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    Clinical Trial Results:
    A randomized, double-blind study to assess the safety and efficacy of different dose levels of Pasireotide (SOM230) subcutaneous (sc) over a 6 month treatment period in patients with de novo, persistent or recurrent Cushing's disease Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2006-004111-22
    Trial protocol
    		 DK   BE   IT   FI   FR   DE   PT   GR   GB   HU   ES  
    Global end of trial date
    21 May 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CSOM230B2305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00434148
    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
    21 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to assess the efficacy of pasireotide in terms of response to pasireotide 600 μg sc bid and 900 μg sc bid independently in patients with Cushing’s disease as measured by mUFC ≤ 1 x ULN after 6 months of treatment and whose dose was not increased prior to Month 6.
    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
    22 Dec 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    China: 20
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Mexico: 5
    Worldwide total number of subjects
    162
    EEA total number of subjects
    74
    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)
    157
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The actual enrollment number in the protocol section is 162. This number reflects the participants who were randomized and received at least one dose of drug.

    Pre-assignment
    Screening details
    		 A total of 165 participants were randomized, but 1 participant from the 600ug group and 2 participants from the 900ug group were not treated. Therefore, enrollment = 162. Participants who completed month 12 and did not enter the extension phase were not counted as discontinuations.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pasireotide 600 ug
    Arm description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    600 ug subcutaneous (sc) twice daily (b.i.d.)

    Arm title
    		 Pasireotide 900 ug
    Arm description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pasireotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    900 ug sc b.i.d.

    Number of subjects in period 1
    		Pasireotide 600 ug Pasireotide 900 ug
    Started
    82
    80
    Completed month 12
    39
    39
    Completed month 12; entered extension
    26
    32
    Completed m. 12; did not enter extension
    13
    7
    Completed
    13
    7
    Not completed
    69
    73
         Consent withdrawn by subject
    15
    15
         Adverse event, non-fatal
    18
    18
         Condition no longer requires study drug
    1
    -
         Administrative problems
    6
    10
         Lost to follow-up
    -
    1
         Abnormal test procedure result
    -
    1
         Lack of efficacy
    25
    28
         Protocol deviation
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pasireotide 600 ug
    Reporting group description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.

    Reporting group title
    Pasireotide 900 ug
    Reporting group description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.

    Reporting group values
    		 Pasireotide 600 ug Pasireotide 900 ug Total
    Number of subjects
    		 82 80 162
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 78 79 157
        From 65-84 years
    		 4 1 5
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 40.5 ± 12.97 39.9 ± 10.77 -
    Gender, Male/Female
    Units: participants
        Female
    		 62 64 126
        Male
    		 20 16 36

    End points

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    End points reporting groups
    Reporting group title
    Pasireotide 600 ug
    Reporting group description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country.

    Reporting group title
    Pasireotide 900 ug
    Reporting group description
    		 At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was <= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotode was available commercially in their country.

    Primary: Number of mUFC (urinary free cortisol) responders by randomized dose group

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    End point title
    		 Number of mUFC (urinary free cortisol) responders by randomized dose group [1]
    End point description
    A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: Responders
        number (confidence interval)
    12 (7 to 22.3)
    21 (16.6 to 35.9)
    No statistical analyses for this end point

    Secondary: Change from baseline in mUFC

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    End point title
    		 Change from baseline in mUFC
    End point description
    Twenty four hour urine samples were collected to obtain mUFC measurements. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 3 months, 12 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: nmol/24h
    arithmetic mean (standard deviation)
        month 3 (n=61,62)
    -375.8 ± 631.07
    -343.4 ± 485.48
        month 12 (n=37,35)
    -572.6 ± 941.44
    -350.7 ± 380.25
    No statistical analyses for this end point

    Secondary: Time to first UFC response

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    End point title
    		 Time to first UFC response
    End point description
    Time to first UFC response is defined as the number of months from baseline to first attainment of UFC response.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: months
        median (inter-quartile range (Q1-Q3))
    1 (0.9 to 2.7)
    1 (0.9 to 2.7)
    No statistical analyses for this end point

