Fatigue - M12 (n = 138, 149)
    0.8 ( 0.95 )
    0.7 ( 0.99 )
        Perspiration - M12 (n = 138, 149)
    0.4 ( 0.81 )
    0.5 ( 0.91 )
        Paresthesia - M12 (n = 138, 149)
    0.3 ( 0.63 )
    0.4 ( 0.72 )
        Osteoarthraliga - M12 (n = 137, 149)
    0.5 ( 0.8 )
    0.7 ( 1 )
        Headache - M25 (n = 64, 40)
    0.4 ( 0.61 )
    0.6 ( 0.77 )
        Fatigue - M25 (n = 64, 40)
    0.5 ( 0.71 )
    0.7 ( 0.89 )
        Perspiration - M25 (n = 64, 40)
    0.4 ( 0.72 )
    0.4 ( 0.67 )
        Paresthesia - M25 (n = 64, 40)
    0.2 ( 0.49 )
    0.4 ( 0.67 )
        Osteoarthraliga - M25 (n = 64, 40)
    0.4 ( 0.79 )
    0.8 ( 1.07 )
    No statistical analyses for this end point

    Secondary: Ring size

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    End point title
    		 Ring size
    End point description
    Ring size (based on jeweler’s finger gauge). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: ring zize
    arithmetic mean (standard deviation)
        Baseline left hand (LH) 4th digit (n = 112, 115)
    11.6 ( 2 )
    11.8 ( 1.97 )
        Baseline left hand 5th digit (n = 21, 18)
    11.7 ( 2.82 )
    12.4 ( 2.88 )
        Baseline right hand (RH) 4th digit (n = 23, 29)
    12.5 ( 2.01 )
    11.4 ( 2.54 )
        Baseline right hand 5th digit (n = 5, 8)
    11.2 ( 3.35 )
    11.3 ( 2.95 )
        M12 LH 4th digit (n = 97, 102)
    10.6 ( 2.05 )
    11.1 ( 1.95 )
        M12 LH 5th digit (n = 12, 10)
    11.8 ( 1.81 )
    12.4 ( 1.78 )
        M12 RH 4th digit (21, 25)
    12.2 ( 2.12 )
    11.3 ( 2.18 )
        M12 RH 5th digit (n = 5, 6)
    10.7 ( 3.96 )
    10.5 ( 2.14 )
        M25 LH 4th digit (n = 49, 33)
    10.1 ( 2.12 )
    11.1 ( 1.95 )
        M25 LH 5th digit (n = 5, 2)
    10 ( 2.45 )
    14.3 ( 0.35 )
        M25 RH 4th digit (n = 8, 4)
    11.8 ( 1.98 )
    10.9 ( 1.65 )
        M25 RH 5th digit (n = 2, 1)
    7.8 ( 4.6 )
    7.5 ( 9.99 )
    No statistical analyses for this end point

    Secondary: Health-related Quality-of-life as measured by the AcroQoL questionnaire

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    End point title
    		 Health-related Quality-of-life as measured by the AcroQoL questionnaire
    End point description
    Acromegalyy quality of life (AcroQoL) total scores. The AcroQoL questionnaire is unidimensional and contains 22 items divided in two scales: one that evaluates physical aspects (eight items) and another one that evaluates psychological aspects (14 items). The scoring of the questionnaire was performed as specified by the instrument developers. Higher scores represent better quality of life. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline (n =173, 178)
    58.4 ( 19.97 )
    55.6 ( 19.79 )
        M12 (n = 136, 148)
    65.7 ( 21.64 )
    61.6 ( 21.01 )
        M25 (n = 58, 38)
    69.3 ( 18.76 )
    62.9 ( 18.86 )
    No statistical analyses for this end point

    Secondary: Summary of prolactin levels

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    End point title
    		 Summary of prolactin levels
    End point description
    Prolactin Levels. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, Months 12, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: μg/L
    arithmetic mean (standard deviation)
        Baseline (n = 176, 182)
    20.6 ( 53 )
    15.8 ( 22.05 )
        M12 (n = 135, 146)
    8.9 ( 19.24 )
    11.7 ( 19.09 )
        M25 (n = 63, 40)
    5.4 ( 4.37 )
    6.7 ( 4.63 )
    No statistical analyses for this end point

    Secondary: Duration of response for patients achieving a reduction of mean GH level to <2.5 μg/L and the normalization of IGF-1 at Month 12 (No. of Responders: Pasireotide LAR = 51, Octreotide LAR = 32)

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    End point title
    		 Duration of response for patients achieving a reduction of mean GH level to <2.5 μg/L and the normalization of IGF-1 at Month 12 (No. of Responders: Pasireotide LAR = 51, Octreotide LAR = 32)
    End point description
    The duration of response is defined as the time from the date that patient first met and maintained the response criteria based on primary efficacy variable to the date that patient lost response status. Median and corresponding 95% CI are derived based on Kaplan-Meier method. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Up to 26 months
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Weeks
        median (confidence interval 95%)
    64.4 (52.1 to 100.4)
    64.6 (40 to 92)
    No statistical analyses for this end point

    Secondary: Pasireotide trough concentrations by incident dose

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    End point title
    		 Pasireotide trough concentrations by incident dose
    End point description
    Pasireotide LAR trough concentrations by incident dose (last dose administered prior to PK sample collection). PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28±2 days window were excluded. 5 patients with evaluable PK data in the pasireotide arm received erroneously 20 mg pasireotide LAR at baseline.
    End point type
    Secondary
    End point timeframe
    Months 1 - 12
    End point values
    		 Pasireotide LAR 20 mg Pasireotide LAR 40 mg Pasireotide LAR 60mg
    Number of subjects analysed
    172
    172
    172
    Units: ng/mL
    arithmetic mean (standard deviation)
        M1 (n = 5, 146, 0)
    4.65 ( 0.645 )
    6.65 ( 3.641 )
    99.99 ( 9.999 )
        M2 (n = 6, 135, 0)
    2.88 ( 1.371 )
    7.81 ( 3.505 )
    99.99 ( 9.999 )
        M3 (n = 2,135, 0)
    3.39 ( 2.659 )
    8.7 ( 5.402 )
    99.99 ( 9.999 )
        M4 (n = 3, 88, 49)
    3.93 ( 1.858 )
    9.51 ( 5.487 )
    13.48 ( 7.75 )
        M5 (n = 4, 77, 56)
    5.22 ( 4.077 )
    10.92 ( 6.017 )
    13.42 ( 6.902 )
        M6 (n = 3, 71, 57)
    2.87 ( 1.101 )
    10.59 ( 6.216 )
    13.08 ( 6.967 )
        M7 (n =3, 69, 60)
    2.29 ( 0.857 )
    11.85 ( 7.781 )
    14.76 ( 6.868 )
        M8 (n =3, 63, 70)
    3.65 ( 1.865 )
    12.33 ( 7.619 )
    15.88 ( 9.073 )
        M9 (n =4, 59, 65)
    4.8 ( 1.957 )
    12.75 ( 8.604 )
    16.03 ( 10.852 )
        M10 (n =5, 61, 59)
    5.66 ( 3.606 )
    12.42 ( 7.252 )
    16.01 ( 11.497 )
        M11 (n =5, 53, 65)
    5.1 ( 2.375 )
    12.62 ( 6.92 )
    16.31 ( 10.596 )
        M12 (n =4, 45, 58)
    4.54 ( 1.634 )
    11.11 ( 6.489 )
    16.16 ( 9.323 )
    No statistical analyses for this end point

