Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43861   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A randomized, double-blind, multicenter, phase III study to evaluate the efficacy and safety of pasireotide LAR in patients with 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
    		 2009-011128-70
    Trial protocol
    		 GB   ES   DE   NL   BE   PL   IT  
    Global end of trial date
    21 Dec 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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CSOM230G2304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01374906
    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, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of two pasireotide long-acting regimens (starting doses of 10 mg and 30 mg followed by up-titration if needed or continuation of the same dose) independently in patients with Cushing’s disease after 7 months of treatment regardless of up titration at Month 4.
    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
    04 Nov 2011
    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
    Argentina: 1
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 36
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Peru: 9
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    150
    EEA total number of subjects
    54
    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)
    147
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 At least 148 patients (Pts.) were planned & 150 were randomized & analyzed. Pts. were all treated with either pasireotide long-acting 10 mg or pasireotide long-acting 30 mg. 81 Pts. completed the Core phase & entered the Extension phase with 39 completing the Extension phase.

    Pre-assignment
    Screening details
    		 Planned: at least 148 patients - Randomized & Analyzed: 150 patients; 74 patients in 10 mg arm and 76 patients in 30 mg arm.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 10 mg pasireotide LAR dose
    Arm description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pasireotide LAR
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Pasireotide long-acting ampoules were supplied to the investigators at dose strengths of 10 mg, 10 mg + 20 mg and 40 mg kits.

    Arm title
    		 30 mg pasireotide LAR dose
    Arm description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pasireotide LAR
    Investigational medicinal product code
    SOM230
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Pasireotide long-acting was administered as an intra-muscular depot intragluteal injection once every 28 days (±2 days). Pasireotide long-acting ampoules were supplied to the investigators at dose strengths of 10 mg, 10 mg + 20 mg and 40 mg kits.

    Number of subjects in period 1
    		10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Started
    74
    76
    Completed
    34
    28
    Not completed
    40
    48
         Abnormal laboratory value(s)
    -
    3
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    15
    9
         Adverse event, non-fatal
    10
    11
         Unsatisfactory therapeutic effect
    11
    19
         Administrative problems
    2
    2
         Protocol deviation
    2
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    10 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.

    Reporting group title
    30 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.

    Reporting group values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose Total
    Number of subjects
    		 74 76 150
    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)
    		 73 74 147
        From 65-84 years
    		 1 2 3
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.3 ± 12.52 38.6 ± 12.99 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 58 60 118
        Male
    		 16 16 32
    Race/Ethnicity
    Units: Subjects
        Caucasian
    		 39 44 83
        Asian
    		 27 24 51
        Black
    		 2 0 2
        Other
    		 6 8 14

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    10 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.

    Reporting group title
    30 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.

    Subject analysis set title
    5 mg pasireotide LAR dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

    Subject analysis set title
    40 mg pasireotide LAR dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

    Subject analysis set title
    5 mg pasireptide LAR dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These patients were dosed with 5 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

    Subject analysis set title
    40 mg pasireotide LAR dose
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    These patients were dosed with 40 mg of Pasireotide LAR to assess Pharmacokinetics (PK).

    Primary: Percentage participants that attained a mUFC ≤ 1.0 x ULN at Month 7 regardless of dose titration

    		 Close Top of page
    End point title
    		 Percentage participants that attained a mUFC ≤ 1.0 x ULN at Month 7 regardless of dose titration [1]
    End point description
    Percentage of participants that attained a mean urinary free cortisol (mUFC) <= 1.0 x upper limit of normal (ULN) at Month 7 regardless of dose up-titration at Month 4. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value.
    End point type
    Primary
    End point timeframe
    Month 7
    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: All analyses in this study were descriptive in nature. No comparisons were made between the two arms, and no p-values are reported. For the primary and key-secondary, success was based on estimating the response rate (and 95% CI) in each arm.
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
        number (confidence interval 95%)
    41.9 (30.51 to 53.94)
    40.8 (29.65 to 52.67)
    No statistical analyses for this end point

    Secondary: Percentage of participants that attained a mUFC ≤ 1.0 x ULN at Month 7 and had not had a dose increase at Month 4

    		 Close Top of page
    End point title
    		 Percentage of participants that attained a mUFC ≤ 1.0 x ULN at Month 7 and had not had a dose increase at Month 4
    End point description
    Percentage of participants that attain a mUFC ≤ 1.0×ULN at Month 7 and had not had a dose increase at Month 4. Patients who had a dose increase prior to Month 7 were counted as non-responders in this analysis. Patients who discontinued before month 4 evaluations classed as non-responders. For patients missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. A responder was defined as a patient who attains mUFC ≤1.0 X ULN and had not had a dose increase at Month 4.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
        number (confidence interval 95%)
    28.4 (18.50 to 40.05)
    31.6 (21.39 to 43.25)
    No statistical analyses for this end point

    Secondary: Actual change in mean urinary free cortisol (mUFC) from baseline

    		 Close Top of page
    End point title
    		 Actual change in mean urinary free cortisol (mUFC) from baseline
    End point description
    Actual change in mUFC (nmol/24h) from baseline by randomized groups.
    End point type
    Secondary
    End point timeframe
    baseline, Month 7 (M7), Month 12 (M12), Month 24 (M24) , Month 36 (M36)
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: nmol/24h
    arithmetic mean (standard deviation)
        M7 (n = 57, 67)
    -192.4 ± 271.59
    -234.3 ± 362.86
        M12 (n = 50, 54)
    -195.1 ± 282.46
    -247.6 ± 387.05
        M24 (n = 33, 25)
    -236.2 ± 292.91
    -265.2 ± 313.47
        M36 (n = 14, 4)
    -398.4 ± 136.09
    -164.6 ± 66.76
    No statistical analyses for this end point