    Secondary: Percent change from baseline in serum cortisol

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    End point title
    		 Percent change from baseline in serum cortisol
    End point description
    Blood samlpes were drawn to obtain serum cortisol levels. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: nmol/L
    arithmetic mean (standard deviation)
        month 0.5 (n=77,76)
    -4 ± 28.23
    -10.8 ± 30.57
        month 1 (n=78,72)
    -7.3 ± 30.13
    -7.7 ± 32
        month 1.5 (n=75,71)
    -5.5 ± 27.65
    -7.1 ± 31.34
        month 2 (n=73,67)
    -0.7 ± 35.81
    -6.4 ± 29.75
        month 2.5 (n=70,67)
    -3.3 ± 31.4
    -10.1 ± 31.23
        month 3 (n=70,67)
    -2.6 ± 35.79
    -10.2 ± 25.6
        month 4 (n=68,61)
    -6.9 ± 31.88
    -10.8 ± 28.1
        month 5 (n=62,58)
    -4.3 ± 36.96
    -10.8 ± 26.5
        month 6 (n=59,57)
    -5.6 ± 34.28
    -9.3 ± 31.45
        month 7 (n=52,53)
    -9.8 ± 34.44
    -5.8 ± 26.35
        month 8 (n=50,46)
    -10.2 ± 30.85
    -9.9 ± 35.79
        month 9 (n=46,48)
    -5.4 ± 33.49
    -5.8 ± 31.56
        month 10 (n=42,47)
    -11.2 ± 30.25
    -9.3 ± 28.39
        month 11 (n=41,41)
    -8.2 ± 38.19
    -14 ± 29.63
        month 12 (n=39,38)
    -11.6 ± 33.75
    -15.2 ± 21.99
        month 15 (n=26,26)
    -10.5 ± 30.14
    -12.5 ± 29.27
        month 18 (n=26,25)
    -7.6 ± 40.35
    -17.8 ± 28.39
        month 21 (n=21,25)
    -12.1 ± 34.23
    -15.5 ± 34.94
        month 24 (n=18,22)
    -17.9 ± 43.46
    -18.1 ± 34.27
        month 27 (n=16,18)
    -9 ± 41.71
    -12.7 ± 28.53
        month 30 (n=14,19)
    -22.8 ± 35.43
    -22.7 ± 32.46
        month 33 (n=13,15)
    -9.5 ± 44.64
    -25.2 ± 25.96
        month 36 (n=10,13)
    -12.7 ± 65.43
    -13.3 ± 37.84
        month 39 (n=10,12)
    -26.6 ± 42.89
    -25.9 ± 33.15
        month 42 (n=10,12)
    -17.8 ± 39.54
    -18.1 ± 35.25
        month 45 (n=10,11)
    -12.5 ± 44.89
    -8.5 ± 32.55
        month 48 (n=9,11)
    -19.7 ± 37.88
    -20.1 ± 39.42
        month 51 (n=9,9)
    -17.6 ± 34.6
    -24 ± 31.53
        month 54 (n=9,9)
    -25 ± 30.49
    -6.8 ± 28.07
        month 57 (n=8,8)
    -11 ± 56.61
    -30.8 ± 22.21
        month 60 (n=8,8)
    -24.5 ± 31.89
    -18.9 ± 22.05
        month 63 (n=6,7)
    -28.6 ± 31.2
    -24 ± 26.41
        month 66 (n=4,6)
    -6.7 ± 29.29
    -22.5 ± 36.19
        month 69 (n=3,5)
    -13.4 ± 42.68
    -33.6 ± 10.31
        month 72 (n=3,4)
    -4.5 ± 40.94
    -22.7 ± 23.57
        month 75 (n=2,3)
    -63.3 ± 41.13
    -23.2 ± 25.71
        month 78 (n=1,1)
    14.5 ± 99999.99
    -53.3 ± 99999.99
    No statistical analyses for this end point

    Secondary: Percent change from baseline in mean adrenocorticotropic hormone (ACTH)