    Secondary: Octreotide trough concentrations by incident dose

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    End point title
    		 Octreotide trough concentrations by incident dose
    End point description
    Octreotide LAR trough concentrations by incident dose (last dose administered prior to PK sample collection). PK observations with missing concentrations, missing dose, missing elapsed time or an elapsed time from previous injection outside of 28±2 days window were excluded.
    End point type
    Secondary
    End point timeframe
    Months 1 - 12
    End point values
    		 Octreotide LAR 10mg Octreotide LAR 20 mg Octreotide LAR 30 mg
    Number of subjects analysed
    178
    178
    178
    Units: ng/mL
    arithmetic mean (standard deviation)
        M1 (n = 0, 153, 0)
    9.99 ( 9.999 )
    0.86 ( 0.493 )
    9.99 ( 9.999 )
        M2 (n = 2, 139, 0)
    0.61 ( 0.28 )
    1.21 ( 0.663 )
    9.99 ( 9.999 )
        M3 (n = 2, 134, 0)
    0.62 ( 0.107 )
    1.29 ( 0.654 )
    9.99 ( 9.999 )
        M4 (n = 1, 79, 64)
    0.19 ( 9.999 )
    1.45 ( 0.653 )
    1.55 ( 0.658 )
        M5 (n = 0, 63, 82)
    9.99 ( 9.999 )
    1.65 ( 0.876 )
    2.14 ( 1.156 )
        M6 (n = 2, 62, 88)
    1.33 ( 0.754 )
    1.58 ( 0.811 )
    2.12 ( 0.99 )
        M7 (n = 1, 61, 82)
    0.7 ( 9.999 )
    1.46 ( 0.704 )
    2.14 ( 1.009 )
        M8 (n = 0, 50, 88)
    9.99 ( 9.999 )
    1.55 ( 0.727 )
    2.16 ( 1.127 )
        M9 (n = 0, 47, 93)
    9.99 ( 9.999 )
    1.74 ( 1.013 )
    2.2 ( 0.992 )
        M10 (n = 0, 49, 82)
    9.99 ( 9.999 )
    1.66 ( 0.995 )
    2.5 ( 1.194 )
        M11 (n = 0, 43, 87)
    9.99 ( 9.999 )
    1.74 ( 0.89 )
    2.39 ( 1.103 )
        M12 (n = 1, 37, 76)
    0.3 ( 9.999 )
    1.58 ( 0.695 )
    2.55 ( 1.252 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction of mean GH Level to < 2.5μg/L and normalization of IGF-1 after crossover

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    End point title
    		 Percentage of participants with a reduction of mean GH Level to < 2.5μg/L and normalization of IGF-1 after crossover
    End point description
    Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS).
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension)
    Number of subjects analysed
    81
    Units: Percentage of participants
    number (confidence interval 95%)
        M3 after crossover
    17.3 (9.8 to 27.3)
        M6 after crossover
    21 (12.7 to 31.5)
        M9 after crossover
    22.2 (13.7 to 32.8)
        M12 after crossover
    17.3 (9.8 to 27.3)
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction of mean GH Level to < 2.5μg/L

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    End point title
    		 Percentage of participants with a reduction of mean GH Level to < 2.5μg/L
    End point description
    Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). Denominator for time points up to Month 12 is the Full Analysis Set. Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover.
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12, 16, 19, 22, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Percentage of participants
    number (confidence interval 95%)
        M3 (n= 176, 182)
    49.4 (41.8 to 57.1)
    43.4 (36.1 to 50.9)
        M6 (n= 176, 182)
    45.5 (37.9 to 53.1)
    47.8 (40.4 to 55.3)
        M9 (n= 176, 182)
    42.6 (35.2 to 50.3)
    46.2 (38.8 to 53.7)
        M12 (n= 176, 182)
    43.2 (35.8 to 50.8)
    47.3 (39.8 to 54.8)
        M16 (n = 147, 153)
    33.3 (25.8 to 41.6)
    22.2 (15.9 to 29.6)
        M19 (n = 147, 153)
    36.7 (28.9 to 45.1)
    21.6 (15.3 to 28.9)
        M22 (n = 147, 153)
    35.4 (27.7 to 43.7)
    22.2 (15.9 to 29.6)
        M25 (n = 147, 153)
    35.4 (27.7 to 43.7)
    24.2 (17.6 to 31.8)
    No statistical analyses for this end point

    Secondary: Percentage of participants with normalization of IGF-1

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    End point title
    		 Percentage of participants with normalization of IGF-1
    End point description
    Percentage of participants with normalization of sex- and age-adjusted IGF-1. Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included). Denominator for time points up to Month 12 is the FAS. Denominator for time points after Month 12 excludes patients who completed the core and did not enter the extension. Patients who discontinued were considered non-responders for the time points after discontinuation, patients who crossed over were considered non-responders for all time points after crossover.
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12, 16, 19, 22, 25
    End point values
    		 Pasireotide LAR (Core & Extension) Octreotide LAR (Core & Extension)
    Number of subjects analysed
    176
    182
    Units: Percentage of participants
    number (confidence interval 95%)
        M3 (n = 176, 182)
    35.2 (28.2 to 42.8)
    25.3 (19.1 to 32.2)
        M6 (n = 176, 182)
    35.8 (28.7 to 43.4)
    24.2 (18.1 to 31.1)
        M9 (n = 176, 182)
    34.1 (27.1 to 41.6)
    28 (21.6 to 35.1)
        M12 (n = 176, 182)
    35.8 (28.7 to 43.4)
    22 (16.2 to 28.7)
        M16 (n = 147, 153)
    29.9 (22.7 to 38)
    13.7 (8.7 to 20.2)
        M19 (n = 147, 153)
    25.2 (18.4 to 33)
    15.7 (10.3 to 22.4)
        M22 (n = 147, 153)
    25.9 (19 to 33.7)
    17 (11.4 to 23.9)
        M25 (n = 147, 153)
    25.9 (19 to 33.7)
    14.4 (9.2 to 21)
    No statistical analyses for this end point