    Secondary: Percentage change in mean urinary free cortisol (mUFC) from baseline

    		 Close Top of page
    End point title
    		 Percentage change in mean urinary free cortisol (mUFC) from baseline
    End point description
    Percentage change in mUFC (nmol/24h) from baseline by randomized groups.
    End point type
    Secondary
    End point timeframe
    M7, M12, M24, M36
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage change
    arithmetic mean (standard deviation)
        M7 (n= 57, 67)
    -29.3 ± 102.76
    -33.2 ± 61.37
        M12 (n= 50, 54)
    -30.3 ± 79.73
    -31.1 ± 78.41
        M24 (n= 33, 25
    -50.9 ± 76.48
    -51.2 ± 35.41
        M36 (n = 14, 4)
    -71.6 ± 20.44
    -48.8 ± 11.36
    No statistical analyses for this end point

    Secondary: Percentage of patients who attain mUFC ≤ 1.0 x ULN

    		 Close Top of page
    End point title
    		 Percentage of patients who attain mUFC ≤ 1.0 x ULN
    End point description
    Controlled responder: mUFC ≤ 1.0×ULN by randomized groups.
    End point type
    Secondary
    End point timeframe
    M7, M12, M24, M36, M48, M60
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (confidence interval 95%)
        M7 - Controlled responder (n = 74, 76)
    39.2 (28.04 to 51.23)
    40.8 (29.65 to 52.67)
        M12 - Controlled responder (n = 74, 76)
    35.1 (24.39 to 47.11)
    25.0 (15.77 to 36.26)
        M24 - Controlled responder (n = 63, 61)
    39.7 (27.57 to 52.80)
    21.3 (11.86 to 33.68)
        M36 - Controlled responder (n = 50, 50)
    22.0 (11.53 to 35.96)
    4.0 (0.49 to 13.71)
    No statistical analyses for this end point

    Secondary: Percentage of patients who attain mUFC ≤1.0 x ULN or have at least 50 % reduction from baseline in mUFC

    		 Close Top of page
    End point title
    		 Percentage of patients who attain mUFC ≤1.0 x ULN or have at least 50 % reduction from baseline in mUFC
    End point description
    Controlled responder: mUFC ≤ 1.0×ULN. Partially controlled responder: at least 50% reduction in mUFC from Baseline, and mUFC >1.0×ULN.
    End point type
    Secondary
    End point timeframe
    M7, M12, M24, M36, M48, M60
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (confidence interval 95%)
        M7 (n = 74, 76)
    44.6 (33.02 to 56.61)
    53.9 (42.13 to 65.45)
        M12 (n= 74, 76)
    45.9 (34.29 to 57.93)
    42.1 (30.86 to 53.98)
        M24 (n= 63, 61)
    46.0 (33.39 to 59.06)
    27.9 (17.15 to 40.83)
        M36 (n = 50, 50)
    28.0 (16.23 to 42.49)
    6.0 (1.25 to 16.55)
    No statistical analyses for this end point

    Secondary: Percentage of patients who are controlled responders (mUFC ≤ 1.0 xULN) on at least 4 of the 7 mUFC assessments by Month 7 & on at least 7 of the 12 mUFC assessments by Month 12.

    		 Close Top of page
    End point title
    		 Percentage of patients who are controlled responders (mUFC ≤ 1.0 xULN) on at least 4 of the 7 mUFC assessments by Month 7 & on at least 7 of the 12 mUFC assessments by Month 12.
    End point description
    Percentage of patients with mUFC ≤ 1.0 x ULN at a minimum of 4 months up to and including Month 7, and at a minimum of 7 months up to and including Month 12 by randomized groups.
    End point type
    Secondary
    End point timeframe
    Month 7, Month 12
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (confidence interval 95%)
        Month 7
    25.7 (16.22 to 37.16)
    31.6 (21.39 to 43.25)
        Month 12
    25.7 (16.22 to 37.16)
    25.0 (15.77 to 36.26)
    No statistical analyses for this end point

    Secondary: Percentage of patients with uncontrolled response at Month 7 & Month 12 within the subset of patients who had uncontrolled response at a) Months 1 and 2; b) Months 1, 2, and 3

    		 Close Top of page
    End point title
    		 Percentage of patients with uncontrolled response at Month 7 & Month 12 within the subset of patients who had uncontrolled response at a) Months 1 and 2; b) Months 1, 2, and 3
    End point description
    Percentage of patients with mUFC > 1.0 xULN at Month 7 and Month 12 within the subset of patients who were uncontrolled at a) Months 1 & 2, b) Months 1, 2, & 3 by randomized groups.
    End point type
    Secondary
    End point timeframe
    Month 7, Month12
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (not applicable)
        Uncontrolled Resp @ M7: subset: M1 & 2 (33, 33)
    60.6
    60.6
        Uncontrolled Resp @ M7: subset: M1,2 & 3 (31, 29)
    61.3
    65.5
        Uncontrolled Resp @ M12: subset: M1 & 2 (33, 33)
    69.7
    69.7
        Uncontrolled Resp @ M12: subset: M1 & 2 (31, 29)
    74.2
    72.4
    No statistical analyses for this end point

    Secondary: Time to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline

    		 Close Top of page
    End point title
    		 Time to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline
    End point description
    Time to first achievement of attaining a mUFC ≤ 1.0 x ULN or at least a 50% reduction in mUFC from baseline by randomized groups.
    End point type
    Secondary
    End point timeframe
    Momth 7, Month 12
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 7
    86.2 (76.1 to 93.5)
    83.4 (72.6 to 91.8)
        Month 12
    90.1 (80.7 to 96.2)
    94.5 (81.0 to 99.4)
    No statistical analyses for this end point