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    End point title
    		 Percent change from baseline in mean adrenocorticotropic hormone (ACTH)
    End point description
    Blood samples were drawn to obtain ACTH levels. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: percent change
    arithmetic mean (standard deviation)
        month 0.5 (n=78,75)
    9.3 ± 181.17
    -15.9 ± 30.75
        month 1 (n=78,71)
    -10 ± 37.29
    -19.1 ± 30.47
        month 1.5 (n=74,69)
    -13.4 ± 31.64
    -10.5 ± 38.05
        month 2 (n=72,66)
    -7.7 ± 40.86
    -13.2 ± 35.38
        month 2.5 (n=69,65)
    -8.2 ± 37.32
    -12 ± 47.02
        month 3 (n=69,66)
    -9.2 ± 40.85
    -16.3 ± 31.93
        month 4 (n=66,61)
    -7.2 ± 38.42
    -12.8 ± 44.06
        month 5 (n=62,55)
    -3 ± 42.5
    -15 ± 38.89
        month 6 (n=58,55)
    -8.4 ± 43.61
    -17.3 ± 35.6
        month 7 (n=52,52)
    -11.4 ± 45.25
    -14.6 ± 30.88
        month 8 (n=48,46)
    -5 ± 51.75
    -17 ± 36.87
        month 9 (n=46,47)
    -5.3 ± 55.27
    -18.2 ± 35.87
        month 10 (n=42,46)
    -10.2 ± 48.82
    -18.2 ± 34.18
        month 11 (n=42,40)
    -11.5 ± 44.52
    -17.4 ± 39.06
        month 12 (n=39,39)
    -7.4 ± 53.83
    -26.5 ± 33.38
        month 15 (n=26,26)
    -14.5 ± 43.44
    -16.3 ± 32.01
        month 18 (n=26,25)
    -5.9 ± 57.56
    -21.2 ± 32.91
        month 21 (n=20,23)
    -1.5 ± 51.52
    -17.3 ± 34.34
        month 24 (n=18,21)
    -10.9 ± 47.95
    -18 ± 26.53
        month 27 (n=16,18)
    -10.4 ± 53.33
    -12.5 ± 39.39
        month 30 (n=14,18)
    -14.7 ± 56.17
    -20 ± 40.82
        month 33 (n=13,14)
    -9.4 ± 55.01
    -2.4 ± 33.07
        month 36 (n=10,13)
    19.1 ± 112.26
    1.2 ± 35.33
        month 39 (n=10,12)
    -20.9 ± 48.68
    -5.3 ± 40.02
        month 42 (n=10,12)
    -6.7 ± 59.61
    2.7 ± 42.35
        month 45 (n=9,11)
    11.9 ± 89.59
    8.1 ± 50.09
        month 48 (n=9,9)
    -10.8 ± 65.52
    11.7 ± 55.85
        month 51 (n=9,9)
    0 ± 65.82
    -3.1 ± 48.21
        month 54 (n=9,9)
    4.6 ± 77.49
    7.3 ± 52.94
        month 57 (n=7,7)
    9.6 ± 59.86
    -5 ± 45.19
        month 60 (n=8,8)
    9.6 ± 61.38
    -1.3 ± 39.01
        month 63 (n=6,7)
    11.9 ± 73.78
    15.4 ± 50.66
        month 66 (n=4,6)
    25.3 ± 75.31
    18.3 ± 61.35
        month 69 (n=3,5)
    38.9 ± 78.34
    -1.2 ± 23.98
        month 72 (n=3,3)
    35.6 ± 78.48
    22 ± 46.15
        month 75 (n=2,3)
    -5 ± 77.78
    23.1 ± 110.92
        month 78 (n=1,1)
    50 ± 99999.99
    -11.1 ± 99999.99
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: sitting sytolic blood pressure (SBP) and sitting diastolic blood pressure (DBP)

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: sitting sytolic blood pressure (SBP) and sitting diastolic blood pressure (DBP)
    End point description
    Sitting blood pressure assessments were performed at every study visit. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: mmHg
    arithmetic mean (standard deviation)
        Sitting SBP, month 3 (n=70,67)
    -7.4 ± 17.37
    -9.9 ± 17.01
        Sitting SBP, month 6 (n=59,57)
    -6.8 ± 19.35
    -11.4 ± 15.92
        Sitting SBP, month 12 (n=39,39)
    -2.8 ± 18.4
    -9.4 ± 14.61
        Sitting SBP, month 24 (n=18,23)
    -11.6 ± 12.82
    -11 ± 11.58
        Sitting SBP, month 36 (n=10,13)
    -3 ± 17.08
    -11.5 ± 16.23
        Sitting SBP, month 48 (n=9,10)
    -12 ± 14.15
    -3.6 ± 14.56
        Sitting SBP, month 60 (n=7,8)
    -12.8 ± 17.1
    -2 ± 11.83
        Sitting DBP, month 3 (n=70,67)
    -3.3 ± 11.01
    -4.1 ± 13.11
        Sitting DBP , month 6 (n=59,57)
    -4.2 ± 13.54
    -5 ± 11.56
        Sitting DBP, month 12 (n=39,39)
    -2 ± 11.65
    -5.4 ± 10.86
        Sitting DBP, month 24 (n=18,23)
    -8.1 ± 11.35
    -6.4 ± 9.37
        Sitting DBP, month 36 (n=10,13)
    -6.8 ± 14.17
    -7.3 ± 8.25
        Sitting DBP, month 48 (n=9,10)
    -11.7 ± 12.02
    -1 ± 9.3
        Sitting DBP, month 60 (n=7,8)
    -9.1 ± 9.79
    0.7 ± 7.34
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: body mass index (BMI)