    Secondary: Change from baseline in tumor volume

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    End point title
    		 Change from baseline in tumor volume
    End point description
    Percentage change from baseline in tumor volume (assessed by pituitary MRI). Analysis was based on data up to crossover (i.e., included data from both blinded core and extension phase up to 26 Months for patients who continued the same treatment in the extension. For patients who switched to the other treatment, only data collected before crossover was included).
    End point type
    Secondary
    End point timeframe
    Baseline, months 6, 12, 19, 25
    End point values
    		 Pasireotide LAR (Core) Octreotide LAR (Core)
    Number of subjects analysed
    176
    182
    Units: mm^3
    arithmetic mean (standard deviation)
        Baseline (n = 166, 169)
    2420.7 ( 4159.21 )
    2259.2 ( 3390.2 )
        M6 (n = 148, 160)
    1614.1 ( 2536.46 )
    1565.4 ( 2245.99 )
        M12 (n = 125, 138)
    1482.4 ( 2387.88 )
    1390.4 ( 2179.93 )
        M19 (n = 59, 37)
    956.6 ( 1806.72 )
    1009.9 ( 1578.75 )
        M25 (n = 59, 36)
    840.4 ( 1706.07 )
    814.1 ( 1306.58 )
        % change at M6 (n = 142, 145)
    -29.9 ( 21.73 )
    -28.8 ( 20.22 )
        % change at M12 (n = 120, 124)
    -39.7 ( 21.83 )
    -38 ( 24.47 )
        % change at M19 (n = 56, 35)
    -48.9 ( 22.81 )
    -47.2 ( 24.08 )
        % change at M25 (n = 54, 34)
    -51.8 ( 20.81 )
    -55 ( 21.27 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with a reduction of mean GH Level to < 2.5μg/L after crossover

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    End point title
    		 Percentage of participants with a reduction of mean GH Level to < 2.5μg/L after crossover
    End point description
    Percentage of participants with a reduction of mean GH levels to < 2.5μg/L (based on a 5-point 2-hour profile). Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS).
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: Percentage of participants
    number (confidence interval 95%)
        M3 after crossover
    49.4 (38.1 to 60.7)
    28.9 (15.4 to 45.9)
        M6 after crossover
    43.2 (32.2 to 54.7)
    31.6 (17.5 to 48.7)
        M9 after crossover
    54.3 (42.9 to 65.4)
    31.6 (17.5 to 48.7)
        M12 after crossover
    44.4 (33.4 to 55.9)
    23.7 (11.4 to 40.2)
    No statistical analyses for this end point

    Secondary: Percentage of participants with normalization of IGF-1 after crossover

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    End point title
    		 Percentage of participants with normalization of IGF-1 after crossover
    End point description
    Percentage of participants with normalization of sex- and age-adjusted IGF-1. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Denominator for all time points is the Crossover Analysis Set (CAS).
    End point type
    Secondary
    End point timeframe
    Months 3, 6, 9, 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: Percentage of participants
    number (confidence interval 95%)
        M3 after crossover
    19.8 (11.7 to 30.1)
    7.9 (1.7 to 21.4)
        M6 after crossover
    30.9 (21.1 to 42.1)
    7.9 (1.7 to 21.4)
        M9 after crossover
    29.6 (20 to 40.8)
    10.5 (2.9 to 24.8)
        M12 after crossover
    27.2 (17.9 to 38.2)
    5.3 (0.6 to 17.7)
    No statistical analyses for this end point

    Secondary: Summary of mean GH values after crossover

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    End point title
    		 Summary of mean GH values after crossover
    End point description
    Mean GH levels (based on a 5-point profile over 2 hours). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over).
    End point type
    Secondary
    End point timeframe
    Extension baseline, months 3, 6, 9, 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: μg/L
    arithmetic mean (standard deviation)
        Ext. Baseline (n = 78, 33)
    5.9 ( 15.02 )
    7.1 ( 9.8 )
        M3 after crossover (n = 72, 36)
    5.9 ( 19.7 )
    9.8 ( 17.09 )
        M6 after crossover (n= 68, 32)
    4.8 ( 14.51 )
    9.8 ( 20.49 )
        M9 after crossover (n = 61, 32)
    2.6 ( 3.03 )
    8.7 ( 19.26 )
        M12 after crossover (n = 57, 29)
    2.5 ( 2.47 )
    10.4 ( 26 )
    No statistical analyses for this end point

    Secondary: Change from extension baseline in tumor volume after crossover

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    End point title
    		 Change from extension baseline in tumor volume after crossover
    End point description
    Percentage change from extension baseline in tumor volume (assessed by pituitary MRI). Extension baseline was defined as last assessment prior to the administration of the new treatment after crossover. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over).
    End point type
    Secondary
    End point timeframe
    Extension baseline, months 6, 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: mm^3
    arithmetic mean (standard deviation)
        Ext. Baseline (n = 73, 32)
    1420.9 ( 1914.58 )
    1809.6 ( 2579.25 )
        Value at M6 after crossover (n = 65, 31)
    1027.5 ( 1282.42 )
    1794.9 ( 2823.08 )
        % change - M6 after crossover (n = 59, 27)
    -18.1 ( 17.68 )
    -12.3 ( 24.11 )
        Value at M12 after crossover (n = 51, 30)
    949 ( 1169.49 )
    1610.4 ( 2666.66 )
        % change - M12 after crossover (n = 46, 26)
    -24.7 ( 25.2 )
    -17.9 ( 27.8 )
    No statistical analyses for this end point