    Secondary: Duration of controlled or partially controlled response

    		 Close Top of page
    End point title
    		 Duration of controlled or partially controlled response
    End point description
    Duration of controlled or partially controlled response is defined as the period starting from the date of patient’s first normalization (mUFC≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient’s mUFC >1.0 x ULN and the reduction from baseline falls to less than 50% for the first time.
    End point type
    Secondary
    End point timeframe
    Month 6, 12, 18
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage of participants
    number (confidence interval 95%)
        Month 6
    78.0 (66.5 to 87.7)
    72.9 (61.2 to 83.4)
        Month 12
    84.0 (73.1 to 92.2)
    82.8 (71.5 to 91.5)
        Month 18
    84.0 (73.1 to 92.2)
    87.1 (74.6 to 95.3)
    No statistical analyses for this end point

    Secondary: Percentage change from baseline on plasma adrenocorticotropic hormone (ACTH) over time

    		 Close Top of page
    End point title
    		 Percentage change from baseline on plasma adrenocorticotropic hormone (ACTH) over time
    End point description
    Percentage change in ACTH (pmol/L) from Baseline by randomized groups.
    End point type
    Secondary
    End point timeframe
    Months 7, 12, 24 & 36
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage change
    arithmetic mean (standard deviation)
        M7 (n = 54, 62)
    2.7 ± 57.14
    -13.5 ± 46.75
        M12 (n = 44, 52)
    -10.2 ± 57.57
    -14.5 ± 38.72
        M24 (n = 31, 23)
    -12.1 ± 43.51
    2.5 ± 68.69
        M36 (n = 13, 5)
    -15.4 ± 36.90
    -0.6 ± 48.13
    No statistical analyses for this end point

    Secondary: Percentage change from baseline on serum cortisol over time

    		 Close Top of page
    End point title
    		 Percentage change from baseline on serum cortisol over time
    End point description
    Percentage change in serum cortisol (nmol/L) from Baseline by randomized groups.
    End point type
    Secondary
    End point timeframe
    Months 7, 12, 24 & 36
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage change
    arithmetic mean (standard deviation)
        M7 (n = 55, 66)
    -8.2 ± 37.83
    -5.1 ± 40.20
        M12 (n = 46, 54)
    -12.1 ± 29.69
    -0.4 ± 35.91
        M24 (n = 32, 25)
    -15.6 ± 30.67
    -7.4 ± 38.37
        M36 (n = 14, 5)
    0.6 ± 55.67
    -23.2 ± 31.19
    No statistical analyses for this end point

    Secondary: Actual change from baseline in clinical signs over time: Blood Pressure

    		 Close Top of page
    End point title
    		 Actual change from baseline in clinical signs over time: Blood Pressure
    End point description
    Change in blood pressure measurements from Baseline.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    57
    67
    Units: mmHg
    arithmetic mean (standard deviation)
        Supine systolic blood pressure (SBP)
    -6.8 ± 15.64
    -4.6 ± 14.51
        Supine diastolic blood (DBP) pressure
    -4.8 ± 12.06
    -3.0 ± 12.12
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in clinical signs over time

    		 Close Top of page
    End point title
    		 Percentage change from baseline in clinical signs over time
    End point description
    Percentage change in parameter measurements: blood pressure, body mass index, waist circumference, fasting serum lipid profile, weight, bone density and body composition (examined by DXA scan) from Baseline
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    57
    67
    Units: Percentage change
    arithmetic mean (standard deviation)
        SBP (n = 57, 67)
    -4.3 ± 11.46
    -3.0 ± 10.18
        DBP (n = 57, 67)
    -4.7 ± 14.19
    -2.6 ± 13.78
        BMI (n = 57, 67)
    -2.6 ± 5.26
    -6.1 ± 6.94
        Weight (n = 57, 67)
    -2.6 ± 5.26
    -6.1 ± 6.91
        Waist circumference (n = 53, 63)
    -1.4 ± 8.60
    -6.6 ± 10.06
        HDL (n = 55, 64)
    -6.7 ± 15.18
    0.3 ± 20.91
        Total cholesterol (n = 56, 64)
    -7.2 ± 16.86
    -6.6 ± 16.40
        Triglycerides (n = 56, 64)
    4.2 ± 39.54
    -0.9 ± 39.61
        Body composition (n = 41, 48)
    -2.4 ± 6.68
    -3.6 ± 10.47
    No statistical analyses for this end point

    Secondary: Percentage of patients having a favorable shift from baseline in clinical signs

    		 Close Top of page
    End point title
    		 Percentage of patients having a favorable shift from baseline in clinical signs
    End point description
    This includes patients with improvements, no change or worsening in symptoms from baseline. Clinical signs over time include: facial rubor, fat pads, hirsutism, striae, (via photographs by a second local physician who was blinded to the treatment dose and time point of the photograph) and muscle strength.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage of participants
    number (not applicable)
        Facial rubor (n = 52, 56)
    32.7
    53.6
        Hirsutism (females only) (n= 42,46)
    22.2
    32.6
        Striae (n = 52, 55)
    23.1
    23.6
        Bruising (n = 52, 56)
    25.0
    14.3
        Supraclavicular fat pad (n= 52,56)
    40.4
    28.6
        Dorsal fat pad (n = 52, 55)
    28.8
    40.0
        Muscle strength (n = 56, 66)
    8.9
    4.5
    No statistical analyses for this end point

    Secondary: Percentage of participants that attained a mean urinary free cortisol (mUFC) <= 1.0 x upper limit of normal (ULN) at Month 7 regardless of dose up-titration at Month 4.