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: body mass index (BMI)
    End point description
    BMI was determined by using height and weight measurements. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48 and month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: kg/m^2
    arithmetic mean (standard deviation)
        month 3 (n=70,67)
    -1 ± 1.26
    -1.4 ± 1.29
        month 6 (n=59,57)
    -1.2 ± 1.64
    -2.1 ± 1.72
        month 12 (n=40,39)
    -2.1 ± 2.19
    -2.8 ± 2.21
        month 24 (n=18,23)
    -3.4 ± 2.97
    -3 ± 2.67
        month 36 (n=10,13)
    -2.9 ± 2.47
    -3.3 ± 3.48
        month 48 (n=9,10)
    -3.1 ± 2.14
    -2.4 ± 2.6
        month 60 (n=8,8)
    -2.8 ± 1.85
    -2 ± 2.2
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: waist circumference

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: waist circumference
    End point description
    Waist circumference was measured with a measuring tape correctly positioned. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: cm
    arithmetic mean (standard deviation)
        month 3 (n=64,66)
    -1 ± 10.47
    -2.2 ± 5.23
        month 6 (n=53,54)
    -1.9 ± 8.33
    -3.4 ± 5.39
        month 12(n=34,35)
    -4.4 ± 9.4
    -5.6 ± 7.86
        month 24 ( n=17,22)
    -8.7 ± 9.54
    -5.1 ± 10.22
        month 36 (n=9,13)
    -7.8 ± 10.46
    -6.4 ± 9.97
        month 48 (n=8,10)
    -8.3 ± 11.59
    -5.1 ± 10.03
        month 60 (n=7,8)
    -7.3 ± 12.08
    -4.6 ± 10.9
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: total cholesterol and triglycerides

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: total cholesterol and triglycerides
    End point description
    Blood samples were drawn to obtain total cholesterol and triglycerides' levels. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: mmol/L
    arithmetic mean (standard deviation)
        Cholesterol, month 3 (n=70,67)
    -0.2 ± 1.06
    -0.3 ± 1.01
        Cholesterol, month 6 (n=59,55)
    -0.4 ± 1.24
    -0.4 ± 0.98
        Cholesterol, month 12 (n=40,39)
    -0.5 ± 1.29
    -0.6 ± 1.18
        Cholesterol, month 24 (n=18,22)
    -0.6 ± 1.39
    -0.3 ± 0.81
        Cholesterol, month 36 (n=10,12)
    -0.8 ± 1.24
    -0.1 ± 0.64
        Cholesterol, month 48 (n=9,10)
    -0.9 ± 1.63
    -0.4 ± 0.8
        Cholesterol, month 60 (n=8,8)
    -1.5 ± 1.57
    -0.4 ± 1
        Triglycerides, month 3 (n=70,67)
    0.1 ± 1.07
    0.1 ± 1.01
        Triglycerides, month 6 (n=59,55)
    0 ± 0.92
    0.1 ± 1
        Triglycerides, month 12 (n=40,39)
    -0.1 ± 0.77
    -0.2 ± 0.69
        Triglycerides, month 24 (n=18,22)
    0 ± 1.05
    0 ± 0.82
        Triglycerides, month 36 (n=10,12)
    -0.2 ± 0.99
    0.3 ± 1.38
        Triglycerides, month 48 (n=9,10)
    -0.5 ± 0.94
    0.4 ± 1.32
        Triglycerides, month 60 (n=8,8)
    -0.7 ± 1.01
    0.2 ± 1.02
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: Beck Depression Inventory (BDI-II) score

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: Beck Depression Inventory (BDI-II) score
    End point description
    The BDI-II is a 21 item self-report rating inventory measuring characteristic attitudes and symptoms of depression. The BDI-II contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The scores range as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; and 29-63: severe depression. A negative change from baseline indicates imrpovement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: score on a scale
    arithmetic mean (standard deviation)
        month 3 (n=66,65)
    -4.6 ± 8.29
    -1.9 ± 9.88
        month 6 (n=56,55)
    -4.6 ± 9.49
    -5.5 ± 8.81
        month 12 (n=38,37)
    -4.6 ± 9.19
    -5.2 ± 9.94
        month 18 (n=6,6)
    -1.3 ± 5.24
    -7.8 ± 5.78
        month 24 (n=0,1)
    99999.99 ± 99999.99
    -12 ± 99999.99
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: Ferriman-Galway hirsutism score