    Secondary: Severity scores of acromegaly symptoms after crossover

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    End point title
    		 Severity scores of acromegaly symptoms after crossover
    End point description
    Severity scores of acromegaly symptoms (Headache, Fatigue, Perspiration, Paresthesias, Osteoarthralgia). Symptoms were scored from 0 (no symptom) to 4 (very severe). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over).
    End point type
    Secondary
    End point timeframe
    Extension baseline, month 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Headache: Ext. BL (n = 81, 38)
    0.6 ( 0.89 )
    0.4 ( 0.6 )
        Headache: M12 after crossover (n = 60, 32)
    0.5 ( 0.83 )
    0.7 ( 0.79 )
        Fatigue: Ext. BL (n = 81, 38)
    0.8 ( 1.07 )
    0.7 ( 0.76 )
        Fatigue: M12 after crossover (n = 60, 32)
    0.8 ( 0.91 )
    0.7 ( 0.68 )
        Perspiration: Ext. BL (n = 81, 38)
    0.5 ( 0.85 )
    0.6 ( 0.86 )
        Perspiration: M12 after crossover (n = 60, 32)
    0.6 ( 0.98 )
    0.5 ( 0.8 )
        Paresthesia: Ext. BL (n = 81, 38)
    0.4 ( 0.75 )
    0.4 ( 0.054 )
        Paresthesia: M12 after crossover (n = 60, 32)
    0.3 ( 0.56 )
    0.4 ( 0.76 )
        Osteoarthralgia: Ext. BL (n=81,38)
    0.6 ( 0.91 )
    0.6 ( 0.79 )
        Osteoarthralgia: M12 after crossover (n =60, 32)
    0.5 ( 0.89 )
    0.7 ( 0.86 )
    No statistical analyses for this end point

    Secondary: Ring size after crossover

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    End point title
    		 Ring size after crossover
    End point description
    Ring size (based on jeweler’s finger gauge). Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). BL = baseline, LH = left hand, RH = right hand, CO = crossover
    End point type
    Secondary
    End point timeframe
    Extension baseline, month 12 after crossover
    End point values
    		 Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    38
    Units: ring size
    arithmetic mean (standard deviation)
        Ext. BL LH 4th digit (n = 55, 26)
    11 ( 1.87 )
        Ext. BL LH 5th digit (n = 6, 5)
    12.3 ( 2.46 )
        Ext. BL RH 4th digit (n = 15, 7)
    12.4 ( 2.11 )
        Ext. BL RH 5th digit (n = 3, 0)
    99.9 ( 9.99 )
        M12 after CO LH 4th digit (n = 42, 24)
    11.2 ( 2.01 )
        M12 after CO LH 5th digit CO (n = 4, 4)
    12.5 ( 1.35 )
        M12 after CO RH 4th digit (n = 11, 4)
    11.4 ( 2.56 )
        M12 after CO RH 5th digit (n =2, 0)
    99.9 ( 9.99 )
    No statistical analyses for this end point

    Secondary: Health-related Quality-of-life as measured by the AcroQoL questionnaire after crossover

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    End point title
    		 Health-related Quality-of-life as measured by the AcroQoL questionnaire after crossover
    End point description
    AcroQoL total scores. The AcroQoL questionnaire is unidimensional and contains 22 items divided in two scales: one that evaluates physical aspects (eight items) and another one that evaluates psychological aspects (14 items). The scoring of the questionnaire was performed as specified by the instrument developers. Extension baseline was defined as last measurement prior to the start of crossover treatment. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Higher scores represent better quality of life.
    End point type
    Secondary
    End point timeframe
    Extension baseline, months 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Ext. Baseline (n = 79, 34)
    58.9 ( 23.11 )
    59.8 ( 22.4 )
        M12 after crossover (n = 57, 30)
    60.3 ( 24.34 )
    61.2 ( 21.62 )
    No statistical analyses for this end point

    Secondary: Summary of prolactin levels after crossover

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    End point title
    		 Summary of prolactin levels after crossover
    End point description
    Prolactin (PRL) levels. Analysis was based on data after crossover (i.e., included data from blinded extension phase collected after the crossover time point for patients who crossed over). Extension baseline was defined as last measurement prior to the start of crossover treatment.
    End point type
    Secondary
    End point timeframe
    Extension baseline, month 12 after crossover
    End point values
    		 Crossed over to Pasireotide LAR (Extension) Crossed over to Octreotide LAR (Extension)
    Number of subjects analysed
    81
    38
    Units: μg/L
    arithmetic mean (standard deviation)
        Ext. Baseline (n = 78, 34)
    11.9 ( 18.42 )
    15.7 ( 36.76 )
        M12 after crossover (n = 60, 31)
    7.5 ( 8.95 )
    16.1 ( 25.37 )
    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 reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Pasireotide LAR - up to 26 Months
    Reporting group description
    		 Includes data from both blinded core and extension phase (up to Month 26 cutoff date of 29-Dec-2011) for patients who continued the same treatment (Pasireotide LAR) as in the core. For patients who switched from blinded Pasireotide LAR to Octreotide LAR treatment, only data collected before crossover is included.

    Reporting group title
    Octreotide LAR - up to 26 Months
    Reporting group description
    		 Includes data from both blinded core and extension phase (up to Month 26 cutoff date of 29-Dec-2011) for patients who continued the same treatment (Octreotide LAR) as in the core. For patients who switched from blinded Octreotide LAR to Pasireotide LAR treatment, only data collected before crossover is included.

    Reporting group title
    Crossed over to Pasireotide LAR - up to 26 Months
    Reporting group description
    		 Includes all data in the extension phase (up to 26-Month cutoff date of 29-Dec-2011) collected after the crossover time point for patients who crossed over from Octreotide LAR in the core to Pasireotide LAR treatment in the extension phase.

    Reporting group title
    Crossed over to Octreotide LAR - up to 26 Months
    Reporting group description
    		 Includes all data in the extension phase (up to 26-Month cutoff date of 29-Dec-2011) collected after the crossover time point for patients who crossed over from Pasireotide LAR in the core to Octreotide LAR treatment in the extension phase.

    Reporting group title
    Pasireotide LAR - up to EOS
    Reporting group description
    		 Includes data from both core and extension phase (up to End-of-study date of 11-Mar-2016) for patients who continued the same treatment (Pasireotide LAR) as in the core. For patients who switched from blinded Pasireotide LAR to Octreotide LAR treatment, only data collected before crossover is included. Per protocol, patients on Pasireotide LAR could continue to receive open-label Pasireotide LAR after treatment unblinding at Month 26, whereas those on Octreotide LAR were not followed after Month 26.

    Reporting group title
    Crossed over to Pasireotide LAR - up to EOS
    Reporting group description
    		 Includes all data in the extension phase (up to End-of-study date of 11-Mar-2016) collected after the crossover time point for patients who crossed over from Octreotide LAR in the core to Pasireotide LAR treatment in the extension phase. Per protocol, patients on Pasireotide LAR could continue to receive open-label Pasireotide LAR after treatment unblinding at Month 26, whereas those on Octreotide LAR were not followed after Month 26.