    		 Close Top of page
    End point title
    		 Percentage of participants that attained a mean urinary free cortisol (mUFC) <= 1.0 x upper limit of normal (ULN) at Month 7 regardless of dose up-titration at Month 4.
    End point description
    All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1: mUFC 1.5x to < 2.0 x ULN Stratum 2: mUFC 2.0x to <= 5.0 x ULN
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (confidence interval 95%)
        stratum:1.5 x ULN to < 2.0 x ULN (n=25,25)
    52.0 (31.31 to 72.20)
    52.0 (31.31 to 72.20)
        stratum:2.0 x ULN to <= 5.0 x ULN (n = 49, 51)
    36.7 (23.42 to 51.71)
    35.3 (22.43 to 49.93)
    No statistical analyses for this end point

    Secondary: Percentage of patients that attain a reduction of at least 50% in mUFC from baseline

    		 Close Top of page
    End point title
    		 Percentage of patients that attain a reduction of at least 50% in mUFC from baseline
    End point description
    All of the participants who discontinued prior to month 4 evaluations were classed as non-responders. For participants missing month 7 mUFC assessments, the last available mUFC assessment at or after month 4 was carried forward as the month 7 mUFC assessment value. Analysis split by screening strata of mUFC Stratum 1:
    End point type
    Secondary
    End point timeframe
    Months 7, 12, 24 & 36
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: percentage of participants
    number (confidence interval 95%)
        M7
    35.1 (24.39 to 47.11)
    43.4 (32.08 to 55.29)
        M12
    35.1 (24.39 to 47.11)
    38.2 (27.25 to 50.02)
        M24 (n = 24, 14)
    83.3 (62.62 to 95.26)
    57.1 (28.86 to 82.34)
        M36 (n = 8, 3)
    100 (63.06 to 100.00)
    33.33 (0.84 to 90.57)
    No statistical analyses for this end point

    Secondary: Time to first achievement of at least a 50% reduction in mUFC from baseline

    		 Close Top of page
    End point title
    		 Time to first achievement of at least a 50% reduction in mUFC from baseline
    End point description
    Time to first achievement of a 5by randomized groups.0% reduction in mUFC from baseline
    End point type
    Secondary
    End point timeframe
    every month in the core phase and every 3 months in the extension phase) up to and including the cut-off date for the Month 12 CSR (10-Nov-2015)
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage of participants
    number (confidence interval 95%)
        M7
    80.5 (69.7 to 89.3)
    73.4 (62.4 to 83.4)
        M12
    84.4 (74.0 to 92.3)
    80.7 (69.4 to 89.8)
    No statistical analyses for this end point

    Secondary: Duration of at least 50% reduction in mUFC from baseline

    		 Close Top of page
    End point title
    		 Duration of at least 50% reduction in mUFC from baseline
    End point description
    Duration of 50% reduction from baseline is defined as the period starting from the date of patient’s first 50% reduction from baseline
    End point type
    Secondary
    End point timeframe
    Months 6, 12 & 18
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: Percentage of participants
    number (confidence interval 95%)
        M6
    78.4 (66.6 to 88.3)
    77.8 (66.0 to 87.7)
        M12
    84.9 (73.7 to 93.1)
    83.7 (72.6 to 92.1)
        M18
    84.9 (73.7 to 93.1)
    83.7 (72.6 to 92.1)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Ctrough

    		 Close Top of page
    End point title
    		 Pharmacokinetic (PK) parameter: Ctrough
    End point description
    Pasireotide trough levels (Ctrough) was one of the parameters used for PK assessments. Ctrough is the pre-dose PK concentration with an elapsed time from previous injection of 28+/-2 days. All patients randomized to the study had at least one PK observation and were therefore included in the pharmacokinetic analysis set (PAS). 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
    Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose 5 mg pasireotide LAR dose 40 mg pasireotide LAR dose
    Number of subjects analysed
    65
    64
    5
    44
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 29 (n = 65, 64, 0, 0)
    2.03 ± 1.25
    7.63 ± 4.58
    9.99 ± 9.99
    9.9 ± 9.99
        Day 57 (n = 57, 61, 1, 0)
    2.35 ± 1.15
    7.82 ± 4.22
    0.83 ± 9.99
    9.99 ± 9.99
        Day 85 (n = 59, 51, 2, 0)
    2.39 ± 1.32
    8.56 ± 4.26
    1.03 ± 0.63
    9.99 ± 9.99
        Day 113 (n = 51, 49, 3, 0)
    2.40 ± 1.11
    8.31 ± 3.87
    1.29 ± 0.24
    9.99 ± 9.99
        Day 141 (n = 25, 50, 2, 20)
    2.47 ± 0.94
    7.88 ± 4.00
    1.04 ± 0.68
    10.7 ± 4.91
        Day 169 (n = 29, 51, 2, 22)
    2.47 ± 0.95
    8.46 ± 3.51
    2.01 ± 0.22
    12.0 ± 5.08
        Day 197 (n = 35, 44, 2, 21)
    2.88 ± 1.29
    9.13 ± 4.25
    0.72 ± 0.39
    11.9 ± 5.87
        Day 225 (n = 22, 28, 3, 34)
    2.68 ± 0.98
    8.57 ± 4.70
    1.19 ± 0.43
    11.3 ± 5.18
        Day 253 (n = 17, 27, 5, 33)
    2.87 ± 1.57
    9.00 ± 4.93
    1.77 ± 0.88
    12.1 ± 5.21
        Day 281 (n = 13, 16, 3, 44)
    3.36 ± 1.48
    8.18 ± 4.23
    1.24 ± 0.52
    11.4 ± 5.85
        Day 309 (n = 23, 19, 1, 43)
    2.50 ± 0.99
    9.34 ± 5.61
    0.66 ± 9.99
    12.0 ± 4.58
        Day 337 (n = 21, 15, 3, 41)
    3.07 ± 1.62
    8.90 ± 4.37
    1.91 ± 1.79
    12.6 ± 6.21
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameter: Cmax