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: Ferriman-Galway hirsutism score
    End point description
    The Ferriman Gallwey scoring system is used to score the degree of excess male pattern body hair. The scorecard of every body location under survey begins from 0 (no excessive terminal hair growth) to 4 (extensive terminal hair growth) and the numbers are added up to a maximum count of 36. A score >= 6 indicates the hirsutism. A negative change from baseline indicates imrpovement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: score on a scale
    arithmetic mean (standard deviation)
        month 3 (n=52,50)
    -1.3 ± 3.02
    -1.3 ± 3.46
        month 6 (n=44,47)
    -0.9 ± 2.88
    -2.4 ± 4.7
        month 12 (n=30,35)
    -1.3 ± 1.99
    -3.5 ± 4.65
        month 24 (n=12,22)
    -2.8 ± 2.72
    -4 ± 4.34
        month 36 (n=7,12)
    -3.7 ± 2.69
    -3.2 ± 4.09
        month 48 (n=6,10)
    -6 ± 3.85
    -2.5 ± 2.84
        month 60 (n=5,8)
    -5 ± 3.32
    -2.9 ± 3.23
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: bone mineral density (BMD)

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: bone mineral density (BMD)
    End point description
    BMD was measured using Lunar or Hologic dual-energy X-ray absorptiometry (DXA) Instruments. Measurements were done in the lumbar vertebrae (L1-L4), proximal femur (total hip) and proximal femur (femur neck). A negative change from baseline indicates imrpovement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: mg/cm^3
    arithmetic mean (standard deviation)
        Lumbar vertebrae, month 3 (n=2,2)
    0 ± 0.02
    0 ± 0
        Lumbar vertebrae, month 6 (n=47,39)
    0 ± 0.06
    0 ± 0.04
        Lumbar vertebrae, month 12 (n=33,29)
    0 ± 0.07
    0 ± 0.05
        Lumbar vertebrae, month 24 (n=16,16)
    0 ± 0.04
    0 ± 0.05
        Lumbar vertebrae, month 36 (n=8,9)
    0 ± 0.09
    0.1 ± 0.12
        Lumbar vertebrae, month 48 (n=9,8)
    0 ± 0.12
    0 ± 0.05
        Lumbar vertebrae, month 60 (n=7,6)
    0 ± 0.14
    0 ± 0.08
        Proximal femur (total hip), month 3 (2,2)
    0 ± 0.04
    0 ± 0.01
        Proximal femur (total hip), month 6 (n=46,38)
    0 ± 0.07
    0 ± 0.05
        Proximal femur (total hip), month 12 (n=33,26)
    0 ± 0.04
    0 ± 0.03
        Proximal femur (total hip), month 24 (n=16,13)
    0 ± 0.04
    0 ± 0.03
        Proximal femur (total hip), month 36 (n=8,8)
    0 ± 0.03
    0 ± 0.06
        Proximal femur (total hip), month 48 (n=8,8)
    0 ± 0.04
    0 ± 0.05
        Proximal femur (total hip), month 60 (n=7,6)
    -0.1 ± 0.14
    0 ± 0.06
        Proximal femur (femur neck), month 3 (n=2,2)
    0 ± 0
    0 ± 0.03
        Proximal femur (femur neck), month 6 (n=46,38)
    0 ± 0.03
    0 ± 0.05
        Proximal femur (femur neck), month 12 (n=33,28)
    0 ± 0.04
    0 ± 0.07
        Proximal femur (femur neck), month 24 (n=16,14)
    0 ± 0.05
    0 ± 0.04
        Proximal femur (femur neck), month 36 (n=8,8)
    0 ± 0.02
    0 ± 0.04
        Proximal femur (femur neck), month 48 (n=9,7)
    0 ± 0.05
    0 ± 0.04
        Proximal femur (femur neck), month 60 (7,6)
    0 ± 0.1
    0 ± 0.05
    No statistical analyses for this end point

    Secondary: Mean change from baseline in clinical signs and symptoms of Cushing's disease: body composition