    Serious adverse events
    		 Pasireotide LAR - up to 26 Months Octreotide LAR - up to 26 Months Crossed over to Pasireotide LAR - up to 26 Months Crossed over to Octreotide LAR - up to 26 Months Pasireotide LAR - up to EOS Crossed over to Pasireotide LAR - up to EOS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 178 (19.66%)
    28 / 180 (15.56%)
    8 / 81 (9.88%)
    6 / 38 (15.79%)
    37 / 178 (20.79%)
    12 / 81 (14.81%)
         number of deaths (all causes)
    1
    2
    1
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign breast neoplasm
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopharyngeal neoplasm
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mixed hepatocellular cholangiocarcinoma
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory papilloma
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Arteriovenous fistula
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concomitant disease progression
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infiltration
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Catatonia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 180 (1.11%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Back injury
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic neck syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Diabetic hyperglycaemic coma
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    3 / 178 (1.69%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    5 / 178 (2.81%)
    4 / 180 (2.22%)
    2 / 81 (2.47%)
    1 / 38 (2.63%)
    5 / 178 (2.81%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
    2 / 2
    1 / 1
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Chronic pigmented purpura
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Acromegaly
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondritis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    3 / 178 (1.69%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    1 / 178 (0.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pasireotide LAR - up to 26 Months Octreotide LAR - up to 26 Months Crossed over to Pasireotide LAR - up to 26 Months Crossed over to Octreotide LAR - up to 26 Months Pasireotide LAR - up to EOS Crossed over to Pasireotide LAR - up to EOS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    169 / 178 (94.94%)
    161 / 180 (89.44%)
    74 / 81 (91.36%)
    33 / 38 (86.84%)
    170 / 178 (95.51%)
    76 / 81 (93.83%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 178 (10.11%)
    16 / 180 (8.89%)
    5 / 81 (6.17%)
    3 / 38 (7.89%)
    21 / 178 (11.80%)
    6 / 81 (7.41%)
         occurrences all number
    24
    17
    5
    3
    27
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 178 (11.24%)
    21 / 180 (11.67%)
    6 / 81 (7.41%)
    3 / 38 (7.89%)
    21 / 178 (11.80%)
    7 / 81 (8.64%)
         occurrences all number
    26
    27
    8
    3
    29
    9
    Injection site pain
         subjects affected / exposed
    13 / 178 (7.30%)
    9 / 180 (5.00%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    14 / 178 (7.87%)
    0 / 81 (0.00%)
         occurrences all number
    17
    13
    0
    1
    18
    0
    Pyrexia
         subjects affected / exposed
    8 / 178 (4.49%)
    10 / 180 (5.56%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    11 / 178 (6.18%)
    2 / 81 (2.47%)
         occurrences all number
    8
    12
    1
    0
    12
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 178 (6.18%)
    17 / 180 (9.44%)
    1 / 81 (1.23%)
    1 / 38 (2.63%)
    16 / 178 (8.99%)
    3 / 81 (3.70%)
         occurrences all number
    13
    19
    1
    1
    18
    3
    Oropharyngeal pain
         subjects affected / exposed
    8 / 178 (4.49%)
    15 / 180 (8.33%)
    3 / 81 (3.70%)
    1 / 38 (2.63%)
    9 / 178 (5.06%)
    4 / 81 (4.94%)
         occurrences all number
    8
    15
    4
    2
    9
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 178 (5.06%)
    7 / 180 (3.89%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    11 / 178 (6.18%)
    2 / 81 (2.47%)
         occurrences all number
    10
    8
    1
    0
    12
    2
    Insomnia
         subjects affected / exposed
    8 / 178 (4.49%)
    9 / 180 (5.00%)
    2 / 81 (2.47%)
    1 / 38 (2.63%)
    12 / 178 (6.74%)
    4 / 81 (4.94%)
         occurrences all number
    11
    10
    3
    1
    16
    5
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 178 (8.43%)
    10 / 180 (5.56%)
    3 / 81 (3.70%)
    0 / 38 (0.00%)
    16 / 178 (8.99%)
    5 / 81 (6.17%)
         occurrences all number
    23
    19
    4
    0
    31
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 178 (6.74%)
    8 / 180 (4.44%)
    3 / 81 (3.70%)
    0 / 38 (0.00%)
    13 / 178 (7.30%)
    5 / 81 (6.17%)
         occurrences all number
    22
    11
    3
    0
    28
    5
    Blood bilirubin increased
         subjects affected / exposed
    9 / 178 (5.06%)
    5 / 180 (2.78%)
    1 / 81 (1.23%)
    1 / 38 (2.63%)
    11 / 178 (6.18%)
    3 / 81 (3.70%)
         occurrences all number
    15
    8
    1
    1
    17
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    25 / 178 (14.04%)
    24 / 180 (13.33%)
    7 / 81 (8.64%)
    6 / 38 (15.79%)
    27 / 178 (15.17%)
    8 / 81 (9.88%)
         occurrences all number
    43
    33
    9
    6
    51
    11
    Blood glucose increased
         subjects affected / exposed
    17 / 178 (9.55%)
    6 / 180 (3.33%)
    8 / 81 (9.88%)
    0 / 38 (0.00%)
    18 / 178 (10.11%)
    8 / 81 (9.88%)
         occurrences all number
    26
    11
    11
    0
    27
    14
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    4 / 178 (2.25%)
    2 / 180 (1.11%)
    1 / 81 (1.23%)
    2 / 38 (5.26%)
    5 / 178 (2.81%)
    1 / 81 (1.23%)
         occurrences all number
    4
    2
    1
    2
    6
    1
    Blood triglycerides increased
         subjects affected / exposed
    4 / 178 (2.25%)
    4 / 180 (2.22%)
    2 / 81 (2.47%)
    4 / 38 (10.53%)
    8 / 178 (4.49%)
    2 / 81 (2.47%)
         occurrences all number
    4
    4
    2
    5
    8
    2
    Blood uric acid increased
         subjects affected / exposed
    6 / 178 (3.37%)
    3 / 180 (1.67%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    10 / 178 (5.62%)
    2 / 81 (2.47%)