    		 Close Top of page
    End point title
    		 Pharmacokinetic (PK) parameter: Cmax
    End point description
    Pasireotide peak levels (Cmax) was one of the parameters used for PK assessments. Cmax is the post-dose PK concentration with an elapsed time from the previous injection of 21+/-2 days. All patients randomized to the study had at least one PK observation and were therefore included in the pharmacokinetic analysis set (PAS). Cmax PK observations ("Day 20" and "Day 104") with an elapsed time from the previous injection outside of 21+/-2 days window were excluded.
    End point type
    Secondary
    End point timeframe
    Days 22, 106, 190
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose 5 mg pasireptide LAR dose 40 mg pasireotide LAR dose
    Number of subjects analysed
    67
    69
    3
    22
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 22 (M 0.75) (n= 67, 69, 0, 0)
    3.0 ± 1.50
    8.2 ± 3.99
    9.99 ± 9.99
    9.99 ± 9.99
        Day 106 (M 3.75) (n = 54, 51, 3, 0)
    3.3 ± 1.92
    9.4 ± 3.72
    1.7 ± 0.42
    9.99 ± 9.99
        Day 190 (M6.75) (n = 32, 40, 2, 22)
    4.0 ± 1.73
    10.0 ± 3.91
    1.4 ± 0.78
    12.1 ± 5.21
    No statistical analyses for this end point

    Secondary: Actual change in standardized score of Cushing’s disease HRQoL (CushingQOL) score from baseline

    		 Close Top of page
    End point title
    		 Actual change in standardized score of Cushing’s disease HRQoL (CushingQOL) score from baseline
    End point description
    CushingQol is a disease-specific patient-reported outcome instrument. It is a single-domain 12 item Cushing's disease quality of life instrument. The Cushing’s syndrome quality of life (CushingQoL) questionnaire is a single domain questionnaire which includes 12 self-report items scored using a five point Likert scale anchored at (1=always/very much and 5=never/not at all). The patient is asked to report what they think or feel about their Cushing’s syndrome and how much the illness has interfered in usual activities over the past 4 weeks. The total score is standardized on a 0-100 scale with lower scores indicating a greater impact on quality of life.
    End point type
    Secondary
    End point timeframe
    Months 7, 12, 24 & 36
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: scores on a scale
    arithmetic mean (standard deviation)
        M7 (n = 56, 64)
    5.7 ± 15.97
    7.8 ± 11.63
        M12 (n = 47, 53)
    6.4 ± 17.56
    6.8 ± 14.42
        M24 (n = 32, 25)
    5.9 ± 15.56
    8.7 ± 12.80
        M36 (n = 13, 4)
    1.4 ± 9.10
    14.6 ± 5.10
    No statistical analyses for this end point

    Secondary: Actual change in SF-12v2 score from Baseline - Mental component summary

    		 Close Top of page
    End point title
    		 Actual change in SF-12v2 score from Baseline - Mental component summary
    End point description
    SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults.
    End point type
    Secondary
    End point timeframe
    Months 7, 12 & 24
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: scores on a scale
    arithmetic mean (standard deviation)
        M7 (n = 33, 37)
    4.1 ± 8.81
    4.3 ± 8.05
        M12 (n = 28, 33)
    2.3 ± 9.97
    3.3 ± 8.26
        M24 (n = 9, 5)
    3.3 ± 10.43
    6.4 ± 2.53
    No statistical analyses for this end point

    Secondary: Actual change in SF-12v2 score from Baseline - Physical component summary

    		 Close Top of page
    End point title
    		 Actual change in SF-12v2 score from Baseline - Physical component summary
    End point description
    SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults.
    End point type
    Secondary
    End point timeframe
    Months 7, 12 & 24
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    74
    76
    Units: scores on a scale
    arithmetic mean (standard deviation)
        M7 (n = 33, 37)
    1.9 ± 8.50
    -0.8 ± 7.46
        M12 (n = 28, 33)
    4.9 ± 5.56
    -0.5 ± 6.73
        M24 (n = 9, 5)
    5.3 ± 4.32
    -1.1 ± 5.54
    No statistical analyses for this end point

    Secondary: Actual change from baseline in clinical signs over time: Body Mass Index (BMI)

    		 Close Top of page
    End point title
    		 Actual change from baseline in clinical signs over time: Body Mass Index (BMI)
    End point description
    Change in BMI measurements from Baseline.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    57
    67
    Units: kg/m2
        arithmetic mean (standard deviation)
    -0.7 ± 1.60
    -1.8 ± 2.05
    No statistical analyses for this end point

    Secondary: Actual change from baseline in clinical signs over time: Weight

    		 Close Top of page
    End point title
    		 Actual change from baseline in clinical signs over time: Weight
    End point description
    Actual change from baseline in clinical signs over time: Weight.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    57
    67
    Units: kg
        arithmetic mean (standard deviation)
    -1.8 ± 4.16
    -4.6 ± 5.08
    No statistical analyses for this end point

    Secondary: Actual change from baseline in clinical signs over time: Body Composition: Region

    		 Close Top of page
    End point title
    		 Actual change from baseline in clinical signs over time: Body Composition: Region
    End point description
    Change in body composition: region measurements from Baseline.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    41
    48
    Units: percentage fat
        arithmetic mean (standard deviation)
    -1.0 ± 2.64
    -1.8 ± 3.97
    No statistical analyses for this end point