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    End point title
    		 Mean change from baseline in clinical signs and symptoms of Cushing's disease: body composition
    End point description
    Body composition as in percentage of body fat by region was assessed by total body scan. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, month 3, month 6, month 12, month 24, month 36, month 48, month 60
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: Percentage of body fat
    arithmetic mean (standard deviation)
        Month 3 (n=2,2)
    2.9 ± 1.48
    0.3 ± 0.78
        Month 6 (n=39,32)
    -0.4 ± 3.77
    -0.9 ± 4.06
        Month 12 (n=29,22)
    -3 ± 4.23
    -1.6 ± 4.27
        Month 24 (n=13,14)
    -1.9 ± 3.24
    -1.9 ± 5.7
        Month 36 (n=5,8)
    -2 ± 4.2
    -1.1 ± 4.94
        Month 48 (n=4,7)
    -2 ± 5.07
    0.1 ± 5.63
        Month 60 (n=4,6)
    -2.8 ± 4.64
    -0.5 ± 4.97
    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
    Pituitary magnetic resonance imaging (MRI) was performed to determine tumor volume. A negative change from baseline indicates imrpovement.
    End point type
    Secondary
    End point timeframe
    baseline, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: cm^3
    arithmetic mean (standard deviation)
        month 6 (n=25, 28)
    9.3 ± 44.02
    -19 ± 36.82
        month 12 (n=15, 18)
    -8.1 ± 62.17
    -43.8 ± 49.47
        month 18 (n=8, 11)
    -18.1 ± 71.62
    -36 ± 65.42
        month 24 (n=7, 13)
    -27.4 ± 82.68
    -11.5 ± 66.28
        month 30 (n=6, 8)
    -52.1 ± 55.2
    -20.9 ± 77.16
        month 36 (n=3, 5)
    -94.1 ± 10.15
    -27.6 ± 78.86
        month 42 (n=3, 3)
    -95.2 ± 8.4
    84 ± 282.6
        month 48 (n=3, 3)
    -20.5 ± 130.9
    29.2 ± 164.67
        month 54 (n=3, 2)
    -29.1 ± 107.4
    20.3 ± 170.15
        month 60 (n=3, 2)
    -13.5 ± 136.97
    127.6 ± 321.88
        month 66 (n= 1, 1)
    -100 ± 99999.99
    269.8 ± 99999.99
        month 72 (n=1, 0)
    45.6 ± 99999.99
    99999.99 ± 99999.99
        month 78 (n=1, 0)
    77.2 ± 99999.99
    99999.99 ± 99999.99
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in health related quality of life (HRQL) score

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    End point title
    		 Percentage change from baseline in health related quality of life (HRQL) score
    End point description
    A Cushing's syndrome health related quality of life (HRQL) questionnaire was completed. The Cushing’s Syndrome HRQL questionnaire contains 12 sentences with 5 possible answers each. The answers are based on Likert scales, with 5 response categories: Always, Often, Sometimes, Rarely and Never; or Very much, Quite a bit, Somewhat, Very little, and Not at all. The answers to each of the items are rated on a scale of 1 to 5. “1” corresponds to the response category “Always” or “Very much” and “5” corresponds to the category “Never” or “Not at all”. The score is the sum of all item responses and can range from 12 to 60 points. The lower the score, the greater the Cushing's Syndrome impacts on HRQoL. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, 3 months, 6 months, 12 months
    End point values
    		 Pasireotide 600 ug Pasireotide 900 ug
    Number of subjects analysed
    82
    80
    Units: Percentage change in HRQL score
    arithmetic mean (standard deviation)
        month 3 (n=67,66)
    20.7 ± 60.26
    40.1 ± 135.47
        month 6 (n= 55,56)
    19.6 ± 47.78
    52.2 ± 169.47
        month 12 (n=20,20)
    54.9 ± 95.83
    111.5 ± 266.75
    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
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Pasireotide 600 ug bid
    Reporting group description
    		 Pasireotide 600 ug bid

    Reporting group title
    Pasireotide 900 ug bid
    Reporting group description
    		 Pasireotide 900 ug bid