         occurrences all number
    8
    4
    1
    0
    15
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    9 / 178 (5.06%)
    10 / 180 (5.56%)
    3 / 81 (3.70%)
    0 / 38 (0.00%)
    10 / 178 (5.62%)
    4 / 81 (4.94%)
         occurrences all number
    13
    13
    3
    0
    15
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 178 (1.69%)
    11 / 180 (6.11%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    3 / 178 (1.69%)
    2 / 81 (2.47%)
         occurrences all number
    4
    19
    1
    0
    4
    3
    Glycosylated haemoglobin increased
         subjects affected / exposed
    11 / 178 (6.18%)
    5 / 180 (2.78%)
    7 / 81 (8.64%)
    0 / 38 (0.00%)
    12 / 178 (6.74%)
    9 / 81 (11.11%)
         occurrences all number
    11
    5
    8
    0
    12
    10
    Insulin-like growth factor decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    2 / 178 (1.12%)
    5 / 81 (6.17%)
         occurrences all number
    1
    0
    1
    0
    2
    7
    Lipase increased
         subjects affected / exposed
    10 / 178 (5.62%)
    13 / 180 (7.22%)
    3 / 81 (3.70%)
    2 / 38 (5.26%)
    11 / 178 (6.18%)
    3 / 81 (3.70%)
         occurrences all number
    14
    21
    3
    4
    16
    3
    Weight decreased
         subjects affected / exposed
    9 / 178 (5.06%)
    8 / 180 (4.44%)
    2 / 81 (2.47%)
    0 / 38 (0.00%)
    9 / 178 (5.06%)
    5 / 81 (6.17%)
         occurrences all number
    9
    8
    2
    0
    9
    5
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    13 / 178 (7.30%)
    10 / 180 (5.56%)
    2 / 81 (2.47%)
    1 / 38 (2.63%)
    15 / 178 (8.43%)
    3 / 81 (3.70%)
         occurrences all number
    16
    12
    2
    1
    19
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 178 (11.80%)
    20 / 180 (11.11%)
    7 / 81 (8.64%)
    4 / 38 (10.53%)
    22 / 178 (12.36%)
    9 / 81 (11.11%)
         occurrences all number
    26
    29
    10
    5
    28
    12
    Headache
         subjects affected / exposed
    41 / 178 (23.03%)
    49 / 180 (27.22%)
    17 / 81 (20.99%)
    5 / 38 (13.16%)
    42 / 178 (23.60%)
    20 / 81 (24.69%)
         occurrences all number
    58
    77
    22
    5
    63
    28
    Paraesthesia
         subjects affected / exposed
    8 / 178 (4.49%)
    4 / 180 (2.22%)
    0 / 81 (0.00%)
    1 / 38 (2.63%)
    9 / 178 (5.06%)
    0 / 81 (0.00%)
         occurrences all number
    11
    4
    0
    1
    14
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 178 (7.87%)
    10 / 180 (5.56%)
    6 / 81 (7.41%)
    1 / 38 (2.63%)
    19 / 178 (10.67%)
    8 / 81 (9.88%)
         occurrences all number
    17
    14
    6
    1
    24
    12
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    1 / 81 (1.23%)
    2 / 38 (5.26%)
    0 / 178 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    1
    2
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    8 / 178 (4.49%)
    1 / 180 (0.56%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    10 / 178 (5.62%)
    0 / 81 (0.00%)
         occurrences all number
    9
    1
    0
    0
    11
    0
    Abdominal distension
         subjects affected / exposed
    21 / 178 (11.80%)
    22 / 180 (12.22%)
    0 / 81 (0.00%)
    2 / 38 (5.26%)
    21 / 178 (11.80%)
    0 / 81 (0.00%)
         occurrences all number
    27
    33
    0
    5
    27
    0
    Abdominal pain
         subjects affected / exposed
    33 / 178 (18.54%)
    43 / 180 (23.89%)
    3 / 81 (3.70%)
    1 / 38 (2.63%)
    36 / 178 (20.22%)
    4 / 81 (4.94%)
         occurrences all number
    52
    67
    4
    1
    58
    6
    Abdominal pain upper
         subjects affected / exposed
    12 / 178 (6.74%)
    17 / 180 (9.44%)
    3 / 81 (3.70%)
    0 / 38 (0.00%)
    14 / 178 (7.87%)
    4 / 81 (4.94%)
         occurrences all number
    14
    18
    3
    0
    16
    4
    Constipation
         subjects affected / exposed
    10 / 178 (5.62%)
    19 / 180 (10.56%)
    4 / 81 (4.94%)
    1 / 38 (2.63%)
    13 / 178 (7.30%)
    5 / 81 (6.17%)
         occurrences all number
    15
    20
    4
    2
    20
    5
    Diarrhoea
         subjects affected / exposed
    70 / 178 (39.33%)
    79 / 180 (43.89%)
    20 / 81 (24.69%)
    6 / 38 (15.79%)
    72 / 178 (40.45%)
    26 / 81 (32.10%)
         occurrences all number
    192
    207
    54
    9
    207
    68
    Dyspepsia
         subjects affected / exposed
    8 / 178 (4.49%)
    7 / 180 (3.89%)
    3 / 81 (3.70%)
    1 / 38 (2.63%)
    9 / 178 (5.06%)
    4 / 81 (4.94%)
         occurrences all number
    8
    12
    3
    1
    9
    4
    Flatulence
         subjects affected / exposed
    10 / 178 (5.62%)
    11 / 180 (6.11%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    11 / 178 (6.18%)
    0 / 81 (0.00%)
         occurrences all number
    10
    12
    0
    0
    11
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 180 (1.11%)
    2 / 81 (2.47%)
    2 / 38 (5.26%)
    2 / 178 (1.12%)
    2 / 81 (2.47%)
         occurrences all number
    2
    2
    2
    2
    2
    2
    Large intestine polyp
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    2 / 81 (2.47%)
    2 / 38 (5.26%)
    1 / 178 (0.56%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    2
    2
    1
    2
    Nausea
         subjects affected / exposed
    27 / 178 (15.17%)
    41 / 180 (22.78%)
    8 / 81 (9.88%)
    2 / 38 (5.26%)
    29 / 178 (16.29%)
    10 / 81 (12.35%)
         occurrences all number
    34
    57
    10
    4
    37
    13
    Vomiting
         subjects affected / exposed
    19 / 178 (10.67%)
    15 / 180 (8.33%)
    3 / 81 (3.70%)
    1 / 38 (2.63%)
    22 / 178 (12.36%)
    4 / 81 (4.94%)
         occurrences all number
    26
    17
    5
    1
    30
    6
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    5 / 178 (2.81%)
    8 / 180 (4.44%)
    4 / 81 (4.94%)
    1 / 38 (2.63%)
    5 / 178 (2.81%)
    5 / 81 (6.17%)
         occurrences all number
    5
    8
    5
    1
    6
    6
    Cholelithiasis
         subjects affected / exposed
    56 / 178 (31.46%)
    69 / 180 (38.33%)
    18 / 81 (22.22%)
    6 / 38 (15.79%)
    59 / 178 (33.15%)
    23 / 81 (28.40%)
         occurrences all number
    91
    99
    21
    9
    102
    31
    Gallbladder polyp
         subjects affected / exposed
    5 / 178 (2.81%)