    Secondary: Actual change from baseline in clinical signs over time: Waist circumference

    		 Close Top of page
    End point title
    		 Actual change from baseline in clinical signs over time: Waist circumference
    End point description
    Change in waist circumference measurements from Baseline.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    53
    63
    Units: cm
        arithmetic mean (standard deviation)
    -1.6 ± 8.47
    -7.1 ± 11.78
    No statistical analyses for this end point

    Secondary: Actual Change From Baseline in Clinical Signs Over Time: cholesterol & triglycerides

    		 Close Top of page
    End point title
    		 Actual Change From Baseline in Clinical Signs Over Time: cholesterol & triglycerides
    End point description
    Change in parameter measurements: cholesterol & triglycerides from Baseline.
    End point type
    Secondary
    End point timeframe
    Month 7
    End point values
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose
    Number of subjects analysed
    56
    64
    Units: mmol/L
    arithmetic mean (standard deviation)
        Total cholesterol (n = 56, 64)
    -0.5 ± 1.07
    -0.4 ± 1.00
        HDL cholesterol (n = 55, 64)
    -0.1 ± 0.28
    0 ± 0.32
        Triglycerides (n = 56, 64)
    0 ± 0.53
    -0.2 ± 0.64
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    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
    19.1
    Reporting groups
    Reporting group title
    10 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 10 mg of Pasireotide LAR.

    Reporting group title
    30 mg pasireotide LAR dose
    Reporting group description
    		 Randomization was stratified based on Screening mUFC to ensure balanced distribution of disease severity in the two dose arms. These patients were dosed with 30 mg of Pasireotide LAR.