    Serious adverse events
    		 Pasireotide 600 ug bid Pasireotide 900 ug bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 82 (28.05%)
    25 / 80 (31.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secretory adenoma of pituitary
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug ineffective
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microlithiasis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve paralysis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue movement disturbance
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 82 (4.88%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    3 / 82 (3.66%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nail infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 82 (1.22%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pasireotide 600 ug bid Pasireotide 900 ug bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 82 (95.12%)
    79 / 80 (98.75%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 82 (12.20%)
    8 / 80 (10.00%)
         occurrences all number
    12
    10
    Hypotension
         subjects affected / exposed
    4 / 82 (4.88%)
    5 / 80 (6.25%)
         occurrences all number
    9
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    13 / 82 (15.85%)
    6 / 80 (7.50%)
         occurrences all number
    21
    8
    Fatigue
         subjects affected / exposed
    12 / 82 (14.63%)
    24 / 80 (30.00%)
         occurrences all number
    14
    30
    Injection site haemorrhage
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    Injection site pain
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    4
    Malaise
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 80 (6.25%)
         occurrences all number
    3
    11
    Oedema peripheral
         subjects affected / exposed
    9 / 82 (10.98%)
    6 / 80 (7.50%)
         occurrences all number
    9
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 80 (3.75%)
         occurrences all number
    6
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 82 (7.32%)
    10 / 80 (12.50%)
         occurrences all number
    8
    10
    Depression
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    7
    Insomnia
         subjects affected / exposed
    3 / 82 (3.66%)
    13 / 80 (16.25%)
         occurrences all number
    3
    16
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 82 (14.63%)
    6 / 80 (7.50%)
         occurrences all number
    15
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 82 (7.32%)
    3 / 80 (3.75%)
         occurrences all number
    7
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 82 (7.32%)
    1 / 80 (1.25%)
         occurrences all number
    7
    1
    Blood glucose increased
         subjects affected / exposed
    6 / 82 (7.32%)
    3 / 80 (3.75%)
         occurrences all number
    6
    3
    Blood insulin decreased
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    2
    7
    Electrocardiogram QT prolonged
         subjects affected / exposed
    5 / 82 (6.10%)
    7 / 80 (8.75%)
         occurrences all number
    8
    7
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 82 (13.41%)
    7 / 80 (8.75%)
         occurrences all number
    13
    9
    Glycosylated haemoglobin increased
         subjects affected / exposed
    10 / 82 (12.20%)
    8 / 80 (10.00%)
         occurrences all number
    11
    9
    International normalised ratio increased
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    Lipase increased
         subjects affected / exposed
    7 / 82 (8.54%)
    5 / 80 (6.25%)
         occurrences all number
    8
    8
    Low density lipoprotein increased
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 80 (3.75%)
         occurrences all number
    9
    3
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    Weight decreased
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 80 (6.25%)
         occurrences all number
    5
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    4
    Procedural pain
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    8 / 82 (9.76%)
    2 / 80 (2.50%)
         occurrences all number
    13
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 82 (10.98%)
    9 / 80 (11.25%)
         occurrences all number
    11
    10
    Dysgeusia
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    5
    5
    Headache
         subjects affected / exposed
    25 / 82 (30.49%)
    25 / 80 (31.25%)
         occurrences all number
    66
    68
    Migraine
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    8
    Somnolence
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 80 (5.00%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 82 (1.22%)
    5 / 80 (6.25%)
         occurrences all number
    1
    7
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 82 (4.88%)
    6 / 80 (7.50%)
         occurrences all number
    5
    7
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 82 (7.32%)
    6 / 80 (7.50%)
         occurrences all number
    10
    7
    Abdominal pain
         subjects affected / exposed
    19 / 82 (23.17%)
    21 / 80 (26.25%)
         occurrences all number
    41
    35
    Abdominal pain upper
         subjects affected / exposed
    11 / 82 (13.41%)
    8 / 80 (10.00%)
         occurrences all number
    15
    9
    Constipation
         subjects affected / exposed
    9 / 82 (10.98%)
    4 / 80 (5.00%)
         occurrences all number
    9
    4
    Diarrhoea
         subjects affected / exposed
    49 / 82 (59.76%)
    46 / 80 (57.50%)
         occurrences all number
    80
    69
    Dyspepsia
         subjects affected / exposed
    1 / 82 (1.22%)
    5 / 80 (6.25%)
         occurrences all number
    1
    6
    Faeces soft
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    6
    Haemorrhoids
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    7
    Nausea
         subjects affected / exposed
    40 / 82 (48.78%)
    47 / 80 (58.75%)
         occurrences all number
    53
    71
    Vomiting
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 80 (11.25%)
         occurrences all number
    4
    11
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    25 / 82 (30.49%)
    25 / 80 (31.25%)
         occurrences all number
    31
    29
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 80 (2.50%)
         occurrences all number
    7
    2
    Alopecia
         subjects affected / exposed
    10 / 82 (12.20%)
    11 / 80 (13.75%)
         occurrences all number
    10
    18
    Dry skin
         subjects affected / exposed
    5 / 82 (6.10%)
    5 / 80 (6.25%)
         occurrences all number