    3 / 180 (1.67%)
    4 / 81 (4.94%)
    2 / 38 (5.26%)
    8 / 178 (4.49%)
    5 / 81 (6.17%)
         occurrences all number
    5
    3
    4
    2
    8
    5
    Hepatic steatosis
         subjects affected / exposed
    10 / 178 (5.62%)
    11 / 180 (6.11%)
    6 / 81 (7.41%)
    3 / 38 (7.89%)
    11 / 178 (6.18%)
    6 / 81 (7.41%)
         occurrences all number
    11
    13
    6
    3
    13
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    34 / 178 (19.10%)
    36 / 180 (20.00%)
    3 / 81 (3.70%)
    1 / 38 (2.63%)
    34 / 178 (19.10%)
    4 / 81 (4.94%)
         occurrences all number
    35
    37
    3
    1
    38
    4
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    6 / 178 (3.37%)
    2 / 180 (1.11%)
    1 / 81 (1.23%)
    2 / 38 (5.26%)
    8 / 178 (4.49%)
    2 / 81 (2.47%)
         occurrences all number
    11
    3
    1
    2
    13
    2
    Pyelocaliectasis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    0 / 81 (0.00%)
    2 / 38 (5.26%)
    0 / 178 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 178 (11.80%)
    25 / 180 (13.89%)
    10 / 81 (12.35%)
    2 / 38 (5.26%)
    24 / 178 (13.48%)
    14 / 81 (17.28%)
         occurrences all number
    23
    33
    13
    2
    30
    20
    Back pain
         subjects affected / exposed
    22 / 178 (12.36%)
    21 / 180 (11.67%)
    6 / 81 (7.41%)
    3 / 38 (7.89%)
    24 / 178 (13.48%)
    8 / 81 (9.88%)
         occurrences all number
    33
    29
    6
    4
    35
    8
    Muscle spasms
         subjects affected / exposed
    8 / 178 (4.49%)
    10 / 180 (5.56%)
    7 / 81 (8.64%)
    1 / 38 (2.63%)
    10 / 178 (5.62%)
    8 / 81 (9.88%)
         occurrences all number
    9
    12
    7
    1
    12
    8
    Musculoskeletal pain
         subjects affected / exposed
    7 / 178 (3.93%)
    3 / 180 (1.67%)
    1 / 81 (1.23%)
    1 / 38 (2.63%)
    9 / 178 (5.06%)
    2 / 81 (2.47%)
         occurrences all number
    10
    3
    1
    1
    12
    2
    Osteoarthritis
         subjects affected / exposed
    4 / 178 (2.25%)
    4 / 180 (2.22%)
    1 / 81 (1.23%)
    2 / 38 (5.26%)
    4 / 178 (2.25%)
    2 / 81 (2.47%)
         occurrences all number
    4
    4
    1
    2
    5
    2
    Pain in extremity
         subjects affected / exposed
    14 / 178 (7.87%)
    8 / 180 (4.44%)
    6 / 81 (7.41%)
    1 / 38 (2.63%)
    16 / 178 (8.99%)
    6 / 81 (7.41%)
         occurrences all number
    15
    10
    7
    1
    18
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 178 (5.62%)
    4 / 180 (2.22%)
    0 / 81 (0.00%)
    0 / 38 (0.00%)
    13 / 178 (7.30%)
    2 / 81 (2.47%)
         occurrences all number
    11
    4
    0
    0
    15
    3
    Influenza
         subjects affected / exposed
    16 / 178 (8.99%)
    11 / 180 (6.11%)
    3 / 81 (3.70%)
    3 / 38 (7.89%)
    18 / 178 (10.11%)
    4 / 81 (4.94%)
         occurrences all number
    19
    11
    4
    4
    23
    5
    Nasopharyngitis
         subjects affected / exposed
    32 / 178 (17.98%)
    29 / 180 (16.11%)
    13 / 81 (16.05%)
    7 / 38 (18.42%)
    34 / 178 (19.10%)
    15 / 81 (18.52%)
         occurrences all number
    76
    54
    28
    9
    120
    56
    Sinusitis
         subjects affected / exposed
    6 / 178 (3.37%)
    6 / 180 (3.33%)
    2 / 81 (2.47%)
    1 / 38 (2.63%)
    9 / 178 (5.06%)
    3 / 81 (3.70%)
         occurrences all number
    6
    6
    4
    1
    12
    11
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 178 (8.99%)
    7 / 180 (3.89%)
    3 / 81 (3.70%)
    2 / 38 (5.26%)
    20 / 178 (11.24%)
    5 / 81 (6.17%)
         occurrences all number
    22
    8
    3
    2
    30
    10
    Urinary tract infection
         subjects affected / exposed
    9 / 178 (5.06%)
    12 / 180 (6.67%)
    5 / 81 (6.17%)
    0 / 38 (0.00%)
    11 / 178 (6.18%)
    10 / 81 (12.35%)
         occurrences all number
    15
    22
    9
    0
    18
    22
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    38 / 178 (21.35%)
    8 / 180 (4.44%)
    18 / 81 (22.22%)
    3 / 38 (7.89%)
    40 / 178 (22.47%)
    19 / 81 (23.46%)
         occurrences all number
    39
    8
    18
    3
    43
    19
    Glucose tolerance impaired
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 180 (0.56%)
    5 / 81 (6.17%)
    0 / 38 (0.00%)
    3 / 178 (1.69%)
    5 / 81 (6.17%)
         occurrences all number
    3
    2
    5
    0
    3
    5
    Hypercholesterolaemia
         subjects affected / exposed
    7 / 178 (3.93%)
    4 / 180 (2.22%)
    2 / 81 (2.47%)
    1 / 38 (2.63%)
    10 / 178 (5.62%)
    2 / 81 (2.47%)
         occurrences all number
    8
    4
    2
    1
    11
    2
    Hyperglycaemia
         subjects affected / exposed
    55 / 178 (30.90%)
    18 / 180 (10.00%)
    25 / 81 (30.86%)
    5 / 38 (13.16%)
    56 / 178 (31.46%)
    29 / 81 (35.80%)
         occurrences all number
    71
    27
    31
    5
    81
    52
    Hyperlipidaemia
         subjects affected / exposed
    5 / 178 (2.81%)
    4 / 180 (2.22%)
    5 / 81 (6.17%)
    2 / 38 (5.26%)
    5 / 178 (2.81%)
    5 / 81 (6.17%)
         occurrences all number
    7
    4
    5
    2
    7
    6
    Hyperuricaemia
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 180 (1.11%)
    1 / 81 (1.23%)
    0 / 38 (0.00%)
    9 / 178 (5.06%)
    2 / 81 (2.47%)
         occurrences all number
    7
    2
    2
    0
    15
    3
    Hypoglycaemia
         subjects affected / exposed
    11 / 178 (6.18%)
    14 / 180 (7.78%)
    7 / 81 (8.64%)
    2 / 38 (5.26%)
    14 / 178 (7.87%)
    8 / 81 (9.88%)
         occurrences all number
    13
    29
    23
    4
    21
    77
    Type 2 diabetes mellitus
         subjects affected / exposed
    12 / 178 (6.74%)
    0 / 180 (0.00%)
    3 / 81 (3.70%)
    0 / 38 (0.00%)
    12 / 178 (6.74%)
    4 / 81 (4.94%)
         occurrences all number
    12
    0
    3
    0
    12
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2008
    The main reason for this protocol amendment was to change the duration of the study. Although six months is an adequate time point to establish steady state pharmacokinetics, it was not adequate to establish long-term efficacy in both treatment groups (Pasireotide LAR and Octreotide LAR). Therefore, the study was extended to twelve months to provide sufficient time to assess the clinical response of patients to the study drugs. Additional secondary efficacy objectives were added in order to further assess the efficacy of pasireotide LAR.