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 74 (29.73%)
    19 / 76 (25.00%)
    41 / 150 (27.33%)
         number of deaths (all causes)
    0
    2
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 76 (1.32%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 76 (2.63%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood cortisol decreased
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 76 (1.32%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood cortisol increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 76 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Coronary artery occlusion
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anogenital dysplasia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 76 (0.00%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 74 (2.70%)
    3 / 76 (3.95%)
    5 / 150 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperadrenocorticism
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pituitary-dependent Cushing's syndrome
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 76 (1.32%)
    3 / 150 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 76 (1.32%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 76 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 76 (1.32%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 10 mg pasireotide LAR dose 30 mg pasireotide LAR dose All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 74 (98.65%)
    76 / 76 (100.00%)
    149 / 150 (99.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 74 (14.86%)
    13 / 76 (17.11%)
    24 / 150 (16.00%)
         occurrences all number
    14
    14
    28
    Hypotension
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 76 (6.58%)
    9 / 150 (6.00%)
         occurrences all number
    5
    5
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 74 (13.51%)
    5 / 76 (6.58%)
    15 / 150 (10.00%)
         occurrences all number
    11
    9
    20
    Fatigue
         subjects affected / exposed
    13 / 74 (17.57%)
    15 / 76 (19.74%)
    28 / 150 (18.67%)
         occurrences all number
    15
    18
    33
    Oedema peripheral
         subjects affected / exposed
    9 / 74 (12.16%)
    12 / 76 (15.79%)
    21 / 150 (14.00%)
         occurrences all number
    15
    13
    28
    Pyrexia
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 76 (2.63%)
    7 / 150 (4.67%)
         occurrences all number
    6
    2
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 76 (5.26%)
    6 / 150 (4.00%)
         occurrences all number
    2
    4
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 74 (10.81%)
    5 / 76 (6.58%)
    13 / 150 (8.67%)
         occurrences all number
    8
    5
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 74 (8.11%)
    5 / 76 (6.58%)
    11 / 150 (7.33%)
         occurrences all number
    10
    6
    16
    Blood cortisol decreased
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 76 (2.63%)
    6 / 150 (4.00%)
         occurrences all number
    4
    5
    9
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    6 / 76 (7.89%)
    7 / 150 (4.67%)
         occurrences all number
    1
    6
    7
    Blood glucose increased
         subjects affected / exposed
    6 / 74 (8.11%)
    7 / 76 (9.21%)
    13 / 150 (8.67%)
         occurrences all number
    7
    7
    14
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 74 (9.46%)
    6 / 76 (7.89%)
    13 / 150 (8.67%)
         occurrences all number
    10
    6
    16
    Glycosylated haemoglobin increased
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 76 (5.26%)
    8 / 150 (5.33%)
         occurrences all number
    5
    4
    9
    Lipase increased
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 76 (5.26%)
    6 / 150 (4.00%)
         occurrences all number
    2
    5
    7
    Weight decreased
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 76 (3.95%)
    7 / 150 (4.67%)
         occurrences all number
    4
    3
    7
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 76 (1.32%)
    5 / 150 (3.33%)
         occurrences all number
    4
    1
    5
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 74 (5.41%)
    3 / 76 (3.95%)
    7 / 150 (4.67%)
         occurrences all number
    4
    3
    7
    Sinus bradycardia
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 76 (6.58%)
    9 / 150 (6.00%)
         occurrences all number
    8
    8
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 74 (13.51%)
    8 / 76 (10.53%)
    18 / 150 (12.00%)
         occurrences all number
    19
    9
    28
    Headache
         subjects affected / exposed
    18 / 74 (24.32%)
    10 / 76 (13.16%)
    28 / 150 (18.67%)
         occurrences all number
    25
    14
    39
    Paraesthesia
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 76 (5.26%)
    5 / 150 (3.33%)
         occurrences all number
    1
    5
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 76 (6.58%)
    9 / 150 (6.00%)
         occurrences all number
    7
    13
    20
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 76 (0.00%)
    5 / 150 (3.33%)
         occurrences all number
    6
    0
    6
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 76 (2.63%)
    6 / 150 (4.00%)
         occurrences all number
    5
    2
    7
    Abdominal distension
         subjects affected / exposed
    4 / 74 (5.41%)
    5 / 76 (6.58%)
    9 / 150 (6.00%)
         occurrences all number
    4
    6
    10
    Abdominal pain
         subjects affected / exposed
    11 / 74 (14.86%)
    13 / 76 (17.11%)
    24 / 150 (16.00%)
         occurrences all number
    15
    15
    30
    Abdominal pain upper
         subjects affected / exposed
    3 / 74 (4.05%)
    8 / 76 (10.53%)
    11 / 150 (7.33%)
         occurrences all number
    4
    9
    13
    Constipation
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 76 (6.58%)
    10 / 150 (6.67%)
         occurrences all number
    5
    5
    10
    Diarrhoea
         subjects affected / exposed
    26 / 74 (35.14%)
    35 / 76 (46.05%)
    61 / 150 (40.67%)
         occurrences all number
    49
    67
    116
    Dry mouth
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 76 (1.32%)
    5 / 150 (3.33%)
         occurrences all number
    6
    1
    7
    Flatulence
         subjects affected / exposed
    3 / 74 (4.05%)
    5 / 76 (6.58%)
    8 / 150 (5.33%)
         occurrences all number
    4
    5
    9
    Frequent bowel movements
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 76 (0.00%)
    4 / 150 (2.67%)
         occurrences all number
    4
    0
    4
    Nausea
         subjects affected / exposed
    17 / 74 (22.97%)
    16 / 76 (21.05%)
    33 / 150 (22.00%)
         occurrences all number
    33
    21
    54
    Vomiting
         subjects affected / exposed
    7 / 74 (9.46%)
    2 / 76 (2.63%)
    9 / 150 (6.00%)
         occurrences all number
    11
    2
    13
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    15 / 74 (20.27%)
    33 / 76 (43.42%)
    48 / 150 (32.00%)
         occurrences all number
    18
    42
    60
    Cholestasis
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 76 (2.63%)
    6 / 150 (4.00%)
         occurrences all number
    4
    2
    6
    Gallbladder cholesterolosis
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 76 (5.26%)
    6 / 150 (4.00%)
         occurrences all number
    2
    4
    6
    Hepatic function abnormal
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 76 (5.26%)
    6 / 150 (4.00%)
         occurrences all number
    1
    4
    5
    Hepatic steatosis
         subjects affected / exposed
    1 / 74 (1.35%)
    6 / 76 (7.89%)
    7 / 150 (4.67%)
         occurrences all number
    1
    6
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 76 (6.58%)
    7 / 150 (4.67%)
         occurrences all number
    2
    5
    7
    Dry skin
         subjects affected / exposed
    2 / 74 (2.70%)
    5 / 76 (6.58%)
    7 / 150 (4.67%)
         occurrences all number
    2
    5
    7
    Erythema
         subjects affected / exposed
    2 / 74 (2.70%)
    4 / 76 (5.26%)
    6 / 150 (4.00%)
         occurrences all number
    2
    5
    7
    Pruritus
         subjects affected / exposed
    5 / 74 (6.76%)
    6 / 76 (7.89%)
    11 / 150 (7.33%)
         occurrences all number
    7
    7
    14
    Rash
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 76 (2.63%)
    6 / 150 (4.00%)
         occurrences all number
    7
    2
    9
    Skin exfoliation
         subjects affected / exposed
    3 / 74 (4.05%)
    4 / 76 (5.26%)
    7 / 150 (4.67%)
         occurrences all number
    4
    4
    8
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    4 / 74 (5.41%)
    6 / 76 (7.89%)
    10 / 150 (6.67%)
         occurrences all number
    30
    7
    37
    Hypothyroidism
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 76 (5.26%)
    5 / 150 (3.33%)
         occurrences all number
    1
    4
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 74 (12.16%)
    4 / 76 (5.26%)
    13 / 150 (8.67%)
         occurrences all number
    14
    4
    18
    Back pain
         subjects affected / exposed
    8 / 74 (10.81%)
    8 / 76 (10.53%)
    16 / 150 (10.67%)
         occurrences all number
    12
    8
    20
    Muscle spasms
         subjects affected / exposed
    1 / 74 (1.35%)
    5 / 76 (6.58%)
    6 / 150 (4.00%)
         occurrences all number
    1
    6
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 74 (0.00%)
    4 / 76 (5.26%)
    4 / 150 (2.67%)
         occurrences all number
    0
    4
    4
    Myalgia
         subjects affected / exposed
    4 / 74 (5.41%)
    4 / 76 (5.26%)
    8 / 150 (5.33%)
         occurrences all number
    4
    4
    8
    Pain in extremity
         subjects affected / exposed
    6 / 74 (8.11%)
    6 / 76 (7.89%)
    12 / 150 (8.00%)
         occurrences all number
    7
    9
    16
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 76 (2.63%)
    7 / 150 (4.67%)
         occurrences all number
    5
    4
    9
    Gastroenteritis
         subjects affected / exposed
    7 / 74 (9.46%)
    2 / 76 (2.63%)
    9 / 150 (6.00%)
         occurrences all number
    9
    2
    11
    Influenza
         subjects affected / exposed
    12 / 74 (16.22%)
    6 / 76 (7.89%)
    18 / 150 (12.00%)
         occurrences all number
    14
    8
    22
    Nasopharyngitis
         subjects affected / exposed
    18 / 74 (24.32%)
    13 / 76 (17.11%)
    31 / 150 (20.67%)
         occurrences all number
    26
    26
    52
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 74 (6.76%)
    6 / 76 (7.89%)
    11 / 150 (7.33%)
         occurrences all number
    6
    7
    13
    Urinary tract infection
         subjects affected / exposed
    10 / 74 (13.51%)
    9 / 76 (11.84%)
    19 / 150 (12.67%)
         occurrences all number
    13
    16
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 74 (4.05%)
    12 / 76 (15.79%)
    15 / 150 (10.00%)
         occurrences all number
    3
    13
    16
    Diabetes mellitus
         subjects affected / exposed
    15 / 74 (20.27%)
    20 / 76 (26.32%)
    35 / 150 (23.33%)
         occurrences all number
    15
    22
    37
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 74 (4.05%)
    6 / 76 (7.89%)
    9 / 150 (6.00%)
         occurrences all number
    3
    6
    9
    Hyperglycaemia
         subjects affected / exposed
    36 / 74 (48.65%)
    35 / 76 (46.05%)
    71 / 150 (47.33%)
         occurrences all number
    58
    53
    111
    Hyperlipidaemia
         subjects affected / exposed
    1 / 74 (1.35%)
    4 / 76 (5.26%)
    5 / 150 (3.33%)
         occurrences all number
    1
    4
    5
    Hyperuricaemia
         subjects affected / exposed
    5 / 74 (6.76%)
    5 / 76 (6.58%)
    10 / 150 (6.67%)
         occurrences all number
    5
    5
    10
    Hypoglycaemia
         subjects affected / exposed
    10 / 74 (13.51%)
    12 / 76 (15.79%)
    22 / 150 (14.67%)
         occurrences all number
    26
    58
    84
    Type 2 diabetes mellitus
         subjects affected / exposed
    3 / 74 (4.05%)
    4 / 76 (5.26%)
    7 / 150 (4.67%)
         occurrences all number
    3
    5
    8