    5
    7
    Ecchymosis
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    Pruritus
         subjects affected / exposed
    6 / 82 (7.32%)
    7 / 80 (8.75%)
         occurrences all number
    9
    8
    Rash
         subjects affected / exposed
    6 / 82 (7.32%)
    4 / 80 (5.00%)
         occurrences all number
    10
    4
    Skin exfoliation
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 80 (3.75%)
         occurrences all number
    7
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 80 (5.00%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 82 (7.32%)
    10 / 80 (12.50%)
         occurrences all number
    15
    11
    Back pain
         subjects affected / exposed
    5 / 82 (6.10%)
    7 / 80 (8.75%)
         occurrences all number
    5
    9
    Muscle spasms
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 80 (5.00%)
         occurrences all number
    1
    5
    Myalgia
         subjects affected / exposed
    11 / 82 (13.41%)
    6 / 80 (7.50%)
         occurrences all number
    30
    8
    Neck pain
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    4
    Pain in extremity
         subjects affected / exposed
    7 / 82 (8.54%)
    4 / 80 (5.00%)
         occurrences all number
    8
    4
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    4
    Influenza
         subjects affected / exposed
    10 / 82 (12.20%)
    5 / 80 (6.25%)
         occurrences all number
    11
    11
    Nasopharyngitis
         subjects affected / exposed
    12 / 82 (14.63%)
    12 / 80 (15.00%)
         occurrences all number
    18
    17
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 82 (7.32%)
    2 / 80 (2.50%)
         occurrences all number
    7
    2
    Urinary tract infection
         subjects affected / exposed
    4 / 82 (4.88%)
    6 / 80 (7.50%)
         occurrences all number
    4
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 82 (9.76%)
    9 / 80 (11.25%)
         occurrences all number
    9
    11
    Diabetes mellitus
         subjects affected / exposed
    17 / 82 (20.73%)
    18 / 80 (22.50%)
         occurrences all number
    17
    22
    Hypercholesterolaemia
         subjects affected / exposed
    8 / 82 (9.76%)
    12 / 80 (15.00%)
         occurrences all number
    11
    13
    Hyperglycaemia
         subjects affected / exposed
    31 / 82 (37.80%)
    35 / 80 (43.75%)
         occurrences all number
    39
    45
    Hyperlipidaemia
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 80 (3.75%)
         occurrences all number
    7
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    6 / 82 (7.32%)
    5 / 80 (6.25%)
         occurrences all number
    10
    6
    Hypoglycaemia
         subjects affected / exposed
    12 / 82 (14.63%)
    5 / 80 (6.25%)
         occurrences all number
    17
    7
    Hypokalaemia
         subjects affected / exposed
    6 / 82 (7.32%)
    5 / 80 (6.25%)
         occurrences all number
    6
    6
    Type 2 diabetes mellitus
         subjects affected / exposed
    10 / 82 (12.20%)
    5 / 80 (6.25%)
         occurrences all number
    11
    7
    Vitamin B12 deficiency
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 80 (6.25%)
         occurrences all number
    4
    6
    Vitamin D deficiency
         subjects affected / exposed
    5 / 82 (6.10%)
    5 / 80 (6.25%)
         occurrences all number
    6
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2006
    Amendment 1 was to add a protocol version number to the cover page of the original protocol and to add a section describing the history of prior protocol amendments.
    15 Mar 2007
    Amendment 2 was to add the requirement for additional gallbladder ultrasounds to be performed every three months at the German sites only.
    18 Apr 2007
    Amendment 3 was to add closer glucose monitoring for patients with diabetes or impaired fasting glucose as an additional safety measure at the French sites only.
    25 May 2007
    Amendment 4 was to change the criteria for dose escalation at Month 3 from mUFC > 1.5 x ULN or ≤ 50% reduction compared to baseline to mUFC < 2 x ULN. It also changed the definition of responders at Month 6 such that any patient dose escalated and unblinded at Month 3 will be automatically counted as a non-responder in the primary efficacy analysis. Other changes, including changes to the inclusion and exclusion criteria were also made.
    15 Jun 2007
    Amendment 5 was to add an analysis of injection site reactions as requested by the German health authorities as well as to specify that DXA scans were not to be performed in Germany.
    10 Dec 2007
    Amendment 6 was to lower the UFC entry criterion from ≤ 2 x ULN to ≤ 1.5 x ULN. The Month 3 dose-determination criteria were adapted as a consequence. The response criteria at Month 6 were amended from mean UFC ≤ 1.5 x ULN and a >50% reduction in mUFC to mUFC ≤ 1 x ULN. Midnight salivary cortisol measurements were added. An extension treatment phase was added for patients benefiting from study treatment. The multiple comparison procedure was removed. Several inclusion and exclusion criteria were amended including a prolongation of the exclusion of pituitary irradiation from 2 to 10 years prior to study start. Further minor changes and corrections to the protocol were also made.
    19 Feb 2008
    Amendment 8 was to include a summary paragraph on dose adjustments and discontinuation during the extension phase for easier understanding and to request additional confirmation of a pituitary ACTH source for patients without IPSS or histological confirmation upon specific request by the French authorities for the French sites only.
    04 Mar 2008
    Amendment 9 was a local amendment valid only for China to set the maximum dose a patient may receive to 900 μg b.i.d. upon specific request by the Chinese Health Authorities.
    30 Apr 2010
    Amendment 10 was issued to allow doses lower than 300 ug bid in patients who require lower doses due to tolerability issues as long as efficacy was maintained, to amend the management of hyperglycemia according to published guidelines, and to add a steering committee.
    12 Dec 2011
    Amendment 11 was issued to include additional hepatic-related safety measures as a result of an internal hepatic medical review of pasireotide studies.

    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.
    No statistical analysis was planned for this outcome measure. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results.
    For support, Contact us.
    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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