    21 May 2008
    Decreased levels of Vitamin B12 were been observed as a rare adverse event in patients treated with Octreotide . Therefore, blood levels of Vitamin B12 was be tested at baseline (visit 2) and every 3 months during the core and the extension phases of the study. The use of Gadolinium as a type of contrast material during the MRI procedure performed during the core and the extension phases of the study was explicitly mentioned in the protocol.
    25 Sep 2008
    As requested by the Chinese Health Authorities, patients enrolled into the study in China had to have a normal serum creatinine level for inclusion.
    23 Apr 2009
    Extended blinding to patient’s treatment from month 12 to month 26. In order to have a benchmark for the evaluation of the long-term safety and efficacy of pasireotide, patients randomized to octreotide, who responded to treatment at month 12 were offered to enter a 14 months extension period with the same medication. Patients not responding to either pasireotide or octreotide at month 12 were offered to be switched to the other study medication in order to explore the safety and efficacy of switching from pasireotide to octreotide and from octreotide to pasireotide. Patients who crossed over to the other treatment arm at month 13 followed the same schedule of evaluations as patients continuing in the extension phase in the same arm. A new secondary objective was added, which was, duration of response for patients considered responders at month 12 in order to evaluate the duration of the efficacy of the study medications. In line with the published guidelines established by experts’ associations for management of diabetes, changes were made in the criteria for monitoring hyperglycemia reflecting standard of care. Clarifications to the schedule of dose increase were made. Serum cortisol is a key safety measure and was added to the list of the tests to be performed at the Central Lab. Modifications to the inclusion and exclusion criteria were made to clarify the eligibility of patients who may have received a single dose of short-acting octreotide or short-acting dopamine agonists prior to study entry. In order to fully utilize the response data in patients who discontinued early, a Last Observation Carried Forward (LOCF) approach was introduced and was applied for the primary analysis.
    03 May 2010
    Recent results from the thorough QT/QTc (TQT) study provided data on the QT/QTc intervals of a supra-therapeutic dose of pasireotide in healthy volunteers. As a consequence of the ECG study results, study discontinuation criteria were modified and additional ECG and pharmacokinetic monitoring was implemented for the ongoing SOM230 clinical trials to further strengthen the safety of patients. This amendment also clarified wording across the protocol for the sake of the consistency as well as added clarification for the applicable procedures for patients who entered the extension prior and after Amendment 4 implementation. Additionally, further recommendations regarding serum cortisol samples collection were provided as well as clarification on first study drug dose administration window. Furthermore, a section including secondary objectives for the analysis of the blinded extension phase was added and clarification was made in the statistical analysis section in order to further explain analysis of the data collected in the extension phase of the study.
    26 Jul 2011
    The purpose of this amendment was to clarify the statistical analysis of the secondary objectives in the extension phase and the statistical analysis of the pharmacokinetics and pharmacodynamics assessments. The amendment did not change any study objectives. The extension phase was divided into two data subsets: data before cross-over and data after crossover. After the first analysis performed with 12 months data, an additional data cut-off for analysis for the purpose of submission was added to include the extension data collected up to the Month 19 (Visit 8E) assessment in addition to the data cut-off at month 27. A second Per Protocol (PP) analysis set was defined for that purpose. As a consequence of the additional data cut-off, Global Novartis team Clinical Trial Team (CTT) were unblinded after database lock, which occurred approximately 4 months prior to last patient last visit (LPLV) of the first year of the extension phase. The cut-off date for this database lock was performed when the last patient completed the Month 19 (Visit 8E) assessment (09-June-2011). There was no impact on study conduct since all measures were in place to ensure that investigators and Local Novartis teams (CPOs) remain blinded as planned until the last patient completed the Month 26 (Visit 15E) assessment. The unblinding process at the clinical sites in preparation of Visit 15E (Month 26) was clarified. In addition, the schedule of assessments during the extension phase after Month 26 regarding GH suppression post OGTT profiles was modified. After this timepoint, this assessment was performed every 6 months instead of every 3 months as this high frequency was not necessary anymore for follow up assessments.
    12 Dec 2011
    The protocol was amended to include additional hepatic-related safety measures as a result of an internal hepatic medical review of pasireotide trials. During this internal medical review of liver related laboratory values, 3 healthy volunteers were identified with elevations in liver function tests. An assessment of liver enzyme categorical outliers was completed across the pasireotide s.c. development program (up to October 2011). The pasireotide Compassionate Use Program was also reviewed. A review of the unblinded data from the clinical program with the pasireotide long acting release (LAR) formulation did not reveal cases meeting the Hy’s law criteria. As a consequence of these observations, enhanced hepatic-related safety measures were taken to ensure patient safety.

    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.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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