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2011
    In the original protocol, the investigators were unblinded to the dose and mUFC value after the patient completed Month 7. This amendment extended the blind of the Investigator until the Month 12 analyses have been performed to prevent bias associated with unblinding of Investigators, and to protect the integrity of the study; the time from the start of each individual 24-hour urine collection by the patient until storage was reduced from 14 days to 6 days to take into account the stability period of urinary creatinine at normal refrigeration temperatures; to ensure the blind was maintained, explicit language was added to prevent sites from assessing any cortisol-related parameters; the exclusion criterion relating to patients with HbA1c >8% was modified to exclude such patients regardless of the use of anti-diabetic medication; exclusion criteria were modified to include hypomagnesemia as a risk factor for torsade de pointes; new process for eligibility confirmation within the IRT system was established; requirement to record salivary cortisol and mUFC on eCRFs for screen failures was removed. Data record was done via central laboratory data transfer; mifepristone washout was added and 24h creatine clearance was removed; inconsistent language was corrected throughout the protocol; editorial and typographical errors were corrected throughout the study.
    13 Dec 2011
    Additional hepatic-related safety measures as a result of an internal hepatic medical review of pasireotide studies were included; the Beck’s Depression Inventory II was removed from the secondary efficacy assessments as it was no longer deemed feasible; the washout period for octreotide LAR, lanreotide SR and lanreotide autogel was clarified to be 14 weeks; in order to prevent unblinding of investigators to dose levels, the instructions for use of the pasireotide long-acting 5 mg ampoule were updated; clarification was provided through edited text and inconsistent language was corrected throughout the protocol
    08 Oct 2012
    Investigators were given the option to allow patients to remain on the current dose at Months 4, 7 and/or 9 visits in case of tolerability issues that in his/her clinical judgment would guide against a potential dose up-titration; language on glucose monitoring and treatment was expanded to reinforce glycemic goals of treatment per current ADA and European Association for the Study of Diabetes guidelines and to emphasize the need to initiate anti-hyperglycemic treatment accordingly; continued measuring quality of life change and Global impression of change over time into the extension phase allowed. In addition, a new SF-12v2 General Health Survey was introduced; pregnancy guidelines were updated; clarification was provided through edited text and inconsistent language was corrected throughout the protocol
    13 May 2013
    Investigators, site staff, Novartis study team and related vendors gained access to mUFC and other cortisol-related assessments throughout the study while maintaining the blinding to the randomized treatment group until the Month 12 analysis. In addition, central MRI readings were also made available to investigators, site staff, Novartis study team and related vendors throughout the study; removal of clinical benefit question pertaining to dose up-titration at Months 7, 9, 12 and during the extension phase; language related to CRH test stimulation was updated; option to roll over patients post extension phase into a long term safety study was clarified; clarification was provided through edited text, and inconsistent language was corrected throughout the protocol
    29 Aug 2013
    Instructions for use were updated for 30 mg dose using 60 mg kit and include procedure for preparation of the 30 mg dose using the 60 mg vial; patients who had completed Month 24 prior to the Month 12 database lock were allowed to continue beyond Month 24, and until the long-term safety study is opened to patients enrolled in the study; additional pregnancy assessments (urine pregnancy test) were added in the study as a safety precaution
    07 Jun 2016
    The purpose of this amendment was to clarify that DXA and MRI scans, required once every six months during treatment, were not required at the End of Study Treatment Visit if previous scan(s) were performed within the last six months. The clinical rationale for this action was that clinically relevant changes in parameters measured by these techniques were not expected to occur or be detected within a six month period.

    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.
    All analyses in this study were descriptive in nature. No comparisons were made between the two arms, and no p-values are reported. For the primary and key-secondary, success was based on estimating the response rate (and 95% CI) in each arm.
    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.

    European Medicines Agency © 1995-Fri Apr 26 01:47:12 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA